Single-domain amnestic mild cognitive impairment identified by cluster analysis predicts Alzheimer's disease in the european prospective DESCRIPA study.

BACKGROUND/AIMS: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). METHODS: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. RESULTS: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aß42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. CONCLUSION: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.

Multi-center comparison of medial temporal atrophy in patients with Alzheimer's disease--data from the ICTUS study.

OBJECTIVE: To study multi-center variability of medial temporal lobe atrophy (MTA) in patients with Alzheimer's disease (AD) recruited in a European observational study of AD. METHODS: 117 mild to moderate AD patients from 5 European centers (Amsterdam, The Netherlands; Brescia and Genova, Italy; Mannheim, Germany; Pamplona, Spain) had magnetic resonance imaging scans performed as part of the routine diagnostic examination. MTA was assessed with the visual Scheltens scale. RESULTS: AD patients from Brescia, Genova, Pamplona, and Mannheim had a mean 32% prevalence of no or borderline MTA vs. 62% of patients from Amsterdam (p = 0.002 for the difference between Amsterdam and all the other centers). The peculiar distribution of MTA in the Amsterdam patients may be attributable to younger age (70.7 +/- 8.4 vs. 75.3 +/- 6.8 years, p = 0.002), milder dementia severity (score 0.5 on the clinical dementia rating scale: 52 vs. 23%, p = 0.003), and less frequent depression (14 vs. 49%, p < 0.0005 in Amsterdam vs. all the other centers, respectively). CONCLUSION: Patients with probable AD recruited in different centers of Europe generally have similar MTA distribution, even if peculiar demographic and clinical findings might explain occasional differences. These results have implications for clinical trials in AD with biological markers as outcome measures.

Development of a Proxy-Free Objective Assessment Tool of Instrumental Activities of Daily Living in Mild Cognitive Impairment Using Smart Home Technologies.

BACKGROUND: The assessment of activities of daily living (ADL) is essential for dementia diagnostics. Even in mild cognitive impairment (MCI), subtle deficits in instrumental ADL (IADL) may occur and signal a higher risk of conversion to dementia. Thus, sensitive and reliable ADL assessment tools are important. Smart homes equipped with sensor technology and video cameras may provide a proxy-free assessment tool for the detection of IADL deficits. OBJECTIVE: The aim of this paper is to investigate the potential of a smart home environment for the assessment of IADL in MCI. METHOD: The smart home consisted of a two-room flat equipped with activity sensors and video cameras. Participants with either MCI or healthy controls (HC) had to solve a standardized set of six tasks, e.g., meal preparation, telephone use, and finding objects in the flat. RESULTS: MCI participants needed more time (1384 versus 938 seconds, p <  0.001) and scored less total points (48 versus 57 points, p <  0.001) while solving the tasks than HC. Analyzing the subtasks, intergroup differences were observed for making a phone call, operating the television, and retrieving objects. MCI participants showed more searching and task-irrelevant behavior than HC. Task performance was correlated with cognitive status and IADL questionnaires but not with participants' age. CONCLUSION: This pilot study showed that smart home technologies offer the chance for an objective and ecologically valid assessment of IADL. It can be analyzed not only whether a task is successfully completed but also how it is completed. Future studies should concentrate on the development of automated detection of IADL deficits.

Optimized neuropsychological procedures at different stages of dementia diagnostics.

OBJECTIVE: To establish a staged procedure in dementia diagnostics and to propose specific, abbreviated test batteries suitable for the three diagnostic stages: Primary medical care, neuro-psychiatry, and memory clinic. METHODS: A total of 159 participants underwent comprehensive clinical, neurological, neuropsychological, and MRI examinations. The neuropsychological examination took approximately 90 min per individual and was based on tests of verbal and visual memory, language, abstract thinking, attention, visuo-constructive and spatial functions. Stepwise discriminant analyses were performed to identify which subset of the 18 variables of the comprehensive test battery was the most appropriate to differentiate between specific diagnostic groups, and which variables could be discarded to abbreviate the test battery without substantial loss in diagnostic accuracy. RESULTS: The abbreviated versions of the test battery retained adequate diagnostic accuracy. The accuracy decreased by maximally 4%, whereas the test administration time dropped substantially from previously 90 min to a maximum of 50 min. CONCLUSION: Depending on the diagnostic question, a specifically abbreviated version of the comprehensive test battery can be used without unacceptably reducing diagnostic accuracy.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.

