***DEMENTIA and AGING (Updated 3/27/2003)
Neurobiology of Aging
Article in Press, Corrected Proof - Note to users
Linear width of the medial temporal lobe can discriminate Alzheimer's disease from normal aging: the Sunnybrook Dementia Study
F. Q. Gao, S. E. Black,, F. S. Leibovitcha, D. J. Callena, C. P. Rockela and J. P. Szalaib
To discriminate Alzheimer's disease (AD) from healthy controls, the thinnest medial temporal lobe (tMTL) width on 3D-MRI was measured according to a newly developed method at the inter-collicular sulcus (ICS) level with scans aligned to the long axis of the hippocampus in 22 mild, 27 moderate probable AD patients and 41 healthy controls. For comparison, MTL width replicating the technique of Jobst et al. (jMTL) as well as hippocampal and parahippocampal volumes, were also measured. Using logistic regression taking into account age, sex, and education, tMTL width classified mild AD from controls with a sensitivity of 86%, specificity of 95% and accuracy of 92%. Similar values were obtained for moderate or total AD group versus controls. By comparison, jMTL width was only useful in distinguishing moderate AD from controls, and volumetric measures were equally sensitive in classifying mild and moderate AD in our sample. This quick, reliable, and standardized measurement of tMTL can be helpful in differentiating even mild AD from controls with reasonable accuracy.
Journal of the Neurological Sciences
Article in Press, Corrected Proof - Note to users
Glucose metabolic dysfunction in subjects with a Clinical Dementia Rating of 0.5
Kazunari Ishii, , a, Tetsuya Moria, Nobutsugu Hironob and Etsuro Morib
a Department of Radiology and
Nuclear Medicine, Hyogo Brain and
b Institute for Aging Brain and
Cognitive Disorders, Hyogo Brain and
Objective: To investigate the cerebral glucose metabolism of subjects who had a Clinical Dementia Rating (CDR) of 0.5, we studied 40 subjects whose CDR was 0.5 and 40 age-matched healthy subjects. Methods: Cerebral glucose image of each subject was obtained by [18F]-2-fluoro-deoxy--glucose (FDG) positron emission tomography (PET). The anatomically standardized images were produced with NEUROSTAT. Then, the two groups were compared with the Statistical Parametric Mappings (SPM) 99. Results: A comparison with the SPM 99 revealed that relative cerebral glucose metabolism was lower in the posterior cingulate gyri and parietal lobules in the CDR 0.5 group than in the healthy subjects group. Conclusion: These findings are very similar to those in patients with probable Alzheimer's disease (AD) and suggest that the majority of subjects with CDR 0.5 are suffering from very mild AD or at least a prodromal state of AD.
International Journal of Psychophysiology
Volume 49, Issue 2 , August 2003, Pages 147-163
Memory-related EEG power and coherence reductions in mild Alzheimer's disease
Michael J. Hogan, , a, Gregory R. J. Swanwicka, Jochen Kaiserb, Michael Rowanc and Brian Lawlora
Objectives: To examine memory-related EEG power and coherence over temporal and central recording sites in patients with early Alzheimer's disease (AD) and normal controls. Method: EEG was recorded from central (Fz, Cz and Pz) and temporal (T3 and T4) electrodes while ten very mild AD patients and ten controls performed a Sternberg-type memory scanning task with three levels of working memory load. Spectral power in delta (0–3 Hz), theta (3–5 Hz), lower alpha1 (5–7 Hz), lower alpha2 (7–9 Hz), upper alpha (9–11 Hz) and beta (15–30 Hz) was averaged for temporal and central electrodes. Coherence was averaged between central electrodes, between central and right temporal electrodes and between central and left temporal electrodes. Results: While behavioral performance of very mild AD patients did not differ significantly from that of normal controls, findings suggest that normal controls but not AD patients respond to memory demands by increasing upper alpha power over temporal cortex. When compared with normal controls, AD patients had reduced upper alpha coherence between central and right temporal cortex. Discussion: Results are consistent with previous research on the role of upper alpha in semantic memory and suggest that very mild AD may inhibit selective synchronization of upper alpha in temporal lobes. Reduced coherence between central and temporal cortex is discussed in light of a neurological model of AD that hypothesizes reduced electrocortical efficiency and a breakdown of neural network communication to temporal lobes possibly resulting from temporal lobe atrophy.
Is Caregiving Hazardous to One’ Physical Health? A Meta-Analysis
Peter P. Vitaliano, Jianping Zhang, James M. Scanlan
Psychological Bulletin, 2003, Vol. 129, No. 6, 946–972
Caring for a family member with dementia is generally regarded as a chronically stressful process, with potentially negative physical health consequences. However, no quantitative analysis has been conducted on this literature. The authors combined the results of 23 studies to compare the physical health of caregivers with demographically similar noncaregivers. When examined across 11 health categories, caregivers exhibited a slightly greater risk for health problems than did noncaregivers. However, sex and the health category assessed moderated this relationship. Stronger relationships occurred with stress hormones, antibodies, and global reported health. The authors argue that a theoretical model is needed that relates caregiver stressors to illness and proffers moderating roles for vulnerabilities
Clin Neurophysiol. 2003 Jul;114(7):1210-6.
Quantitative EEG and dynamic susceptibility contrast MRI in Alzheimer's disease: a correlative study.
Mattia D, Babiloni F, Romigi A, Cincotti F, Bianchi L, Sperli F, Placidi F, Bozzao A, Giacomini P, Floris R, Grazia Marciani M.
Fondazione Santa Lucia, I.R.C.C.S.,
OBJECTIVE: To investigate the relationship between the electroencephalographic (EEG) power spectra features obtained by quantitative EEG (qEEG) and the hemodynamic parameters detected by dynamic susceptibility contrast-enhanced MR imaging (DSC MRI) in patients with Alzheimer's disease (AD). METHODS: Fourteen patients with probable AD and 15 elderly healthy controls were included in the study. All subjects underwent both EEG recording in a rest condition and perfusion MRI. Three EEG scalp areas were defined (anterior, central and posterior) and power spectra values were obtained from each scalp area. Relative values of temporoparietal and sensorimotor regional cerebral blood volume (rCBV) were measured bilaterally and successively averaged to obtain a total perfusion index. The brain atrophy index was calculated and used as a covariate to rCBV. Correlation analysis was performed between EEG variables and hemodynamic-morphological parameters. RESULTS: qEEG power spectra of AD patients were characterized by an increase in mean relative power of theta (4-7.75 Hz) associated with a decrease in alpha (8-12.75 Hz) frequency bands with a topographic distribution over the central and posterior EEG scalp regions, when compared with controls; beta (13-31 Hz) frequency band also displayed a significant decrease over the anterior and posterior EEG scalp regions of AD patients with respect to controls. The DSC MRI revealed a bilateral reduction in the temporoparietal and sensorimotor rCBV with respect to controls. Correlation analysis showed that the total level of hypoperfusion selectively correlates with the EEG power spectra in theta and alpha frequency bands distributed over anterior/central and central region, respectively. Within AD patients, the lower the level of hypoperfusion, the higher the content of EEG power spectra in theta frequency band, and the lower the level of hypoperfusion, the lower the content of EEG power spectra in alpha band. CONCLUSIONS: The combined qEEG and DSC MRI technology unveiled a selective correlation between neurophysiological and hemodynamical patterns in AD patients. Further investigations will ascertain the relevance of this multi-modal approach in the heterogeneous clinical context of AD.
International Journal of Geriatric Psychiatry
Volume 18, Issue S1 , Pages S23 - S32
The NMDA receptor antagonist memantine
as a symptoma
Wojciech Danysz *, Chris G. Parsons
email: Wojciech Danysz (email@example.com)
There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder....may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg2+ ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg2+ concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine - an uncompetitive NMDA receptor antagonists with features of an improved Mg2+ (voltage-dependency, kinetics, affinity) - attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 M). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or -amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium.
International Journal of Geriatric Psychiatry
Volume 18, Issue S1 , Pages S47 - S54
Memantine: update on the current evidence
Hans J. Möbius *
email: Hans J. Möbius (firstname.lastname@example.org)
The present paper attempts to provide an update on the
currently available pharmacological and clinical evidence on memantine, including earlier clincial
data, e.g. in vascular dementia. As the clinical database broadens, and various
additional conditions are being tested in ongoing controlled clinical trials,
we are approaching an ever more precise profile of memantine's
spectrum of safety and
International Journal of Geriatric Psychiatry
Volume 18, Issue S1 , Pages S41 - S46
Treating the full spectrum of dementia with memantine
Bengt Winblad *, Vesna Jelic email: Bengt Winblad (email@example.com)
Recent clinical trials with the antiglutamatergic drug memantine have shown that cognitive benefit could be observed in patients with vascular dementia and reduced care dependence in those with moderately severe to severe form of the disease. The later findings are results from the M-BEST study, which is briefly rewieved here with some of the epidemiological, socioeconomical and clinical implications of such therapy.
Journal of Neurology
Volume 250, Number 8, Pages: 907 - 912, 2003
Prevalence of non-dementing cognitive disturbances and their association with vascular risk factors in an elderly population
M. Prencipe, M. Santini A. R. Casini, F. R. Pezzella, N. Scaldaferri, F. Culasso
To assess the prevalence of "Cognitive Impairment No Dementia" (CIND) and circumscribed memory impairment (CMI) and to evaluate their association with vascular risk factors and stroke, we examined all people aged 65 years or over living in three rural Italian villages. The survey was conducted by means of a doorto-door 2-phase procedure. As phase 1 screening tests, we used the Mini-Mental State Examination (MMSE), or the Mental Status Questionnaire (MSQ) for people with < 3 years of schooling. In phase 2, four neurologists examined people with MMSE scores < 28 or MSQ scores < 10. The diagnostic study consisted of a clinical and neuropsychological examination which included a structured interview with a close respondent. Dementia was diagnosed by means of DSM III-R criteria. The study protocol was completed by 968 (84.4%) of the 1147 eligible people. Of the 968 participants, 690 (71.3 %) had no cognitive abnormalities, 78 (8.1%) were demented and 200 (20.6 %) suffered from CIND. The CIND group included 59 people (6.1% of the study population) with CMI. At the multiple logistic regression analysis, CIND was associated with age = 75 years (OR 1.6, 95 % CI 1.1.-2.2), < 5 years of schooling (OR 3.7, 95% CI 2.5.-5.5), stroke (OR 3.3, 95% CI 1.8.-6.1) and hypertension (OR 2.3, 95% CI 1.5.-3.5),while CMI was associated with < 5 years of schooling (OR 3.8, 95 % CI 1.9.-7.7), stroke (OR 3.1, 95% CI 1.2.-7.9) and hypertension (OR 3.7, 95% CI 1.7.-8.0).Using normotensive people as a reference group and adjusting for age, sex, education and stroke, the ORs for CIND were 1.9 (95 % CI 1.2.-3.0) for treated and 2.9 (95 % CI 1.8.-4.6) for untreated hypertensive patients. In conclusion, hypertension is significantly and independently associated with both CIND and CMI, and the risk of CIND is higher in untreated than treated hypertensive patients.
