The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile.

OBJECTIVES: The aim of the study was to examine baseline neurocognitive impairment (NCI) prevalence and factors associated with NCI among patients enrolled in the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. METHODS: The NAMACO study is an ongoing, prospective, longitudinal, multicentre and multilingual (German, French and Italian) study within the Swiss HIV Cohort Study. Between 1 May 2013 and 30 November 2016, 981 patients ≥ 45 years old were enrolled in the study. All underwent standardized neuropsychological (NP) assessment by neuropsychologists. NCI was diagnosed using Frascati criteria and classified as HIV-associated or as related to other factors. Dichotomized analysis (NCI versus no NCI) and continuous analyses (based on NP test z-score means) were performed. RESULTS: Most patients (942; 96.2%) had viral loads < 50 HIV-1 RNA copies/mL. NCI was identified in 390 patients (39.8%): 263 patients (26.8%) had HIV-associated NCI [249 patients (25.4%) had asymptomatic neurocognitive impairment (ANI)] and 127 patients (13%) had NCI attributable to other factors, mainly psychiatric disorders. There was good correlation between dichotomized and continuous analyses, with NCI associated with older age, non-Caucasian ethnicity, shorter duration of education, unemployment and longer antiretroviral therapy duration. CONCLUSIONS: In this large sample of aging people living with HIV with well-controlled infection in Switzerland, baseline HIV-associated NCI prevalence, as diagnosed after formal NP assessment, was 26.8%, with most cases being ANI. The NAMACO study data will enable longitudinal analyses within this population to examine factors affecting NCI development and course.

A Novel Study Paradigm for Long-term Prevention Trials in Alzheimer Disease: The Placebo Group Simulation Approach (PGSA): Application to MCI data from the NACC database.

INTRODUCTION: The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. METHODS: Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. RESULTS: The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. CONCLUSION: An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.

Quantitative EEG and apolipoprotein E-genotype improve classification of patients with suspected Alzheimer's disease.

OBJECTIVE: To establish a model for better identification of patients in very early stages of Alzheimer's disease, AD (including patients with amnestic MCI) using high-resolution EEG and genetic data. METHODS: A total of 26 patients in early stages of probable AD and 12 patients with amnestic MCI were included. Both groups were similar in age and education. All patients had a comprehensive neuropsychological examination and a high resolution EEG. Relative band power characteristics were calculated in source space (LORETA inverse solution for spectral data) and compared between groups. A logistic regression model was calculated including relative band-power at the most significant location, ApoE status, age, education and gender. RESULTS: Differences in the delta band at 34 temporo-posterior source locations (p<.01) between AD and MCI groups were detected after correction for multiple comparisons. Classification slightly increased when ApoE status was added (p=.06 maximum likelihood test). Adjustment of analyses for the confounding factors age, gender and education did not alter results. CONCLUSIONS: Quantitative EEG (qEEG) separates between patients with amnestic MCI and patients in early stages of probable AD. Adding information about Apo ε4 allele frequency slightly enhances diagnostic accuracy. SIGNIFICANCE: qEEG may help identifying patients who are candidates for possible benefit from future disease modifying treatments.

[Consensus 2012--diagnosis and treatment of patients with dementia in Switzerland]. / Consensus 2012 sur le diagnostic et le traitement des patients atteints de démence en Suisse.

The 2012 Swiss consensus paper on diagnosis and management of patients suffering from dementia resulted from the work of an expert panel who met on March 23d to 25th in Luzem. Based on a literature review, panel members wrote a first draft that was subsequently circulated among multiple dementia experts in Switzerland. After adaptation and revisions according to comments, all consulted dementia specialists and panel members fully endorse the consensus content. The conference was financed by the Swiss Alzheimer Forum.

[Consensus recommendations for the assessment of fitness to drive in cognitively impaired patients]. / Konsensusempfehlungen zur Beurteilung der medizinischen Mindestanforderungen für Fahreignung bei kognitiver Beeinträchtigung.

