[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.

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.

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.

Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type.

The performances of 89 patients with dementia of the Alzheimer type (DAT) and 53 demographically matched elderly normal control subjects were compared on four verbal fluency measures (category, letter, first names, and supermarket fluency). Receiver operating characteristic curves were plotted to determine each fluency tasks' sensitivity (ie, true-positive rate) and specificity (ie, true-negative rate). Category fluency demonstrated the greatest degree of discrimination between patients with DAT and normal control subjects (sensitivity, 100%; specificity, 92.5%); letter fluency was the least accurate (sensitivity, 89%; specificity, 85%). Separation of patients with DAT by gender revealed similar findings. In further analyses with a subgroup of 21 mildly impaired patients with DAT, category fluency lost none of its discriminative capabilities, whereas all other fluency measures showed marked reductions in discriminability. We conclude that this superiority of category fluency is due to its dependence on the structure of semantic knowledge, which deteriorates in the early stages of DAT.

Folstein vs modified Mini-Mental State Examination in geriatric stroke. Stability, validity, and screening utility.

OBJECTIVE: Two studies were conducted with the Folstein Mini-Mental State Examination (MMS) and the Modified Mini-Mental State Examination (3MS) to examine whether the expanded version is a more useful screening tool in stroke populations. DESIGN: Clinical utility of screening tests (MMS and 3MS) was evaluated in reference to neuropsychological performance and functional outcome in rehabilitation. SETTING: Medical rehabilitation unit of university-affiliated hospital. PATIENTS: Two groups (n = 77, and n = 70) of patients who were admitted consecutively. MAIN OUTCOME MEASURES: Neuropsychological performance and functional outcome (functional independence measure). RESULTS: The reliability, stability, and validity of the 3MS were established in the stroke population. Classification accuracy did not differ between the MMS and 3MS, although the 3MS had higher sensitivity. In detecting cognitive impairment when compared with the extended neuropsychological battery, both instruments were adequate in patients with left-sided cerebrovascular accidents and were ineffective in patients with right-sided cerebrovascular accidents. The 3MS correlated with some cognitive domains missed by the MMS, thus adding useful clinical information. Finally, the 3MS was a significantly better predictor of functional outcome than the MMS. CONCLUSIONS: The 3MS was found to be a reliable, valid, and stable cognitive screening instrument in the stroke population. Classification accuracy indicates that both screening instruments are not strong in their ability to detect cognitive impairment in patients with stroke, especially in right-sided cerebrovascular accidents. The 3MS does have some advantages over the MMS; the expanded version of the screen not only provides additional cognitive information but also allows for better predicting of functional outcome.

Clinical validity of the Mattis Dementia Rating Scale in detecting Dementia of the Alzheimer type. A double cross-validation and application to a community-dwelling sample.

OBJECTIVE: To assess the clinical validity of the Dementia Rating Scale (DRS) in detecting patients with dementia of the Alzheimer type (DAT). BACKGROUND: The DRS is widely used to evaluate cognitive functioning in older adults. Adequate normative data are unavailable; studies addressing the clinical validity of the DRS are limited by small sample sizes. DESIGN AND METHODS: Administered the DRS to 254 outpatients with DAT and 105 healthy elderly subjects. Performed (1) multiple regressions of demographic factors on the DRS and its subscales; (2) derivation of optimal DRS cutoff scores using receiver operating characteristic curves; (3) double cross-validation with stepwise logistic regressions; and (4) application of results to a community-dwelling sample. RESULTS: Age- and education-adjusted DRS scores were computed. The optimal DRS cutoff score for DAT of 129 or less revealed a sensitivity of 98% and a specificity of 97%. The logistic regressions resulted in a combination of the Memory and Initiation/Perseveration subscales that correctly classified 98% of all subjects, 92% of a subsample of 76 patients with mild DAT, and 100% of the 51 patients with autopsy-confirmed DAT. The resultant equation was then applied to a community-dwelling sample (238 healthy elderly subjects and 44 patients with DAT): 91% of patients and 93% of normal subjects were correctly classified. Of an additional 77 individuals with questionable DAT, 43 were classified as demented and 34 were classified as nondemented. CONCLUSIONS: The DRS is a clinically valid psychometric test for the detection of DAT. The Memory and Initiation/Perseveration subscales are its best discriminative indexes for an abbreviated version.

Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults.

OBJECTIVE: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE-epsilon 4). BACKGROUND: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE-epsilon 4 allele. METHODS: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n = 17) or absence (n = 35) of one or two APOE-epsilon 4 alleles. RESULTS: APOE- epsilon 4 and non-epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE-epsilon 4 subjects demonstrated significantly poorer mean performances than non-epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 < p < 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE-epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non-epsilon 4 subjects who received follow-up demonstrated any cognitive decline. CONCLUSIONS: Results suggest that episodic memory changes in older adults are associated with APOE-epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT.

Random number generation in dementia of the Alzheimer type: a test of frontal executive functions.

The quality of attempts at generating a random sequence of the numbers 1-6 was studied in 30 patients with dementia of the Alzheimer type (DAT) and 30 elderly normal control (NC) subjects. Three main findings emerged: (1) DAT patients' subjective random sequences were more streotyped (contained fewer digit combinations) than those of NC subjects. (2) This difference in response stereotypy was due to patients' enhanced tendency to arrange consecutive numbers in an ascending series ('counting bias'). (3) In the patient group, degree of sequential nonrandomness was positively correlated with overall severity of dementia and with the extent to which performance on neuropsychological tests specifically assessing executive functions (fluency, naming, error monitoring) was impaired. These results illustrate a loss of behavioral complexity in the course of dementia and are interpreted as reflecting a frontal dysexecutive syndrome in DAT.

Screening for dementia of the alzheimer type in the community: the utility of the Clock Drawing Test.

This study reports the sensitivity and specificity of the Clock Drawing Test (CDT) for detecting dementia of the Alzheimer type in a community-dwelling sample of elderly subjects. Forty-two patients with clinically diagnosed Alzheimer's disease and 237 cognitively intact subjects were administered the CDT as part of an epidemiological study of aging and dementia. Three individual measures of clock drawing performance (quantitative score, qualitative score, and combined quantitative and qualitative score) were determined for each participant. When qualitative elements such as errors and strategies were incorporated into the CDT score, the sensitivity was 84% and the specificity was 72%. The findings suggest that a CDT score which evaluates qualitative and quantitative features provides reasonably good discrimination between normal elderly individuals and DAT patients. However, the CDT appears to have limited utility as a single screening instrument in the community. Instruments such as the Dementia Rating Scale (Mattis, 1976) provide better discrimination of DAT, indicating that functions such as memory and verbal fluency need to be assessed during screening.

Unawareness of smell loss in normal aging and Alzheimer's disease: discrepancy between self-reported and diagnosed smell sensitivity.

Awareness of loss in smell sensitivity was assessed in 80 normal elderly subjects, 80 patients with probable Alzheimer's disease (AD), and 80 patients with sinusitis by comparing measured smell sensitivity to questionnaire-based, self-reported sensitivity. Both AD patients and sinusitis patients had significantly poorer diagnosed smell sensitivity than the normal elderly. Both patient groups had thresholds which on average were about nine times more concentrated than those of the normal elderly. However, 74% of the AD patients and 77% of the normal elderly with smell loss reported normal smell sensitivity. In contrast, only 8% of the sinusitis patients with loss reported normal smell sensitivity.

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.

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.

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 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.

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.

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.