Journal of Neurology
Volume 250, Number 8, 917 - 923, 2003
Effects of pallidotomy and bilateral subthalamic stimulation on cognitive function in Parkinson disease: A controlled comparative study
A. Gironell, J. Kulisevsky, L. Rami, N. Fortuny, C. García-Sánchez, B. Pascual-Sedano
Unilateral pallidotomy and bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) have demonstrated a positive effect on motor functions. However, further studies are needed of the unintended cognitive effects accompanying these new surgical procedures. We studied the consequences of unilateral pallidotomy and STN-DBS on cognitive function in a controlled comparative design. Sixteen consecutive PD patients were assessed before and 6 months after unilateral pallidotomy (n = 8) and bilateral STN-DBS (n = 8). The same assessments were performed in a control group of eight non-operated matched PD patients recruited from surgery candidates who refused operation. The neuropsychological battery consisted of test measuring memory, attention, arithmetic, problem solving and language, as well as visuospatial, executive and premotor functions. An analysis of variance (factors time and treatment) was applied. No statistically significant differences were found in the presurgical evaluation of clinical and demographic data for the three treatment groups. The controlled comparison between presurgical and postsurgical performance revealed no significant changes in the cognitive domains tested in the pallidotomy group. The STN-DBS group showed a selective significant worsening of semantic verbal fluency (p = 0.005). This controlled comparative study suggests that neither unilateral pallidotomy nor bilateral STN-DBS have global adverse cognitive consequences, but bilateral STN-DBS may cause a selective decrease in verbal fluency.
Br J Psychiatry. 2003 Sep;183:248-54.
Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial.
Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M.
BACKGROUND: A recent Cochrane review of reality orientation therapy identified the need for large, well-designed, multi-centre trials. AIMS: To test the hypothesis that cognitive stimulation therapy (CST) for older people with dementia would benefit cognition and quality of life. METHOD: A single-blind, multi-centre, randomised controlled trial recruited 201 older people with dementia. The main outcome measures were change in cognitive function and quality of life. An intention-to-treat analysis used analysis of covariance to control for potential variability in baseline measures. RESULTS: One hundred and fifteen people were randomised within centres to the intervention group and 86 to the control group. At follow-up the intervention group had significantly improved relative to the control group on the Mini-Mental State Examination (P=0.044), the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) (P=0.014) and Quality of Life - Alzheimer's Disease scales (P=0.028). Using criteria of 4 points or more improvement on the ADAS-Cog the number needed to treat was 6 for the intervention group. CONCLUSION: The results compare favourably with trials of drugs for dementia. CST groups may have worthwhile benefits for many people with dementia.
Neurobiology of Aging
Article in Press, Corrected Proof - Note to users
Neurochemical diagnosis of Alzheimer's dementia by CSF A42, A42/A40 ratio and total tau Piotr Lewczuk, Hermann Esselmann, Markus Otto, Juan Manuel Maler, Andreas Wolfram Henkel, Maria Kerstin Henkel, Oliver Eikenberg, Christof Antz, Wolf-Rainer Krause, Udo Reulbach, Johannes Kornhuber and Jens Wiltfang
Cerebrospinal fluid (CSF) concentrations of amyloid peptides ending at positions 42 and 40 (A42 and A40, respectively), and total tau (tTau) protein were measured by ELISA in order to compare their accuracy in discriminating patients with Alzheimer's disease (AD, n=22), non-Alzheimer dementia (nAD, n=11) and control subjects (CON, n=35). As compared to the other groups, the concentrations of A42 and tTau were decreased (P<0.001) and increased (P<0.001) in AD, respectively, while A40 did not differ significantly among the groups. Receiver operating characteristic (ROC) analysis was performed to define cut-off values for maximized sensitivity and specificity. For all groups compared the A peptide ratio 42/40 classified more patients correctly, as compared to the concentration of A42 alone: AD versus controls, 94 and 86.7%; AD versus nAD, 90 and 85% and AD versus nAD plus controls, 90.8 and 87%, respectively. The percentage of correctly classified patients was further improved when the A ratio was combined with the analysis of the tTau concentration. Presence of the apolipoprotein E 4 allele, age or degree of mental disability did not significantly influence the parameters studied.
Psychiatry Research: Neuroimaging,
Volume 123, Issue 3,
Brain metabolism in Alzheimer disease and vascular dementia assessed by in vivo proton magnetic resonance spectroscopy
Sebastian Herminghaus, Lutz Frölich, Corrina Gorriz, Ullrich Pilatus, Thomas Dierks, Hans-Jörg Wittsack, Heinrich Lanfermann, Konrad Maurer and Friedhelm E. Zanella
magnetic resonance spectroscopy (MRS) allows the assessment of various cerebral
metabolites non-invasively in vivo. Among 1H MRS-detectable metabolites,
N-acetyl-aspartate and N-acetyl-aspartyl-glutamate
(TMA), creatine and creatine
phosphate (tCr), inosi
Neurobiology of Aging, Article in Press
Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume
Naftali Raz, , a, b, Faith Gunning-Dixonc, Denise Headd, Karen M. Rodriguea, Adrienne Williamsone and James D. Ackerf
We examined age-, sex-, and hemisphere-related differences in the cerebral cortex. Volumes of the cerebral hemispheres and 13 regions of interest (ROIs) were measured on magnetic resonance images of 200 healthy adults. The strength of association between age and volume differed across ROIs. The lateral prefrontal cortex exhibited the greatest age-related differences, whereas significantly weaker associations were observed in the prefrontal white matter, sensory-motor, and visual association regions. The hippocampal shrinkage was significant in people in their mid-fifties. The primary visual, anterior cingulate, the inferior parietal cortices, and the parietal white matter showed no age-related differences. The pattern of age-related regional differences replicated the findings previously obtained on an independent sample drawn from the same population. Men evidenced larger volumes in all ROIs except the inferior parietal lobule, even after sexual dimorphism in body size was statistically controlled. In some regions (hippocampus and fusiform gyrus) men exhibited steeper negative age-related trends than women. Although a typical pattern of global hemispheric asymmetry was observed, the direction and magnitude of regional volumetric asymmetry was as inconsistent as in the previous reports. Thus, a pattern of age-related shrinkage suggesting increased vulnerability of the lateral prefrontal cortex to aging appears stable and replicable, whereas little consistency exists in sex-related and hemispheric differences in regional cortical volumes.
Neurobiology of Aging
Article in Press, Corrected Proof - Note to users
Hippocampus and entorhinal cortex in mild cognitive impairment and early AD
Corina Pennanena, Miia Kivipeltoa, Susanna Tuomainena, Päivi Hartikainenb, Tuomo Hänninena, b, Mikko P. Laaksoa, Merja Hallikainena, Matti Vanhanena, Aulikki Nissinenc, Eeva-Liisa Helkalad, Pauli Vainioe, Ritva Vanninene, Kaarina Partanene and Hilkka Soininen, Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimer's disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control>MCI>AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.
Dement Geriatr Cogn Disord. 2003;15(2):106-14.
Quantitative EEG abnormalities and cognitive dysfunctions in frontotemporal dementia and Alzheimer's disease.
Lindau M, Jelic V, Johansson SE, Andersen C, Wahlund LO, Almkvist O.
Karolinska Institutet, Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Huddinge University Hospital, Stockholm, Sweden. firstname.lastname@example.org
OBJECTIVE: To investigate the relationship between quantitative EEG (qEEG) measurements in frontotemporal dementia (FTD), Alzheimer's disease (AD) and healthy controls and to study to what extent qEEG in FTD and AD or neuropsychological test results of FTD and AD patients or a combination of both contribute to classification accuracy. METHOD: The FTD sample consisted of 19 patients, the AD sample of 16 patients, and the control group of 19 subjects. Groups were matched on the group level with respect to demographic variables. For qEEG the global field power was calculated for six frequency bands: delta (1.0-3.5 Hz), theta (4.0-7.5 Hz), alpha (8.0-11.0 Hz), beta1 (12.0-15.5 Hz), beta2 (16.0-19.5 Hz), beta3 (20.0-23.5 Hz), and spectral ratio as the ratio of the sum of fast frequency bands alpha + beta1 + beta2 + beta3 and slow frequency bands delta + theta. RESULTS: In comparison to controls FTD patients were marked by an absence of an increase in slow qEEG activities and a decrease in fast activities, whereas AD patients were marked by an increase in slow activities and a smaller decrease in fast activities. According to the Mann-Whitney U test the cognitive functions of attention, visuospatial thinking and episodic memory were significantly better in FTD than in AD. Using logistic regression analysis the best predictors of FTD and AD were in a model using the delta and theta activities, and high levels of visuospatial ability and episodic memory. Classification accuracy of the model was 93.3%. CONCLUSION: FTD patients reveal a different pattern of qEEG changes than AD patients. This result demonstrates the importance of qEEG for FTD diagnosis. Cognition is selectively better in FTD than in AD. A combination of qEEG and neuropsychology is recommended for differential diagnoses of FTD and AD.
Acta Neurol Scand Suppl. 2003;179:52-76.
Acta Neurol Scand Suppl. 2003 Jul;108(1):68.
A critical discussion of the role of neuroimaging in mild cognitive impairment.
Wolf H, Jelic V, Gertz HJ, Nordberg A, Julin P, Wahlund LO.
Neurotec, Division of Geriatric Medicine,
OBJECTIVE: In this paper, the current neuroimaging literature is reviewed with regard to characteristic findings in mild cognitive impairment (MCI). Particular attention is drawn to the possible value of neuroimaging modalities in the prediction and early diagnosis of Alzheimer's disease (AD). METHODS: First, the potential contribution of neuroimaging to an early, preclinical diagnosis of degenerative disorders is discussed at the background of our knowledge about the pathogenesis of AD. Second, relevant neuroimaging studies focusing on MCI are explored and summarized. Neuroimaging studies were found through Medline search and by systematically checking through the bibliographies of relevant articles. RESULTS: Structural volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET)/single photon emission tomography (SPECT) are currently the most commonly used neuroimaging modalities in studies focusing on MCI. There were considerable variations in demographical and clinical characteristics across studies. However, significant hippocampal and entorhinal cortex volume reductions were consistently found in subjects with MCI as compared with cognitively unimpaired controls. While hippocampal and entorhinal cortex atrophy in subjects with MCI are also well-established risk factors for the development of AD, these measures cannot be regarded as being of high predictive value in an individual case. Evidence for other typical neuroimaging changes in MCI is still scarce. In PET and SPECT studies, reduced blood flow and/or glucose metabolism in temporoparietal association areas, posterior cingulate and hippocampus were associated with a higher risk of progressive cognitive decline in MCI. In quantitative electroencephalogram (QEEG), low beta, high theta, low alpha and slowed mean frequency were associated with development of dementia. CONCLUSIONS: Existing studies suggest that neuroimaging measures have the potential to become valuable tools in the early diagnosis of AD. To establish their value in routine use, larger studies, preferably with long prospective follow-up are needed.
Neurobiology of Aging
Volume 24, Issue 7 , November 2003, Pages 985-1003
Effect of age and glucoregulation on cognitive performance
Claude Messier, , a, Maria Tsiakasa, Michèle Gagnonb, Alain Desrochersa and Nesrine Awada
Non-insulin dependent diabetes mellitus (NIDDM) has been
associated with a number of physiological consequences including neuropathy,
retinopathy and incidence of vascular disease. Recently,
several authors reviewed studies that suggested that NIDDM is associated with
cognitive impairments leading to a higher incidence of dementia. In the
present experiment, we measured cognitive function in 57 healthy male and
female non-diabetic older participants who ranged in age from 55 to 84. Various
biological measures were obtained including a glucose
Neurobiology of Aging
Volume 24, Issue 6 , October 2003, Pages 883-892
Is procedural memory relatively spared from age effects?