Memory Clinics provide evidence based diagnosis and treatment of dementia. Whenever a diagnosis of dementia is made, it is important to inform the patients about the possible impact of dementia on driving. Patients and their next of kin require competent advice whenever this difficult question is addressed and the mobility desire and the risks related to driving need to be carefully weight up. The time of diagnosis does not necessarily equate to the time when a person with dementia becomes an unsafe driver. The cause and severity of dementia, comorbidities and the current medication need to be carefully taken into account for this decision. On behalf of the association of the Swiss Memory Clinics, a group of experts has developed recommendations to assess fitness to drive in cognitively impaired older adults.

Turning principles into practice in Alzheimer's disease.

The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most important aspects and challenges of dementia diagnosis and treatment. These issues are reviewed in light of the six principles of the recent ADI Charter: promoting dementia awareness and understanding; respecting human rights; recognizing the key role of families and caregivers; providing access to health and social care; stressing the importance of optimal diagnosis and treatment; and preventing dementia through improvements in public health. The authors continue to hope that, one day, a cure for Alzheimer's disease will be found. Meanwhile, healthcare professionals need to unite in rising to the challenge of managing all cases of dementia, using the tools available to us now to work toward improved patient care.

Neuropsychological dysfunction, depression, physical disability, and coping processes in families with a parent affected by multiple sclerosis.

BACKGROUND: Families with a parent suffering from multiple sclerosis (MS) must cope with the unpredictable course of the disease. Most studies analyzing factors that influence coping abilities in families with a member affected with MS used questionnaires to assess this ability. METHODS: On the contrary, the present study used a semi-structured psychiatric interview and used the resulting information to calculate a general measure of coping ability (coping index [CI]). We administered this interview to 44 MS patients, their partners and offspring and conducted a neuropsychological and physical evaluation of the patients to determine the impact of physical disability, cognitive dysfunction, and depression on the process of coping by the patient, the healthy partner, and children. RESULTS: The CI of patients was best predicted by measures of their depressive symptoms, divided attention, and estimated verbal intelligence. None of the patient variables predicted the CI of healthy partners or their offspring. We found an association between the CI of the healthy partner and the children. CONCLUSIONS: These findings suggest that MS patients' emotional and neuropsychological functions are associated with their ability to cope with the disease. These should be carefully assessed at the beginning of treatment so that those factors known to negatively influence patient coping are targeted in the treatment plan if necessary. Comprehensive care of a patient with MS should include support of coping abilities of the family members.

[Mild cognitive impairment with predictors of rapid decline]. / Leichte kognitive Beeinträchtigung mit Vorzeichen rascher Verschlechterung.

Half the patients with mild cognitive impairment (MCI) will develop dementia over a four-year period. The scientific literature was searched and analysed for predictors of rapid decline (MCI-plus) in patients with MCI. The most important predictors of fast cognitive deterioration were found to be: old age, previous rapid decline, severity and multiplicity of cognitive deficits, somatic co-morbidity, vascular and Alzheimer-type changes in the brain, Alzheimer-type cerebrospinal fluid findings and apolipoprotein E4 polymorphism. Many patients with MCI suffer from anxiety, depression or apathy and subtle, but subjectively significant, difficulties in the activities of daily living. It is concluded that MCI-plus offers a window for medical and psychological prophylaxis and rehabilitation.

Evaluation of diagnostic scores with adjustment for covariates.

Diagnostic tests yield measurements on very different types of scales. Quantitative scales may consist of non-negative integers, either unbounded or bounded, with a fixed number of different values, or they may consist of continuous or percentage values. Remembering a different threshold value for each diagnostic variable would be cumbersome, in particular if covariates have to be taken into account. As a convenient way to overcome such problems we propose to compute z-scores for all measurements. They will be adjusted for covariates so that any individual can be judged on any test result on one single scale with an appropriate standard normal quantile as threshold. Two issues need to be addressed: Selection of covariates in the regression model which delivers the adjustment and normality of the residuals. The first will be treated by cross-validation and the latter by applying an appropriate transformation. We apply this methodology to neuropsychological tests and adjust for age, length of education and sex. Normality of residuals is needed on the diagnostically relevant side only. This allows to use parametric transformations, which can be easily implemented, e.g. in database systems. Since we have measurements at baseline and at follow-up we also analyze change values in a similar manner. For ease of interpretation, we transform the resulting z-scores back to the original scale.

Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

BACKGROUND: Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer's disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. OBJECTIVE: To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). METHODS: 93 patients with mild Alzheimer's disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. RESULTS: The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. CONCLUSIONS: In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.