Efficacy and cognitive side effects of electroconvulsive therapy (ECT) in depressed elderly inpatients with coexisting mild cognitive impairment or dementia.

OBJECTIVE: To study cognitive performance in depressed geriatric inpatients with or without preexisting cognitive impairment who received a first course of electroconvulsive therapy (ECT). METHOD: Forty-four elderly inpatients with major depressive disorder (ICD-10 criteria) were included in a prospective consecutive case series of a university hospital. The patients were divided into 3 groups (no cognitive impairment [NCI], mild cognitive impairment [MCI], dementia) and rated for cognitive performance with the MMSE before first ECT, after sixth ECT, and 6 weeks and 6 months after ECT termination. Affective symptoms were rated by 21-item Hamilton Depression Rating Scale (HDRS-21) before and 6 weeks after ECT. Analysis of variance or Kruskal-Wallis tests on ECT-induced MMSE and HDRS-21 score changes were compared to baseline. Binary logistic regression was used for predictor analysis. The study was conducted from April 2004 to April 2008. RESULTS: After initial nonsignificant cognitive deterioration in all 3 groups, the NCI group improved cognitively 6 weeks (P = .018) and 6 months (P = .027) after ECT. The MCI group improved in cognition 6 months (P = .036) after ECT. In the dementia group, mean MMSE scores also improved numerically over the course of ECT without significance. Dementia patients with antidementia treatment improved in cognition to a clinically relevant extent after the sixth ECT. Dementia subjects without antidementia treatment deteriorated. After the sixth ECT, 70.0% of dementia patients (P = .004) presented a cognitive decline, and 68.8% of MCI patients (P < .001) presented a decline 6 weeks after ECT. Six months after ECT, one-third of the dementia patients (P < .036) still had a cognitive decline. Affective symptoms remitted after ECT in all 3 groups (P < .001). Pre-ECT cognitive deficits were the best predictor of MMSE decline (6 weeks after ECT, P = .007; 6 months after ECT, P = .055). CONCLUSIONS: ECT is effective and well tolerated in geriatric depressed inpatients regardless of preexisting cognitive impairment. Cognitive deficits were transient.

[Optimised neuro-psychological tests on different stages of dementia diagnostics]. / Optimierte neuropsychologische Verfahren für unterschiedliche Ebenen der Demenzdiagnostik.

OBJECTIVE: We postulated three level of dementia diagnostics: the general practitioner, the neuro-psychiatrist and the memory clinic. For each level, definite diagnostic questions were defined as the main diagnostic focus. The aim was to establish a staged process in dementia diagnostics, proposing for each diagnostic level a specific test battery suitable for the respective diagnostic focus. On each level, the test battery can be supplemented by other tests proposed on the subsequent diagnostic level. METHOD: 159 patients were examined clinically, neuropsychologically, and neuroradiologically. Discriminant analyses were computed to find out which tests out of a comprehensive test battery are most suitable in differentiating between several diagnostic groups. RESULTS: The diagnostic accuracy of the test batteries proposed for general practitioners and neuro-psychiatrists were maximally 3 % below that of the complete test battery which we suggest for memory clinics. CONCLUSION: Depending on the diagnostic level, a definite short form of a comprehensive test battery can be implemented without unacceptably reducing diagnostic accuracy.

SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in cholesterol and fatty acid synthesis. Recently, a polymorphism in the 5'-region of the SREBP-1a gene has been described to be correlated with alterations in the plasma levels of cholesterol. Consequently the relationship between this SREBP-1a gene polymorphism and Alzheimer's disease (AD) alone and in combination with the apolipoprotein E (ApoE) 4 allele was evaluated. No association between SREBP-1a polymorphism alone and AD could be seen. However, in the group of healthy ApoE4 allele carriers, the number of homozygote SREBP-1a DeltaG allele carriers was significantly higher than in AD patients. Cerebrospinal fluid levels of cholesterol were lower in AD patients who were carriers of the SREBP-1a DeltaG allele, and the ratio of 24S-hydroxycholesterol to cholesterol was increased in these probands. Our data suggest a reduced risk of AD in carriers of an ApoE4 allele who are additionally homozygous for the SREBP-1a DeltaG allele, which is possibly due to the influence of SREBP-1a polymorphism on brain cholesterol metabolism. This is the first report on a genetic factor which prevents the deleterious effect of the ApoE4 allele and thus reduces the risk of AD.