James D. Churchilla, Jessica J. Stanisd, Cyrus Pressd, Michael Kushelevd and William T. Greenough
Numerous types of age-related deficits in the nervous system have been well documented. While a distinction between general types of memories that are susceptible to compromise with advanced age has been fairly well agreed upon, it is often difficult to determine exactly which specific processes are detrimentally influenced. In this study, we used a paradigm that enabled us to distinguish between effects associated with gross motor deficits and those due to learning and memory of a motor skill, per se. In terms of both latency and errors, senescent animals were, on average, impaired in their ability to traverse an elevated obstacle course, compared to younger animals. Yet, if gross motor abilities are accounted for, a fraction of these deficits is readily explained. Moreover, if individual baseline performance differences are normalized, no memory differences are evident across age groups. These observations suggest that memory for a procedural task is not impaired with advanced age.
Neurobiology of Aging
Volume 24, Issue 3 , May-June 2003, Pages 463-479
Non-invasive localization of P300 sources in normal aging and age-associated memory impairment
P. Anderer, , a, B. Saletua, H. V. Semlitscha and R. D. Pascual-Marquib
....Significant reductions in LORETA source strength in normal aging and in AAMI were found mainly medially frontally, right dorsolaterally prefrontally and right inferiorly parietally. Since these anatomically highly interconnected brain regions in the right hemisphere are part of a network associated with sustained attention, the results speak for a decline in attentional resource capacity in AAMI patients and elderly subjects.
Neurobiology of Aging
Volume 24, Issue 5 , September 2003, Pages 753-760
Age-related changes in cerebral lactate metabolism in sleep-disordered breathing
Masayuki Kamba, Yuichi Inoue, Shigeru Higamic and Yuji Suto
Thirty-one patients, aged 22–71 years, with nocturnal apneic episodes and/or habitual snoring were studied with magnetic resonance spectroscopy (MRS) and diagnostic polysomnography separately to determine whether accumulation of lactate caused by cerebral hypoxia during sleep is associated with sleep-disordered breathing (SDB), aging and co-morbidities related to SDB. ...Our findings suggest that SDB combined with aging is related to accumulation of lactate during sleep.
Curr Drug Target CNS Neurol Disord. 2002 Dec;1(6):575-92.
Depressed or demented: common CNS drug targets?!
Sun MK, Alkon DL; email@example.com
A body of evidence emerging in antidepressant and antidementia research has revealed a convergence of molecular events known to regulate neuronal plasticity in learning and memory with molecular actions of drugs for the treatment of depression. Many antidepressants are reported to have positive impact on learning and memory. These include agents acting through monoaminergic neurotransmitter systems, non-monoaminergic transmitter systems, and hormones. On the other hand, agents that appear to have memory-enhancing or antidementia value are frequently found to exhibit antidepressant activity in patients and animal depression models. It is becoming clear that the comorbidity of depression and dementia does not occur by chance, but rather is an inevitable consequence of pathologic relationships between the conditions. Molecular mechanisms and cascades that underlie memory may be shared by mood regulation and are vulnerable to stress and injuries. This review focuses on recent findings regarding effects of a variety of agents on dementia and depression and their common molecular mechanisms as well as their differences. A better understanding of the key underlying molecular components whose changed activities have dramatic influences on mood and cognition may lead to the development of novel and more effective therapeutic agents for the treatment of depression and dementia. In this review, some of the recent findings that suggest novel therapeutic strategies are also highlighted.
J Neuropsychiatry Clin Neurosci 15:354-358, August 2003
Accelerated Memory Decline in Alzheimer's Disease With Apolipoprotein 4 Allele
Nobutsugu Hirono, M.D., Ph.D., Mamoru Hashimoto, M.D., Ph.D., Minoru Yasuda, M.D., Ph.D., Hirokazu Kazui, M.D., Ph.D. and Etsuro Mori, M.D., Ph.D; firstname.lastname@example.org To investigate a possible effect of the apolipoprotein (APOE) 4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE 3/3, 3/4, or 4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE 4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE 4 allele is related to an accelerated memory decline in AD.
J Neuropsychiatry Clin Neurosci 15:346-353, August 2003
Psychiatric Symptoms Vary With the Severity of Dementia in Probable Alzheimer's Disease
Oscar L. Lopez, M.D., James T. Becker, Ph.D.,
This cross-sectional study examines relationships among the constellation of psychiatric syndromes in Alzheimer's disease (AD) as a function of dementia severity in 1155 patients with probable AD. The frequency of major depression decreased in severe stages, while agitation, aggression, and psychosis were more frequent in late stages. Major depression was associated with anhedonia, sleep disorders, depressed mood, low self-esteem, anxiety, and hopelessness in mild/moderate and severe stages. Agitation was associated with aggression and psychosis in mild/moderate stages, and psychosis was associated with aggression in moderate/severe stages. In addition, there was a constellation of psychiatric symptoms (e.g., anxiety, wandering, irritability, inappropriate behavior, uncooperativeness, emotional lability) associated with agitation, aggression, and psychosis, which varied according to the severity of the dementia, suggesting a progressive deterioration of frontal-temporal limbic structures. Education and race were independently associated with psychosis. However, while education was associated with psychosis in mild/moderate stages, race was associated with psychosis in moderate/severe stages.
Neuropsychiatry Clin Neurosci 15:340-345, August 2003
The Incidence of Mental and Behavioral Disturbances in
Dementia: The Cache
Martin Steinberg, M.D., Jeannie-Marie Sheppard, B.A., JoAnn T. Tschanz, Ph.D., Maria C. Norton, Ph.D., David C. Steffens, M.D., John C.S. Breitner, M.D., M.P.H. and Constantine G. Lyketsos, M.D., M.H.S.; email@example.com
population-based prevalence sample of 355 residents of
Psychological Medicine (2003), 33:1263-1275
Neuropsychological performance and dementia in depressed patients after 25-year follow-up: a controlled study
H. BRODATY a1c1, G. LUSCOMBE a1, K. J. ANSTEY a1, J. CRAMSIE a1, G. ANDREWS a1 and C. PEISAH a1
Background. Previous research has yielded conflicting evidence regarding the long-term cognitive outcome of depression. Some studies have found evidence for a higher incidence of subsequent cognitive impairment or dementia, while others have refuted this.
Method. Depression, neuropsychological performance, functional ability and clinical variables were assessed in a sample of patients who had been hospitalized for depression 25 years previously.
Results. Data were available on 71 depressed patients (10 of whom were deceased) and 50 surgical controls. No significant differences were found between depressed subjects and controls on any neuropsychological measure. Ten depressed patients but no controls were found to have dementia at follow-up (continuity corrected [chi]2=5·93, P<0·01). Presence of dementia was predicted by older age at baseline. Vascular dementia was the most common type.
Conclusions. We conclude that this study did not find evidence that early onset depression is a risk factor for Alzheimer's disease, but that for a small subgroup there appears to be a link with vascular dementia. Several plausible explanations for this link, such as lifestyle factors, require further investigation.
Psychological Medicine (2003), 33:1277-1284
Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression
N. MICHAEL a1c1, A. ERFURTH a1, P. OHRMANN a1, V. AROLT a1, W. HEINDEL a1 and B. PFLEIDERER a1
Background. The dorsolateral prefrontal cortex (DLPFC) is involved in the pathophysiology of major depression. In particular, metabolic (functional hypometabolism) and structural alterations have been described. In this study metabolic changes within the DLPFC of severely depressed patients before and after electroconvulsive therapy (ECT) were evaluated by proton STEAM spectroscopy (1H-MRS).
Method. Twelve severely depressed patients with a diagnosis of major depressive episode, unipolar with melancholic features (DSM-IV), were enrolled, and the left dorsolateral prefrontal cortex (DLPFC) was investigated before and after unilateral ECT by 1H-MRS. Three of the four non-responding patients were remeasured a third time after a combined ECT/antidepressant pharmacotherapy. The results were compared with 12 age- and gender-matched controls.
Results. In depressed patients reduced glutamate/glutamine (Glx) levels were measured pre-ECT; Glx concentrations correlated negatively with severity of depression. After successful treatment, Glx increased significantly and levels no longer differed from those of age-matched controls.
Conclusions. Our results indicate that major depressive disorder is accompanied by state-dependent metabolic alterations, especially in glutamate/glutamine metabolism, which can be reversed by successful ECT.
Psychological Medicine (2003), 33:959-967
Cognition in mania and depression
J. V. TAYLOR TAVARES , W. C. DREVETS and B. J. SAHAKIAN
The inclusion of cognitive symptoms in the DSM-IV criteria for major depressive and manic episodes highlight the importance of cognition in both of these psychiatric disorders (American Psychiatric Association, 1994). For example, criteria for diagnosis of these conditions include a diminished ability to concentrate and indecisiveness. In addition, numerous studies have demonstrated wide-ranging cognitive deficits in depression (for example Elliott et al. 1996; Purcell et al. 1997; Murphy et al. 2003) and mania (Goldberg et al. 1993; Murphy et al. 1999, 2001; Sweeney et al. 2000). These include deficits in early information processing (Tsourtos et al. 2002), recollection memory (MacQueen et al. 2002) and planning (Elliott et al. 1996) as well as affective biases (Murphy et al. 1999) and abnormal responses to negative feedback (Elliott et al. 1996, 1997; Murphy et al. 2003). Some residual deficits are also evident in a proportion of remitted subjects, even when controlling for mood (for example, Clark et al. 2002).
Psychological Medicine (2003), 33:1039-1050
Sensitivity and specificity of neuropsychological tests for mild cognitive impairment, vascular cognitive impairment and Alzheimer's disease
C. A. DE JAGER a1c1, E. HOGERVORST a1, M. COMBRINCK a1 and M. M. BUDGE a1
Background. Early diagnosis of dementia is important for those who might benefit from treatment. We designed a brief comprehensive neuropsychological test battery to help differentiate control subjects from patients with mild cognitive impairment (MCI) and dementia.
Method. The battery included tests of memory, attention, executive function, speed, perception and visuospatial skills. It was administered to subjects from the OPTIMA cohort: 51 controls, 29 with MCI, 60 with ‘possible’ or ‘probable’ Alzheimer's disease (AD) (NINCDS/ADRDA) and 12 with cerebrovascular disease (CVD). Mann–Whitney U tests were used to compare performance of controls with other diagnostic groups. The sensitivity and specificity of the tests were determined using Receiver Operating Characteristic curve analyses. The effects of age, gender and years of education on test performance were determined with Spearman's rank correlations.
Results. The AD group performed worse than controls on all tests except an attention task. The Hopkins Verbal Learning Test and The Placing Test for episodic memory showed significant discriminative capacity between controls and other groups. Attention and processing speed tests discriminated CVD from controls. Category fluency, episodic memory tests and the CLOX test for executive function distinguished MCI from AD. Spearman's correlations showed negative associations between age and processing speed. Years of education affected performance on all tests, except The Placing Test.