Frontotemporal dementia, semantic dementia, and Alzheimer's disease: the contribution of standard neuropsychological tests to differential diagnosis.

CERAD-NAB (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer's disease. There were statistically significant differences between the 3 groups. Compared with patients with Alzheimer's disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer's disease. Multiple logistic regression analysis revealed that in the differentiation between frontotemporal dementia and Alzheimer's disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer's disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. These findings demonstrate that the Mini Mental State Examination and the language subtests of the CERAD-NAB are valuable clinical instruments for the differential diagnosis between early frontotemporal dementia, semantic dementia, and Alzheimer's disease.

Weight change and cognitive performance.

OBJECTIVE: To investigate whether under- or overweight and weight change is associated with cognitive performance of elderly citizens. DESIGN: Explorative analysis out of the Basel Study cohort. SUBJECTS: In all, 531 healthy subjects (445 men/86 women) were assessed with the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB) in 2000 (age: 69.4+/-7.8 y) and weight measurements obtained in 1990 (body mass index (BMI): 25.2+/-3.1 kg/m(2)) and in 2000 (BMI: 25.6+/-3.4 kg/m(2)). METHODS: The predictive power of the annual change in BMI with cognitive performance was investigated by a binary logistic regression analysis (backward) using sex, age, BMI 1990, BMI 2000, diastolic blood pressure, diabetes status, and optimal health status as additional predictors. RESULTS: In the last step, the following variables remained in the model: annual change in BMI (quadratic term; P<0.01); ApoE genotype (P<0.05); and optimal health status (P<0.01). CONCLUSION: The association between the extent of weight change and poorer cognitive performance could be either a consequence of cognitive impairment or an early symptom of neurodegenerative decline.

Apolipoprotein E3Basel: new insights into a highly conserved protein region.

BACKGROUND: Apolipoprotein E is important for the receptor-mediated uptake of triglyceride-rich lipoproteins. Mutations in the gene encoding apolipoprotein E may cause a reduced uptake of these lipoproteins. Particular apolipoprotein E mutations have been also found to be associated with nephrologic, neurologic, and even ophthalmologic diseases. Hence, a continuously expanding role in biology is being attributed to this protein. DESIGN: Randomly selected volunteers from of a large Swiss cohort were genotyped for the common apolipoprotein E isoforms (apolipoprotein E2, apolipoprotein E3, apolipoprotein E4). RESULTS: In one of the volunteers, a novel C-to-T mutation causing an alanine-to-valine substitution (A106V, designated apolipoprotein E3Basel) was discovered. Alanine at residue 106 is highly conserved between mammalian species and is located in the immediate vicinity of the 112C/R polymorphism (apolipoprotein E4). Recombinant apolipoprotein E3Basel, expressed in the baculovirus system, displayed no detectable reduction in its low density lipoprotein (LDL) receptor- and heparin-binding activities. Despite normal binding functions, apolipoprotein E3Basel might cause modifications in the lipoprotein pattern. In the index case, plasma triglycerides were elevated and in two further apolipoprotein E3Basel-carriers, cholesterol, phospholipid, apolipoprotein CIII levels, LDL-cholesterol/apoB-100- and VLDL-triglyceride/VLDL-cholesterol-ratios were higher compared with apolipoprotein E3Basel-noncarriers when pair-matched for age and gender. One of the four apolipoprotein E3Basel-carriers from the index family had a personal history of Alzheimer's disease. CONCLUSIONS: Alanine at amino acid position 106 is highly conserved but not crucial in the receptor-mediated uptake of lipoprotein particles. Nevertheless, amino acid position 106 might be involved in the apolipoprotein E-dependent regulation of the lipoprotein lipase that hydrolyzes triglycerides and in the development of Alzheimer's disease.

[German-speaking memory clinics: state of the art and practical recommendations]. / Erkennung und Behandlung der Demenz in den deutschsprachigen Memory-Kliniken: Empfehlungen für die Praxis.