Conclusions. Certain neuropsychological tests have been shown to be sensitive and specific in the differential diagnosis of various types of dementia and may prove to be useful for detection of MCI.
Annual Review of Neuroscience
Jul 2003, Vol. 26, pp. 267-298
PROTOFIBRILS, PORES, FIBRILS, AND NEURODEGENERATION: Separating the Responsible Protein Aggregates from The Innocent Bystanders**
Byron Caughey and Peter T. Lansbury, Jr.: firstname.lastname@example.org;
Many neurodegenerative diseases, including Alzheimer's and Parkinson's and the transmissible spongiform encephalopathies (prion diseases), are characterized at autopsy by neuronal loss and protein aggregates that are typically fibrillar. A convergence of evidence strongly suggests that protein aggregation is neurotoxic and not a product of cell death. However, the identity of the neurotoxic aggregate and the mechanism by which it disables and eventually kills a neuron are unknown. Both biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibrillar form that is typically observed at autopsy may actually be neuroprotective. A subpopulation of protofibrils may function as pathogenic amyloid pores. An analogous mechanism may explain the neurotoxicity of the prion protein; recent data demonstrates that the disease-associated, infectious form of the prion protein differs from the neurotoxic species. This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates.
The British Journal of Psychiatry (2003) 183: 248-254
Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia
Randomised controlled trial
AIMEE SPECTOR, PhD and LENE THORGRIMSEN, BA, BOB WOODS, Msc, LINDSAY ROYAN, BA, STEVE DAVIES, Msc, MARGARET BUTTERWORTH (deceased), BA and MARTIN ORRELL, PhD: email@example.com
Background A recent Cochrane review of reality orientation therapy identified the need for large, well-designed, multi-centre trials. Aims To testthe hypothesis that cognitive stimulation therapy (CST) for older people with dementia would benefit cognition and quality of life. Method A single-blind, multi-centre, randomised controlled trial recruited 201 older people with dementia. The main outcome measures were change in cognitive function and quality of life. An intention-to-treat analysis used analysis of covariance to control for potential variabilityin baseline measures. Results One hundred and fifteen people were randomised within centres to the intervention group and 86 to the control group. At follow-up the intervention group had significantly improved relative to the control group on the Mini-Mental State Examination (P=0.044), the Alzheimer’s Disease Assessment Scale – Cognition (ADAS–Cog) (P=0.014) and Quality of Life – Alzheimer’s Disease scales (P=0.028). Using criteria of 4 points or more improvement on the ADAS–Cog the number needed to treat was 6 for the intervention group. Conclusion The results compare favourably with trials of drugs for dementia. CST groups may have worthwhile benefits for many people with dementia.
BMC Neurology 2002 2:9 (published
Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment
Chaorui Huang , Lars-Olof Wahlund , Leif Svensson , Bengt Winblad and Per Julin
Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD. Methods: rCBF was investigated in 54 MCI subjects using Tc-99m hexamethylpropyleneamine oxime (HMPAO). An automated analysis software (BRASS) was applied to analyze the relative blood flow (cerebellar ratios) of 24 cortical regions. After the baseline examination, the subjects were followed clinically for an average of two years. 17 subjects progressed to Alzheimer's disease (PMCI) and 37 subjects remained stable (SMCI). The baseline SPECT ratio values were compared between PMCI and SMCI. Receiver operating characteristic (ROC) analysis was applied for the discrimination of the two subgroups at baseline. Results: The conversion rate of MCI to AD was 13.7% per year. PMCI had a significantly decreased rCBF in the left posterior cingulate cortex, as compared to SMCI. Left posterior cingulate rCBF ratios were entered into a logistic regression model for ROC curve calculation. The area under the ROC curve was 74%–76%, which indicates an acceptable discrimination between PMCI and SMCI at baseline. Conclusion: A reduced relative blood flow of the posterior cingulate gyrus could be found at least two years before the patients met the clinical diagnostic criteria of AD.
Annals of General Hospital Psychiatry 2003 2:8 (published
Clinical and neuroimaging correlates of abnormal short-latency Somatosensory Evoked Potentials in elderly vascular dementia patients: A psychophysiological exploratory study
Iacovos Tsiptsios , Konstantinos N Fountoulakis , Konstantinos Sitzoglou , Anastasia Papanicolaou , Konstantinos Phokas , Fotis Fotiou and George St Kaprinis
Short Latency Somatosensory Evoked Potentials (SEPs) may serve to the testing of the somatosensory tract function, which is vulnerable and affected in vascular encephalopathy. The aim of the current study was to search for clinical and neuroimaging correlates of abnormal SEPs in vascular dementia (VD) patients. Materials and Methods: The study included 14 VD patients, aged 72.93 ± 4.73 years, and 10 controls aged 71.20 ± 4.44 years. All subjects underwent a detailed clinical examination, blood and biochemical testing, brain MRI and were assessed with the MMSE. SEPs were recorded after stimulation from upper and lower limbs. The statistical Analysis included 1 and 2-way MANCOVAs and Factor analysis Results: The N13 latency was significantly prolonged, the N19 amplitude was lower, the P27 amplitude was lower and the N11-P27 conduction time was prolonged in severely demented patients in comparison to controls. The N19 latency was prolonged in severely demented patients in comparison to both mildly demented and controls. The same was true for the N13-N19 conduction time, and for the P27 latency. Patients with subcortical lesions had all their latencies prolonged and lower P27 amplitude. Discussion: The results of the current study suggest that there are significant differences between patients suffering from VD and healthy controls in SEPs, but these are detectable only when dementia is severe or there are lesions located in the subcortical regions. The results of the current study locate the abnormal SEPs in the white matter, and are in accord with the literature.
BMC Geriatrics 2003 3:4 (published
Validity of a novel computerized cognitive battery for mild cognitive impairment
Tzvi Dwolatzky , Victor Whitehead, Glen M Doniger, Ely S Simon, Avraham Schweiger, Dena Jaffe and Howard Chertkow
The NeuroTrax Mindstreams computerized cognitive assessment system was designed for widespread clinical and research use in detecting mild cognitive impairment (MCI). However, the capability of Mindstreams tests to discriminate elderly with MCI from those who are cognitively healthy has yet to be evaluated. Moreover, the comparability between these tests and traditional neuropsychological tests in detecting MCI has not been examined. Methods: A 2-center study was designed to assess discriminant validity of tests in the Mindstreams Mild Impairment Battery. Participants were 30 individuals diagnosed with MCI, 29 with mild Alzheimer's disease (AD), and 39 healthy elderly. Testing was with the Mindstreams battery and traditional neuropsychological tests. Receiver operating characteristic (ROC) analysis was used to examine the ability of Mindstreams and traditional measures to discriminate those with MCI from cognitively healthy elderly. Between-group comparisons were made (Mann-Whitney U test) between MCI and healthy elderly and between MCI and mild AD groups. Results: Mindstreams outcome parameters across multiple cognitive domains significantly discriminated among MCI and healthy elderly with considerable effect sizes (p < 0.05). Measures of memory, executive function, visual spatial skills, and verbal fluency discriminated best, and discriminability was at least comparable to that of traditional neuropsychological tests in these domains. Conclusions: Mindstreams tests are effective in detecting MCI, providing a comprehensive profile of cognitive function. Further, the enhanced precision and ease of use of these computerized tests make the NeuroTrax system a valuable clinical tool in the identification of elderly at high risk for dementia.
Journal of the American Geriatrics Society
Volume 51 Issue 11 Page 1621 - November 2003
Self- and Informant Report of Financial Abilities in Patients with Alzheimer's Disease: Reliable and Valid?
Virginia G. Wadley, PhD, Lindy E. Harrell, MD, PhD and Daniel C. Marson, JD, PhD
Objectives: To evaluate the consistency, stability, and accuracy of reports by patients with Alzheimer's disease (AD) and their caregivers regarding the patients' premorbid and current financial abilities. Design: Consistency of reports was assessed within patient/caregiver dyads and within control/control informant dyads. Stability of reports over a 1-month interval was assessed for each group: patients with AD, caregivers, controls, and control informants. Accuracy of each group's reports was evaluated in reference to patients' and controls' performance on a direct psychometric measure of financial capacity. Setting: University medical center. Participants: Twenty patients with AD and 20 family caregivers; 23 controls and 23 family informants. Measurements: The Prior Financial Capacity Form (PFCF) and the Current Financial Capacity Form (CFCF) were used. Parallel versions assessed self-report (patients, controls) and informant report (caregivers, control informants) at two visits 1 month apart. Patients with AD and controls were also administered the Financial Capacity Instrument (FCI), a direct assessment of the same abilities reported on the PFCF and CFCF. Results: Patients with AD reported that they had more-intact current abilities than their caregivers reported. Patients with AD and their caregivers showed lower levels of stability over time on the PFCF and CFCF than did controls and their informants. Half of the patients with AD overestimated their current abilities relative to their FCI performance, whereas caregivers demonstrated both underestimation and overestimation errors. Controls and informants evidenced high levels of consistency, stability, and accuracy in PFCF and CFCF ratings. Conclusion: Patients with AD overestimate their financial abilities in comparison with the reports of their family caregivers. Both patients and caregivers' reports of patients' financial abilities showed limited stability and validity. The reliability and accuracy of self- and informant reports of financial abilities may be compromised in the context of dementia and caregiving, underscoring the need for direct assessment methods to augment self- and informant report in assessing functional decline in dementia.
Journal of the American Geriatrics Society
Volume 51 Issue 11 Page 1633 - November 2003
Influence of Executive Function on Locomotor Function: Divided Attention Increases Gait Variability in Alzheimer's Disease
Pamela L. Sheridan, MD, Judi Solomont, Mat, Neil Kowall, MD, and Jeffrey M. Hausdorff, PhD
To evaluate how cognitive function and divided attention affect gait in
Alzheimer's disease (AD). Design: Cross-sectional intervention study with
subjects serving as their own controls. Setting: Inpatient unit and outpatient
clinic for patients with dementia located at a
Journal of the American Geriatrics Society
Volume 51 Issue 11 Page 1638 - November 2003
Cognitive Impairment Decreases Postural Control During Dual Tasks in Geriatric Patients with a History of Severe Falls
Klaus Hauer, PhD, Mathias Pfisterer, MD, Christine Weber, Nikolai Wezler, MD, Mattias Kliegel, PhD, and Peter Oster, MD
Objectives: To investigate the influence of dual tasks, cognitive strategies, and fear of falling on postural control in geriatric patients with or without cognitive impairment and with a history of falls resulting in injury. Design: Experimental three-group design. Setting: Geriatric hospital. Participants: Twenty young healthy adults (mean age±standard deviation=25.4±4.4), 20 geriatric patients with a history of severe falls without cognitive impairment (mean age=82.6±5.5, mean Mini-Mental State Examination (MMSE) score=27.8±2.0) and 20 geriatric patients with a history of severe falls and cognitive impairment (mean age=83.2±5.5, mean MMSE=19.2±3.3). Measurements: Motor performance: sway area and lateral and anterior-posterior sway angles. Cognition: semiautomated calculation steps (serial 2 forward) and nonautomated calculation derived from MMSE (serial 7 retro). Motor and cognitive performances were examined as single and dual tasks. Strategy decision, fear of falling, and subjective perception of motor and cognitive performance were assessed as covariates for dual-task performances. Results: Motor performance decreased significantly during all dual tasks in geriatric patients with cognitive impairment and a history of falls resulting in injury. Cognitive performance was different depending on the task and group. Choice of cognitive strategies or fear of falling did not influence the dual-task performances. Conclusion: Even simple additional tasks substantially decrease postural stability due to attention-related cognitive deficits in cognitively impaired geriatric patients with a history of severe falls. The findings may help to explain the increased incidence and severity of falls in geriatric patients with cognitive impairment and a history of falls resulting in injury.
Archives of Geron
In Press, Corrected Proof ,
Frail elderly, nutritional status and drugs
This review focuses on the interactions between nutritional status and drugs in frail elderly persons. Impairment of nutritional status, a component of clinical presentation in the frail elderly, has a major impact on the pharmacology of many drugs devolving from the physiological alterations it generates. Food itself plays a central role in nutritional status and in possible interactions with drugs. Conversely, drugs have often, directly and indirectly, a deleterious effect on the nutritional state of the elderly. However, research in this domain is scarce, and future clinical studies will need to include more elderly and frail elderly individuals, to help clinicians to better understand these interactions.
Archives of Geron
In Press, Corrected Proof ,
Measuring the suffering of end-stage dementia:
reliability and validity of the
Bechor Z. Aminoff, Elena Purits, Shlomo Noya and Abraham Adunskya
Assessment of suffering is extremely important in dying end-stage dementia patients (ESDP). We have developed and examined the reliability and validity of the Mini-Suffering State Examination (MSSE), in 103 consecutive bedridden ESDP. Main outcome measures included inter-observer reliability and concurrent validity. Reliability of the MSSE questionnaire was satisfactory, with Cronbach values of 0.735 and 0.718 for the two physicians (Ph-1, Ph-2), respectively. The agreement coefficient was 0.791. There was a high agreement for seven items ( 0.882–0.972) and a substantial agreement for the other three items ( 0.621–0.682) of the MSSE. MSSE was validated versus the comfort assessment in dying with dementia (CAD-EOLD) scale and resulted in a significant Pearson correlation (r=-0.796, P<0.001). We conclude that the MSSE scale is a reliable and valid clinical tool, recommended for evaluating the severity of the patient's condition and the level of suffering of ESDP. Use of MSSE may improve medical management and facilitate communication between patients and caregivers.
Archives of Geron
Volume 38, Issue 1 , January-February 2004, Pages 85-99
Social relations as determinant of onset of disability in aging
Kirsten Avlund, , Rikke Lund, Bjørn E. Holstein and Pernille Due
The purpose of the study was to analyze whether social relations are related to onset of disability among old people at 1.5 year follow-up and whether these relations vary by age and gender. The study is based on baseline and 1.5 year follow-up data on 1396 older non-disabled adults. Social relations were measured by questions about diversity in social relations, social participation, satisfaction with social relations and instrumental social support. Onset of disability was described as developing need of help in at least one of six mobility activities. The results showed that a large diversity in social relations and high social participation were important factors for maintaining functional ability among the 75-year-old men and women, while social support was a risk factor for functional decline among the 80-year-old men. The present study suggests that being "embedded" in a strong network of social relations provides protection against disability by reducing risk of developing disability.
International Journal of Geriatric Psychiatry
Volume 18, Issue 11 , Pages 988 - 993
What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson's disease with dementia
Thaís S. C. Minett, Alan Thomas, Lucy M. Wilkinson, Sarah L. Daniel, Jonathan Sanders, Jonathan Richardson, Elizabeth Littlewood, Pat Myint, Jane Newby, Ian G. McKeith: firstname.lastname@example.org)
This open label study was designed to assess the effects
of donepezil treatment, its withdrawal and subsequent
recommencement on cognitive functioning, behaviour
and parkinsonian symptoms in patients with probable
dementia with Lewy bodies (DLB) and with Parkinson's
disease who subsequently developed dementia (PDD). Methods Eight patients with
DLB and 11 with PDD were treated with up to 10mg of donepezil
daily for 20 weeks followed by a 6-week withdrawal period. The primary outcome
measures were the Mini-Mental State Examination (MMSE), the total Neuropsychiatric Inventory (NPI) and the Unified
Parkinson's Disease Rating Scale III. Testing was conducted before dosing, at
week 20, at a withdrawal visit and 3 months after recommencement on donepezil. Results: Patients with DLB and PDD showed a
significant improvement in cognition with treatment, loss of this improvement
on withdrawal and restoration of treatment gains on recommencement. Both groups
also demonstrated favourable, behavioural
changes with treatment, PDD patients in particular deteriorating significantly
after withdrawal. The only NPI symptom domain that showed a consistent
significant response to both treatment (positive) and
withdrawal (negative) was hallucinations. The medication was well
International Journal of Geriatric Psychiatry
Volume 18, Issue 11 , Pages 994 - 1001
Comorbidity and risk-patterns of depression, generalised anxiety disorder and mixed anxiety-depression in later life: results from the AMSTEL study
R. A. Schoevers, A. T. F. Beekman, D. J. H. Deeg, C. Jonker, W. van Tilburg: R. A. Schoevers (email@example.com)
Background: Depression and generalised anxiety disorder frequently overlap. The question remains unresolved whether these are specific disorders, or that they represent different dimensions of a single disorder. Although both are highly prevalent disorders in this age group, studies on this issue in the elderly are scarce. Research is needed that investigates patterns of comorbidity and possibly different risk profiles for pure depression, pure generalised anxiety and mixed anxiety-depression in older people. Methods: GMS-AGECAT diagnoses were obtained from 4051 community living older persons. Comorbidity was studied along a severity gradient for men and women separately. Multivariate analysis of risk factors included demographic variables, environmental vulnerability, longstanding vulnerability, physical/functional stresses and gender. Results: The prevalence of pure depression was 12.2%, pure generalised anxiety 2.9%, mixed anxiety-depression 1.8%. Comorbidity increased with higher severity levels of both depression and generalised anxiety. Comorbidity was twice as likely in women than in men. Different risk profiles for diagnostic categories were not demonstrated for concurrent risk factors. Longstanding vulnerability was associated significantly stronger with mixed anxiety-depression than with pure anxiety and pure depression. Mixed anxiety-depression was overrepresented in women. Conclusions: Both lines of investigation suggest that, in the elderly, a dimensional classification is more appropriate than a categorical classification of depression and generalised anxiety. Mixed anxiety-depression is a more severe form of psychopathology that is almost specific to women in this age group.
International Journal of Geriatric Psychiatry
Volume 18, Issue 11 , Pages 1021 - 1028
Rey verbal learning test is a useful tool for differential diagnosis in the preclinical phase of Alzheimer's disease: comparison with mild cognitive impairment and normal aging
Armando Estévez-González, Jaime Kulisevsky, Anunciación Boltes, Pilar Otermín, Carmen García-Sánchez: Armando Estévez-González (firstname.lastname@example.org)
Objective: To confirm that performance in verbal learning and memory test (Rey's Auditory Verbal Learning Test-RAVLT) is a helpful early neuropsychological marker of dementia of Alzheimer's type (DAT). Methods: RAVLT was administered as part of a more extensive neuropsychological battery at baseline evaluation in 116 unselected patients referred by subjective memory complaints (SMC). Patients were followed longitudinally for 2 years (average interval of 27.7±4 months). Seventy patients were included in the study: 27 developed probable DAT; 17 were diagnosed as cognitively normal persons and 26 were diagnosed with Mild Cognitive Impairment (MCI). Remaining patients abandoned or they did not meet the criteria for DAT, MCI or control. Performance on RAVLT at the baseline evaluation was compared between groups. Results: Patients diagnosed two years later with probable DAT showed lower results, more frequently performed a score of zero at the delayed recall test (Trial 6) and had a percentage of forgetting (difference between Trials 5 and 6) higher than 75%. Score at delayed recall test and percentage of forgetting correlated with functional scales such as MMSE, Geriatric Depression Screening, Informant Questionnaire and Blessed's Dementia Rating. Conclusions: RAVLT could help to identify those patients with SMC who would progress to DAT over a few years, and also to differentiate between the preclinical phase of Alzheimer's disease, mild cognitive impairment and normal aging. A score of zero at the delayed recall test or a percentage of forgetting 75% in patients with SMC is suggestive of probable DAT in the future.
International Journal of Geriatric Psychiatry
Volume 18, Issue 11 , Pages 1050 - 1055
A new approach to the qualitative evaluation of functional disability in dementia
X. Kurz, J. Scuvee-Moreau, B. Rive, A. Dresse: A. Dresse (Albert.Dresse@ulg.ac.be)
Background: Dementia patients
suffer from the progressive deterioration of cognitive and functional
abilities. Instrumental disabilities usually appear in the earlier stages of
the disease while basic disabilities appear in the more advanced stages. In
order to differentiate between mild, moderate and severe patients both
instrumental and basic functional disabilities should be taken into account
simultaneously. Objectives: The objective of this study was to find a new
method for classifying dementia patients based on their disabilities by using a
basic and an instrumental Activities of Daily Living (ADL) scale. Methods:
Functional disability was assessed in a Belgian cohort of dementia patients
using the Katz and Lawton Instrumental Activities of Daily Living (IADL)
scales. A k-means derived clustering method allocated patients to disability clusters
according to their Katz and
International Journal of Geriatric Psychiatry
Volume 18, Issue 11 , Pages 1007 - 1012
Family carers' responses to behavioural and psychological symptoms of dementia
Sandy Ward, Janet Opie, Daniel W. O'Connor: Daniel W. O'Connor (email@example.com)
To describe the responses of family carers to the behavioural and psychological symptoms associated with
dementia. Methods: Thirty family carers of people
with dementia were identified in a survey of mental disorder in general
practice. Another 20 were referred by local aged mental health services. Carers were interviewed using the
Journal of Anxiety Disorders
Volume 17, Issue 6 , 2003, Pages 627-646
Structural differentiation of self-reported depression and anxiety in late life
Suzanne Meeks, , Janet Woodruff-Borden and Colin A. Depp
Research has shown impressive support for tripartite models of anxiety and depression that include a common factor of negative affect, and the unique factors positive affect and arousal. It is not clear whether this structure extends into later life. The current study used confirmatory factor analysis to model the structural relationship of anxiety and depression in two samples of older adults: a large probability sample (N=1429) and a smaller convenience sample (N=210). Across all analyses, a correlated, two-factor, psychometric model was most parsimonious. The tripartite model could be fit to the data, but added no explanatory power; in some cases a one-factor model also fit. The results suggest that there is a unitary factor of "distress" that incorporates anxiety and depression, but that the structure is not consistent with factor structures found in younger samples. Instead, the broad constructs may be represented in a more complex manner among older adults, and are less easily differentiated.
Journal of Medical Speech - Language Pathology, March 2002 v10 i1 p73(10)
Dysgraphia in Alzheimer's disease with mild cognitive impairment.
Sunita Kavrie; Jean Neils-Strunjas.