The 7th annual meeting of the memory clinics of Germany, Switzerland and Austria in March 2002 in Göttingen, Germany was an optimal opportunity to make an inventory about the state of the art in diagnostic and therapy of dementia and mild cognitive impairment in German-speaking memory clinics. Several problems were discussed including difficulties in 1) diagnosis of patients with aphasia or foreign patients, 2) handling of demented patients without a caregiver, 3) psychological support for patients, who have been diagnosed in a very early stage, 4) misunderstandings between general practitioners, neurologists and psychiatrists in private practice on the one hand and the memory clinics on the other hand, 5) recommendations for prevention of dementia, 6) recommendations concerning dementia and car driving and 7) questions of genetic counselling. The following paper is a summary of the results of a workshop in Göttingen and gives practical recommendations based on the experiences of the memory clinics.

Normal ranges of neuropsychological tests for the diagnosis of Alzheimer's disease.

The diagnosis of early stage dementia is a highly complex process involving not only a somatic examination but also a neuropsychological assessment of the patient's cognitive capability. The American 'Consortium to Establish a Registry for Alzheimer's Disease' (CERAD) has proposed a set of tests in English which has been translated into German. This paper presents the statistical methodology applied to determine normal ranges adjusted for demographic variables for the German CERAD neuropsychological assessment battery (CERAD-NAB). The study population consists of participants of the Basel Study on the Elderly (Project BASEL) which aims at identifying preclinical markers of Alzheimer's disease. The normative sample has been defined by carefully excluding potentially relevant medical history and concomitant diseases and consists of 617 participants which are between 53 and 92 years old. Test results should be adjusted for gender, age, and years of education. For this purpose, a set of linear models including these predictors and subsets of their interactions and squares was evaluated for all 11 test scores derived from the CERAD-NAB battery. Model selection was based on the PRESS (predicted residual sum of squares) statistic. Although a strict application of this criterion selected 6 different models, a slight compromise allowed to fit all test scores by two models. In several tests of the CERAD-NAB many participants achieve maximal scores. Residuals of such test scores are heavily skewed. An arcsine transformation has been tuned to the data, so that residuals are close to a normal distribution, at least for residuals in the lower quartile which is relevant in diagnosing cognitive impairment. Test results are finally presented as z-scores which can be easily compared to a standard normal distribution. The evaluation of the CERAD-NAB is implemented on the Internet and in an Excel application.

Assessment of dementia in elderly outpatients: a comparative study of European centers and consensus statement.

Large numbers of elderly patients, suspected of having dementia, need medical evaluation, often in early phases of their illness. A complete outpatient assessment clearly could be advantageous. Thirty-five centers from 15 European countries, known to their scientific gerontological and geriatric societies to have experience in outpatient care for elderly patients with dementia, participated in an effort to develop a consensus statement for the assessment needs of these patients. The comparison of the centers showed that a wide variety of approaches was currently in practice. Differences appeared to be mainly based on local facilities and organization. A consensus for diagnostic outpatient assessment was easily reached. Diagnosis should be based on DSM-IV criteria, which requires a standardized assessment (including neuropsychological, functional and technical evaluation) and should be multidisciplinary. An assessment of dementia of elderly outpatients appears to be very feasible - a consensus approach with minimum diagnostic requirements is presented.

[Argyrophilic grain disease: differentiation from Alzheimer disease]. / Die Silberkornkrankheit--Abgrenzung zur Alzheimer'schen Erkrankung.

Argyrophilic grain disease (AgD) constitutes one cause of late onset dementia and is histologically characterized by the presence of abundant argyrophilic grains and coiled bodies. Both abnormalities are found mainly in limbic structures, among them the sector CA1 of the hippocampus, the entorhinal cortex, and the amygdala. Using appropriate silver staining techniques, they are easily detectable and can easily be distinguished from neurofibrillary lesions of Alzheimer's disease (i.e., tangles and threads). Although the histopathology of AgD is well characterized, the nosological status is still unclear because most cases of AgD are associated with Alzheimer-type changes. For some authors, therefore, AgD is considered a variant of Alzheimer's disease rather than a distinct disease entity. The present review is aimed at presenting argyrophilic grain disease to a larger readership than just neuropathologists who are interested in neurodegenerative disorders. In this review we summarize morphological, immunohistochemical, clinico-pathological and genetic data obtained in more than 90 subjects with AgD. The main conclusions of this review are that AgD represents one of the most frequent, dementing disorders of old age and that it has to be clearly distinguished from Alzheimer's disease.