The objectives of this study were (a) to examine the prevalence and onset of dysgraphia (i.e. writing impairment) in comparison with other neuropsychological deficits commonly associated with mild Alzheimer's disease (AD); and (b) to determine the patterns of neuropsychological deficits, if any, that are associated with dysgraphia in the early stages of the disease. Fourteen people diagnosed with mild AD and fourteen age-, sex-, and education-matched healthy individuals were administered a battery of writing tests along with a comprehensive neuropsychological test battery traditionally administered in the diagnosis of AD. Seven of the fourteen AD subjects presented with dysgraphia in the early stage of the disease. Memory and reasoning were more often impaired than writing; however, dysgraphia was more common than deficits of attention, visuospatial functions, language, and visuoconstruction. Regression analysis indicated that the cumulative effects of deficits in language and attention predicted the occurren ce of dysgraphia. Analysis of errors on the individual writing tasks showed more spelling errors in homophones written to dictation than in regular and irregular words written to dictation. A spontaneous writing sample elicited with the Boston Diagnostic Examination cookie theft picture did not yield as many errors as homophone spelling.
2003, Vol.9, No.6, pp. 482-492
Metamemory Accuracy in Alzheimer’s Disease and Frontotemporal Lobe Dementia
Céline Souchay, Michel Isingrini, Bernard Pillon and Roger Gil
Metamemory is a multifaceted concept, which deals with an individual’s knowledge and control of his or her own memory system. The ability to monitor memory performance accurately was examined in 16 patients with Alzheimer’s disease (AD), 6 patients with frontotemporal lobe dementia (FTD) and 16 elderly subjects. Participants made global memory predictions in a single experimental task, both prior to and after studying 20 critical cue-target words. Prediction accuracy was evaluated with traditional score-difference measures. Our data showed that in the case of the after-study prediction FTD patients were more inaccurate in predicting their memory performance than were the AD patients, suggesting that FTD patients were more impaired than AD patients in monitoring their memory performance. Nevertheless, there seems to be no difference regarding their metacognitive knowledge or beliefs of their own memory, as indicated by the absence of difference in prediction accuracy made before study. Moreover, analyses of covariance showed that the difference in metamemory performance between AD and FTD may be related to the executive differences observed in these two populations. In sum, our results suggest that metamemory evaluation could be useful to distinguish between patients with AD and those with FTD.
In Press, Corrected Proof ,
Magnetoencephalographic––Features related to mild cognitive impairment
We recorded changes of brain activity from 10 MCI patients and 10 controls related to shallow (nonsemantic) and deep (semantic) word encoding using a whole-head MEG. During the following recognition tasks, all participants had to recognize the previously encoded words, which were presented again together with new words. In both groups recognition performance significantly varied as a function of depth of processing. No significant differences were found between the groups. Reaction times related to correctly classified new words (correct rejections) and incorrectly classified repetitions (misses) of MCI patients showed a strong tendency toward prolongation compared to controls, although no statistically significant differences occurred. Strikingly, in patients the neurophysiological data associated with nonsemantic and semantic word encoding differed significantly between 250 and 450 ms after stimulus onset mainly over left frontal and left temporal sensors. They showed higher electrophysiological activation during shallow encoding as compared to deep encoding. No such significant differences were found in controls. The present results might reflect a dysfunction with respect to shallow encoding of visually presented verbal information. It is interpreted that additional neural activation is needed to compensate for neurodegeneration. This finding is suggested to be an additional tool for MCI diagnosis.
Archives of Clinical
Article in Press, Corrected Proof
Relationship between plasticity, mild cognitive impairment and cognitive decline
M. Dolores Calero, and Elena Navarro
of great interest in geron
Measurement of Phosphorylated Tau Epitopes in the Differential Diagnosis of Alzheimer Disease: A Comparative Cerebrospinal Fluid Study
Harald Hampel, MD; Katharina Buerger, MD; Raymond Zinkowski, PhD; Stefan J. Teipel, MD; Alexander Goernitz, MD; Niels Andreasen, MD, PhD; Magnus Sjoegren, MD; John DeBernardis, PhD; Daniel Kerkman, PhD; Koichi Ishiguro, PhD; Hideto Ohno, PhD; Eugeen Vanmechelen, PhD; Hugo Vanderstichele, PhD; Cheryl McCulloch, BS; Hans-Jürgen Möller, MD; Peter Davies, PhD; Kaj Blennow, MD, PhD
Arch Gen Psychiatry. 2004;61:95-102.
Background Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). Objective To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. Design and Setting Cross-sectional, bicenter, memory clinic–based studies. Participants One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). Main Outcome Measures Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. Results The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. Conclusions The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.
Neuropsychological Studies in Geriatric Psychiatry
Rebecca E Ready, Jane S Paulsen
Curr Opin Psychiatry 16(6):643-648, 2003.
This review is a comprehensive summary of recent work in the field of neuropsychology that is relevant to geriatric psychiatry. Recent Findings: Recent research identified neuropsychological predictors of functioning in geriatric samples, elucidated the neuropathology and neuropsychology of geriatric depression, further clarified the association between dementia and depression, contributed to advancements in the early detection and diagnosis of dementia, investigated emotion processing in aging, and adapted neuropsychological tests for severely impaired samples. There were encouraging trends indicating that neuropsychological investigations are becoming increasingly culturally diverse. Summary: Recent research in neuropsychology will facilitate both the prediction of important clinical outcomes in geriatric samples and accurate differential diagnosis of psychiatric patients.
Archives of Clinical
Article in Press, Corrected Proof
Executive dysfunction and visuospatial ability among depressed elders in a community setting
Virginia Elderkin-Thompson, , a, Anand Kumara, Jim Mintzb, Kyle Boonec, Enjey Bahnga and Helen Lavretskya
Visuospatial ability is frequently compromised among elderly depressed patients, but it is unclear whether the impairment is a consequence of a visuospatial memory deficit or of an executive dysfunction that impacts visuospatial ability. The Boston Qualitative Scoring System is a method of scoring the Rey–Osterrieth Complex Figure (ROCF) that assesses the process used to draw the figure, the executive aspect of the task, as well as the accuracy and location of the completed elements. The hypotheses that executive scores as measured by the BQSS would separate diagnostic groups and that executive function would mediate the relationship between depression and nonverbal recall were tested using a between groups design with elderly depressed volunteers (N=31) and healthy controls (N=31). Participants were screened for other Axis I disorders with the Structured Clinical Interview for DSM-IV Diagnosis, diagnosed for major depression per DSM-IV criteria, and administered the ROCF. The copy and recall drawings were scored using BQSS criteria, and scores were grouped into executive and drawing scores from both copy and recall phases. Executive scores during the copy phase and drawing scores from the recall phase separated the diagnostic groups [F(1,59)=4.14, P=.05] and [F(1,59)=6.88, P=.01], respectively. Follow-up ANCOVAS showed that copy Planning, the score that quantified the process by which the figure was drawn, separated the diagnostic groups. Planning also mediated the association between depression and the percent of the figure recalled after the short delay (Z=1.84, P<.05). The significance of the depression-to-recall pathway was eliminated when Planning was controlled for, but Planning remained related to percent recalled [B=-6.90, P<.007]. A dimension of executive dysfunction, represented here by Planning, may be one underlying source of the observed decline in nonverbal recall among elderly depressed patients. This result is consistent with the theory that dysfunction of the prefrontal cortex is a critical feature of late-life depression.
The Relationship Between Neuropsychological Functioning and Driving Ability in Dementia: A Meta-Analysis
Mark A. Reger
A meta-analysis of 27 primary studies was conducted to examine the relationship between neuropsychological functioning and driving ability for adults with dementia. When studies using a control group were included, the relationship between cognitive measures and on-road or non-road driving measures was significant for all reported domains; mean correlations ranged from .35 to .65. Caregiver reports of driving ability and cognitive variables were correlated significantly only on measures of mental status and visuospatial skills. When studies using a control group were excluded, moderate mean correlations were observed for visuospatial skills and on-road or non-road measures, and for mental status with non-road tests. Other effects were small or nonsignificant. Implications for basing driving recommendations on neuropsychological testing are discussed.
Selection Ability in Alzheimer's Disease: Investigation of a Component of Semantic Processing
Lynette J. Tippett and Angela Gendall, Martha J. Farah and Sharon L. Thompson-Schill
Selection ability (selecting a response from several competing semantic and/or lexical representations) was tested in 21 participants with Alzheimer's disease (AD) and 28 control participants to help clarify the nature of semantic impairments in AD. Selection demands were manipulated in 3 tasks (lexical fluency, comparison, and verb generation). In each, high-selection conditions required response selection from competing alternatives, whereas low-selection conditions had a reduced need for selection. Patients with AD were disproportionately impaired on the high-selection conditions of all tasks, even when this condition was easier. Selection deficits on verb generation were evident only relative to nonspeeded controls. Overall results indicate impaired semantic selection abilities in AD, which may contribute to poor performance on some semantic tasks.
Implicit Spatial Contextual Learning in Healthy Aging
James H. Howard, Jr., Darlene V. Howard, Nancy A. Dennis, Helen Yankovich and Chandan J. Vaidya
Three experiments investigated the aging of implicit spatial and spatiotemporal context learning in 2 tasks. In contextual cuing, people learn to use repeated spatial configurations to facilitate search for a target, whereas in higher order serial learning, they learn to use subtle sequence regularities to respond more quickly and accurately to a series of events. Results reveal a dissociation; overall contextual cuing is spared in healthy aging, whereas higher order sequence learning is impaired in the same individuals. This finding suggests that these 2 forms of implicit learning rely on different neural substrates that age differently; the results are also consistent with recent evidence that fronto–striatal circuits are particularly susceptible to decline in health aging.
Use of IQ-Adjusted Norms to Predict Progressive Cognitive Decline in Highly Intelligent Older Individuals
Dorene M. Rentz,
Terri J. Huh,
Identifying high-functioning older individuals in preclinical phases of Alzheimer's disease (AD) may require more sensitive methods than the standard approach. The authors explored the utility of adjusting for premorbid intelligence to predict progressive cognitive decline or Mild Cognitive Impairment (MCI) in 42 highly intelligent older individuals. When scores were adjusted for baseline IQ, 9 participants had executive impairments, 11 had memory impairments, and 22 scored in the normal range. None were impaired according to standard age norms. Three and a half years later, 9 participants with IQ-adjusted memory impairment declined in naming, visuospatial functioning, and memory; 6 converted to MCI. Three participants with normal memory declined. Implications for using IQ-adjusted norms to predict preclinical AD are discussed.
Archives of Clinical
The neuropsychological profile of vascular cognitive impairment––no dementia: comparisons to patients at risk for cerebrovascular disease and vascular dementia
Kelly Davis Garrett, Jeffrey N. Browndyke, William Whelihan,
Hachinski and co-workers have used the term vascular cognitive impairment––no dementia (VaCIND) to represent the earliest stages of cognitive decline associated with vascular changes [Neurology 57 (4) (2001) 714]. However, the neuropsychological profile of vascular CIND remains unclear. Twenty-five healthy elders, 29 individuals at risk for cerebrovascular disease (R-CVD), 18 individuals with VaCIND, and 26 individuals with vascular dementia (VaD) were examined to determine whether patterns of neuropsychological assessment performance can assist in the differentiation of patients at varying levels of risk and severity for cerebrovascular disease and VaD. The R-CVD group performed within normal expectations on most cognitive measures as compared to the elderly control sample and published clinical norms. Relative to elderly controls, the VaCIND group demonstrated significant difficulties on measures of cognitive flexibility, verbal retrieval, and verbal recognition memory, but not on measures of confrontational naming or verbal fluency. The VaD group was impaired on all cognitive measures assessed. The current findings suggest that poor cognitive flexibility and verbal retrieval in the context of preserved function in other domains may characterize the prodromal stage of VaD.
Volume 69, Issue 1 , January 2004, Pages 1-16
Identification of naturally occurring spirostenols preventing -amyloid-induced neurotoxicity
Laurent Lecanua, Wenguo Yao, Gary L. Teper, Zhi-Xing
22R-Hydroxycholesterol is an intermediate in the steroid biosynthesis pathway shown to exhibit a neuroprotective property against -amyloid (1–42) (A) toxicity in rat PCl2 and human NT2N neuronal cells by binding and inactivating A. In search of potent 22R-hydroxycholesterol derivatives, we assessed the ability of a series of naturally occurring entities containing the 22R-hydroxycholesterol structure to protect PC12 cells against A-induced neurotoxicity, determined by measuring changes in membrane potential, mitochondrial diaphorase activity, ATP levels and trypan blue uptake. 22R-Hydroxycholesterol derivatives sharing a common spirost-5-en-3-ol or a furost-5-en-3-ol structure were tested. Although some of these compounds were neuroprotective against 0.1 M A, only three protected against the 1–10 M A-induced toxicity and, in contrast to 22R-hydroxycholesterol, all were devoid of steroidogenic activity. These entities shared a common structural feature, a long chain ester in position 3 and common stereochemistry. The neuroprotective property of these compounds was coupled to their ability to displace radiolabeled 22R-hydroxycholesterol from A, suggesting that the A-22R-hydroxycholesterol physicochemical interaction contributes to their beneficial effect. In addition, a 22R-hydroxycholesterol derivative inhibited the formation of neurotoxic amyloid-derived diffusible ligands. Computational docking simulations of 22R-hydroxycholesterol and its derivatives on A identified two binding sites. Chemical entities, as 22R-hydroxycholesterol, seem to bind preferentially only to one site. In contrast, the presence of the ester chain seems to confer the ability to bind to both sites on A, leading to neuroprotection against high concentrations of A. In conclusion, these results suggest that spirost-5-en-3-ol naturally occurring derivatives of 22R-hydroxycholesterol might offer a new approach for Alzheimer's disease therapy.
When Sporadic Disease Is Not Sporadic: The Potential for Genetic Etiology
Jill S. Goldman, MS, MPhil, CGC; Bruce L. Miller, MD; Jiri Safar, MD; Sunita de Tourreil, MSc; Jennifer L. Martindale, BS, BA; Stanley B. Prusiner, MD; Michael D. Geschwind, MD, PhD
Arch Neurol. 2004;61:213-216.
Background Approximately 2% of Alzheimer disease cases and 10% to 15% of prion disease cases are due to mutations in autosomal dominant genes. Mutations have been found in patients without family histories of neurological disease. Objectives To emphasize the need for consideration of a genetic etiology of prion disease and early-onset Alzheimer disease, regardless of the absence of a significant family history, as well as the need for pretest genetic counseling of all patients or their families. Design Three case reports. Patients and Results Patient 1, a 53-year-old man with possible Creutzfeldt-Jakob disease, was enrolled in a research study that included sequencing of the prion protein gene. Although there was no family history of neurological disease, an E200K mutation was found. This unexpected result caused the family significant distress. Patient 2, a 55-year-old woman with biopsy-proven Creutzfeldt-Jakob disease, participated in a prion disease research study. Her family was counseled about the possibility of hereditary Creutzfeldt-Jakob disease, despite the lack of family history. After assessing the ramifications, the family decided not to learn about the patient's genetic test results. Patient 3 was a 54-year-old man with a 6-year history of memory loss. A diagnosis of probable Alzheimer disease was given, and the patient and his family were counseled on the availability of presenilin 1 testing, although there was no known family history of dementia. The family agreed to testing, and a presenilin 1 mutation was identified. Conclusions Certain neurodegenerative diseases may have a genetic etiology, despite the lack of a positive family history. Revealing a newly discovered hereditary cause of Creutzfeldt-Jakob disease or Alzheimer disease can have a profound effect on families. Pretest counseling on genetic issues is essential to better prepare families and to allow them to make an informed choice about learning genetic test results.
Journal of Neurology Neurosurgery and Psychiatry 2004;75:370-376
Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer’s disease
L Mosconi1, B Nacmias2, S Sorbi2, M T R De Cristofaro1, M Fayazz1, A Tedde2, L Bracco2, K Herholz3 and A Pupi1 ; firstname.lastname@example.org
Objectives: Declines in brain glucose metabolism have been described early in Alzheimer’s disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods. Methods: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected). Results: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers. Conclusions: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients.
Journal of Neurology Neurosurgery and Psychiatry 2004;75:377-381
Association study of Notch 4 polymorphisms with Alzheimer’s disease
J-C Lambert1, D Mann3, J Harris2, L Araria-Goumidi1, M-C Chartier-Harlin1, D Cottel1, T Iwatsubo4, P Amouyel1 and C Lendon2 ; Jean-Charles.Lambert@pasteur-lille.fr
The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have
significant linkage with Alzheimer’s disease.
Objective: To investigate the potential impact of two polymorphisms
within this gene on the risk of developing Alzheimer’s disease. Methods: Genotyping of promoter and 5'-UTR
polymorphisms was done in Scottish, English, and French populations. The
potential functionality of the 5'-UTR polymorphism was assessed by testing its
impact on Aß load in Alzheimer brains and also by
undertaking electrophoretic mobility shift assays and
transfection experiments. Results: No association of the Notch4
polymorphisms alone with the disease was observed in any of the populations.
However, an interaction of the 5'-UTR C/T polymorphism with the 4 allele of the
APOE gene was detected in
Journal of Neurology Neurosurgery and Psychiatry 2004;75:382-387
Fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease is qualitatively distinct
J Bradshaw1,2, M Saling1,2, M Hopwood1,3, V Anderson2 and A Brodtmann1: email@example.com
Objectives: To document and illustrate qualitative features of fluctuating cognition as described by care givers of patients with probable dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). To determine whether the quality of the fluctuations differs between DLB and AD. To examine the clinical utility of two recently developed rating scales. Methods: Care givers of 13 patients with early probable DLB and 12 patients with early probable AD were interviewed using the Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale, both developed recently. Descriptions of fluctuating cognition were recorded verbatim, analysed, and rated. Results: Descriptions of fluctuating cognition in DLB had a spontaneous, periodic, transient quality, which appeared to reflect an interruption in the ongoing flow of awareness or attention that impacted on functional abilities. Descriptions of fluctuations in AD frequently highlighted episodes of memory failure, or a more enduring state shift in the form of "good" and "bad" days, typically occurring in response to the cognitive demands of the immediate environment. These qualitative differences could be detected reliably by independent raters, but were not always captured in standard severity scores. Conclusion: Fluctuations occuring in DLB have particular characteristics that are distinguishable from fluctuations occurring in AD. Interpretation and application of the fluctuation criterion continues to limit the diagnostic sensitivity of the consensus criteria for DLB. Findings suggest that explicit documentation and a wider appreciation of these distinctions could improve the reliability with which less experienced clinicians identify this core diagnostic feature in the clinical setting.
characteristics of magnetic resonance imaging-defined subcortical
Krishnan KR, Taylor WD, McQuoid DR, MacFall JR, Payne ME, Provenzale JM, Steffens DC.
Biol Psychiatry. 2004 Feb 15;55(4):390-7.
BACKGROUND: There is a substantial body of research
supporting the vascular depression hypothesis of late-life depression. To
update this hypothesis so it incorporates recent research, we propose that the
term subcortical ischemic vascular
depression may be a more accurate representation of the disease process. We
sought to investigate this diagnosis as a construct by examining differences
between depressed subjects with and without magnetic resonance imaging defined subcortical ischemic vascular depression. METHODS: This
case-control study examined 139 depressed elderly subjects. Demographic data,
psychiatric, medical, and family history, depressive symptoma
Archives of Clinical
Investigation of profile difference between Alzheimer's disease patients declining at different rates: examination of baseline neuropsychological data
Timothy B. Atchison , Major Bradshaw and Paul J. Massman
The rate of cognitive decline in AD has been noted to vary significantly among patients. The ability to predict the probable rate of decline early in the disease process would be of great practical importance. Attempts to analyze early cognitive deficits to find patterns associated with rapid decline have met with limited success. This paper utilized a large sample of patients with a diagnosis of probable AD evaluated longitudinally in ongoing research at the ADRC at Baylor College of Medicine and a statistical procedure of profile analysis to assess the initial data for a pattern associated with rapid decline. The findings indicated that despite initial equality of MMSE scores, patients showing rapid MMSE decline at one year displayed significantly more impaired performance on neuropsychological measures at diagnosis. Discussion includes discussion on the use of the MMSE for tracking general cognitive function and the difficulties of ascertaining stable profiles for prediction.
Cerebral Cortex April 2004; 14:410-423
Differential Vulnerability of Anterior White Matter in Nondemented Aging with Minimal Acceleration in Dementia of the Alzheimer Type: Evidence from Diffusion Tensor Imaging
Denise Head, Randy L. Buckner, Joshua S. Shimony, Laura E. Williams, Erbil Akbudak, Thomas E. Conturo, Mark McAvoy, John C. Morris and Abraham Z. Snyder
White matter microstructural integrity was assessed using diffusion tensor imaging (DTI) in 25 young adults, 25 nondemented older adults, and 25 age-matched older adults with dementia of the Alzheimer type (DAT). For each individual, measures of anisotropy and diffusivity were obtained from atlas-transformed images in the anterior and posterior callosum and in the frontal, parietal, temporal and occipital white matter. These data revealed age differences in anisotropy and diffusivity in all assessed regions. Age effects were greater in the anterior as opposed to the posterior corpus callosum and greater in the frontal white matter than in the temporal, parietal and occipital white matter, suggesting age-associated differences in white matter that exhibit a roughly anterior-to-posterior gradient. In contrast, individuals with early-stage dementia exhibited minimal, if any, additional change in anterior regions but did show greater deterioration of white matter in posterior lobar regions. Taken collectively, these results indicate that nondemented aging is characterized by significant changes in white matter most prominently in anterior brain regions. The dissociation between the regional effects of age and dementia status suggests that the mechanisms underlying age-associated cognitive decline are likely distinct from those underlying DAT.
Proceedings of the National Academy of Sciences the week of March 15-19
Metabolite-initiated protein misfolding may trigger Alzheimer's disease
Qinghai Zhang, Evan T. Powers, Jorge Nieva , Mary E. Huff, Maria A. Dendle, Jan Bieschke, Charles G. Glabe, Albert Eschenmoser, Paul Wentworth Jr., Richard A. Lerner, Jeffery W. Kelly
Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify A, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.
Cognitive Therapy for Depression: A Comparison of Individual Psychotherapy and Bibliotherapy for Depressed Older Adults
Mark Floyd ; Forrest Scogin ; Nancy L. McKendree-Smith ; Donna L. Floyd ; Paul D. Rokke
Behavior Modification Volume: 28 Number: 2 Page: 297 -- 318
Abstract: Thirty-one community-residing older adults age 60 or over either received 16 sessions of individual cognitive psychotherapy (Beck, Rush, Shaw, & Emery, 1979) or read Feeling Good (Burns, 1980) for bibliotherapy. Posttreatment comparisons with the delayed-treatment control indicated that both treatments were superior to a delayed-treatment control. Individual psychotherapy was superior to bibliotherapy at posttreatment on self-reported depression, but there were no differences on clinician-rated depression. Further, bibliotherapy participants continued to improve after posttreatment, and there were no differences between treatments at 3-month follow-up. Results suggest that bibliotherapy and that individual psychotherapy are bothviable treatment options for depression in older adults.
Cognitive Behavioral Treatment for Older Adults with Generalized Anxiety Disorder: A Therapist Manual for Primary Care Settings
Melinda A. Stanley ; Gretchen J. Diefenbach ; Derek R. Hopko
Behavior Modification Volume: 28 Number: 1 Page: 73 -- 117
Abstract: At least four academic clinical trials have demonstrated the utility of cognitive behavior therapy (CBT) for older adults with generalized anxiety disorder (GAD). These data may not generalize, however, to more heterogeneous and functionally impaired patients and the medical settings in which they typically receive care. A recent pilot project suggested the potential benefits of a new version of CBT for GAD among older patients in primary care. The manual developed and tested in this pilot project is presented here. Treatment components include motivation and education, relaxation skills, cognitive therapy, problem-solving-skills training, exposure exercises, and sleep-management-skills training. Procedures are designed to be administered flexibly to maximize attentionto individualpatient needs. Examples of session summaries, patient handouts, and homework forms are provided.
Journal of the International Neuropsychological Society (2003), 9, 698-709.
Relationship between positive and negative symptoms and neuropsychological scores in frontotemporal dementia and Alzheimer’ disease
KYLE BRAUER BOONE, BRUCE L. MILLER,
Patients with dementia, particularly those with frontotemporal dementia (FTD), are reported to display marked negative symptoms, including apathy, lack of initiative, and flattened affect, similar to those observed in schizophrenic patients. However, negative symptoms have yet to be formally quantified in an FTD population. Twenty-seven patients with FTD (11 primarily right-sided, 8 primarily left-sided, and 4 symmetric) and 7 patients with Alzheimer’ disease were rated on the Scale for the Assessment of Negative Symptoms, the Positive and Negative Syndrome Scale, and the Emotional Blunting scale. The FTD patients registered significantly more negative symptoms than the Alzheimer’ patients, averaging a threefold increase; groups did not significantly differ in positive symptoms. Negative symptom scale scores were negatively correlated with nonverbal executive skills (23– shared variance), verbal executive skills (up to 25% shared variance) and verbal memory (up to 20% shared variance), but were unrelated to measures of attention, verbal and nonverbal information processing, nonverbal memory, language, and constructional skill. In contrast, positive symptoms were positively correlated with constructional skill (19% shared variance) and attentional scores (15% shared variance). These findings add to the existing literature relating negative symptoms to anterior cerebral hypofunction, and suggest that positive symptoms, at least in this population, may be tied to increased posterior activation.
Scandinavian Journal of Psychology
Volume 45 Issue 2 Page 123 - April 2004
Effects of age and anxiety on episodic memory: Selectivity and variability
Juan Li1,2, Lars-Göran Nilsson2 and Zhenyun Wu3
Li, J., Nilsson, L.-G. & Wu, Z. (2004). Effects of age and anxiety on episodic memory: Selectivity and variability. Scandinavian Journal of Psychology, 45, 123-129.
Selective age-related differences in source memory relative to item memory, and individual differences in memory performance in relation to anxiety were explored with high- and low-anxious subjects screened from normal young and elderly adults. They were read false facts about the locations of well-known and unknown sights in a male or female voice. Intentional and incidental learning instructions were administered for source memory. Selective age-related deficits in source memory were observed under both encoding conditions. Higher level of anxiety was related to lower memory performance only in the old group; this relation was stronger in source recall. The findings suggest that the presence of such selectivity is unrelated to the tradeoff between item encoding and source encoding. Anxiety affects the variability, and mediates the selectivity of age effects on episodic memory.
Emotional Support From Parents Early in Life, Aging, and Health
Benjamin A. Shaw, Neal Krause, Linda M. Chatters, Cathleen M Connell, and Berit Ingersoll-Dayton
Psychology and Aging, 2004, Vol. 19, No. 1, 4–12
The purpose of this study is to estimate the relationship between receiving emotional support from parents early in life and an individual's health in adulthood. Analysis of data from a nationally representative sample of adults ages 25–74 years suggests that a lack of parental support during childhood is associated with increased levels of depressive symptoms and chronic conditions in adulthood. These associations between early parental support and adult health persist with increasing age throughout adulthood. Personal control, self-esteem, and social relationships during adulthood account for a large portion of these long-term associations. These findings underscore the importance of adopting a life course perspective in studying the social determinants of health among adults.
A Meta-Analytic Review of Prospective Memory and Aging
Julie D. Henry, Mairi S. MacLeod, Louise H. Phillips, and John R. Crawford
Psychology and Aging, 2004, Vol. 19, No. 1, 27–39
A meta-analysis of prospective memory (PM) studies revealed that in laboratory settings younger participants outperform older participants on tests of both time- and event-based PM (rs = -.39 and -.34, respectively). Event-based PM tasks that impose higher levels of controlled strategic demand are associated with significantly larger age effects than event-based PM tasks that are supported by relatively more automatic processes (rs = -.40 vs. -.14, respectively). However, contrary to the prevailing view in the literature, retrospective memory as measured by free recall is associated with significantly greater age-related decline (r = –.52) than PM, and older participants perform substantially better than their younger counterparts in naturalistic PM studies (rs = .35 and .52 for event- and time-based PM, respectively).
Toward an Alternative Representation for Disentangling Age-Associated Differences in General and Specific Cognitive Abilities
Florian Schmiedek and Shu-Chen Li
Psychology and Aging, 2004, Vol. 19, No. 1, 40–56
Much of cognitive aging research concerns whether age-associated differences in various cognitive performances can be accounted for by general explanatory constructs or whether several specific processes are involved. Structural equation models have been proposed to disentangle general and specific age-associated differences in cognitive performance. This article demonstrates that existing methods that employ stepwise procedures run the risk of biasing results toward general resource accounts. An alternative model representation (i.e., the nested factor model) is proposed that affords simultaneous estimation of general and specific effects and is applied to data from the Berlin Aging Study. Using the nested factor model allowed the authors to detect that specific group factors explained 25% of the age-associated variance in addition to the general factor.
Change in Cognitive Capabilities in the Oldest Old: The Effects of Proximity to Death in Genetically Related Individuals Over a 6-Year Period
Boo Johansson, Scott M. Hofer, Jason C. Allaire, Mildred M. Maldonado-Molina, Andrea M. Piccinin, Stig Berg, Nancy L. Pedersen, Gerald E. McClearn
Psychology and Aging, 2004, Vol. 19, No. 1, 145–156
Change in cognitive abilities was assessed over a 6-year period in a sample of monozygotic and same-sex dizygotic twin pairs (N = 507 individuals), aged 80 and older (mean age = 83.3 years; SD = 3.1), who remained nondemented over the course of the study. Latent growth models (LGMs) show that chronological age and time to death are consistent predictors of decline in measures of memory, reasoning, speed, and verbal abilities. Multivariate LGM analysis resulted in weak and often negative correlations among rates of change between individuals within twin pairs, indicating greater differential change within twin pairs than occurs on average across twin pairs. These findings highlight several challenges for estimating genetic sources of variance in the context of compromised health and mortality-related change.
Age-Related Differences in Localized Attentional Interference
Jason S. McCarley, Jeffrey R. W. Mounts, Arthur F. Kramer
Psychology and Aging, 2004, Vol. 19, No. 1, 203–210
Attentional selection of an object in the visual field degrades processing of neighboring stimuli in young adults. A pair of experiments examined the effects of aging on such localized attentional interference. In Experiment 1, younger and older observers made speeded same–different judgments of target shapes that varied in spatial separation. Performance declined for both age groups as the distance between targets decreased, but an Age × Distance interaction indicated that the magnitude of this effect was larger for older adults. Experiment 2 ruled out sensory masking as an explanation for these findings. Results indicate that older observers experience losses in the ability to attend to multiple spatially proximal stimuli within the visual field
Aging and the Perception of Biological Motion
J. Farley Norman and Sharon M. Payton, Jennifer R. Long, Laura M. Hawkes
Psychology and Aging, 2004, Vol. 19, No. 1, 219–225
Two experiments examined how observers' ability to perceive biological motion changes with increasing age. The observers discriminated among kinetic figures, depicting walking, jogging, and skipping. The direction, duration, and temporal correspondence of the motions were manipulated. Quantitative differences occurred between the recognition performances of younger and older observers, but these differences were often modest. The older and younger observers' performances were comparable for most conditions at stimulus durations of 400 ms. The older observers also performed well above chance at shorter durations of 240 and 120 ms. Unlike their performance on other 2- or 3-dimensional motion tasks, older observers' ability to perceive biological motion is relatively well preserved.
The Role of Primary and Secondary Control in Adaptation to Age-Related Vision Loss: A Study of Older Adults With Macular Degeneration
Hans-Werner Wahl, Stefanie Becker, David Burmedi, and Oliver Schilling
Psychology and Aging, 2004, Vol. 19, No. 1, 235–239
This study examines the effect of primary and secondary control on 3 major outcomes experienced by visually impaired older adults, that is, functional ability, adaptation to vision loss, and positive affect. The authors' theoretical model is based on the J. Heckhausen and R. Schulz (1995) control framework, as well as a conceptual integration of these outcomes, and they hypothesized that control beliefs can substantially contribute to explaining interindividual differences in these outcomes. A path model applied to data from a sample (N = 90) of visually impaired older adults, suffering from age-related macular degeneration, the major cause of vision loss in old age, generally supports this expectation.
Physiology & Behavior
Volume 80, Issue 4 , January 2004, Pages 515-524
Correlation between driving errors and vigilance level: influence of the driver's age
Aurelie Campagne, Thierry Pebayle and Alain Muzet
During long and monotonous driving at night, most drivers progressively show signs of visual fatigue and loss of vigilance. Their capacity to maintain adequate driving performance usually is affected and varies with the age of the driver. The main question is to know, on one hand, if occurrence of fatigue and drowsiness is accompanied by a modification in the driving performance of the driver and, on the other hand, if this relationship partially depends on the driver's age. Forty-six male drivers, divided into three age categories: 20–30, 40–50, and 60–70 years, performed a 350-km motorway driving session at night on a driving simulator. Driving errors were measured in terms of number of running-off-the-road incidents (RORI) and large speed deviations. The evolution of physiological vigilance level was evaluated using electroencephalography (EEG) recording. In older drivers, in comparison with young and middle-aged drivers, the degradation of driving performance was correlated to the evolution of lower frequency waking EEG (i.e., theta). Contrary to young and middle-aged drivers, the deterioration of the vigilance level attested by EEG correlated with the increase in gravity of all studied driving errors in older drivers. Thus, depending on the age category considered, only part of the driving errors would constitute a relevant indication as for the occurrence of a state of low arousal.