In vivo SPECT imaging of vesicular acetylcholine transporter using [(123)I]-IBVM in early Alzheimer's disease.

INTRODUCTION: Little is known about cholinergic activity in the early stage of Alzheimer's disease. We investigated differences in the distribution of vesicular acetylcholine transporter, using [(123)I]-iodobenzovesamicol ([(123)I]-IBVM) and Single Photon Computed Tomography (SPECT), in early AD and age-matched controls. MATERIALS AND METHODS: Sixteen subjects (8 controls, 8 AD) underwent [(123)I]-IBVM SPECT scanning, T1-weighted anatomic scan by Magnetic Resonance (MR) imaging and Mini-Mental State Evaluation (MMSE). Image analysis, using Statistical Parametric Mapping (SPM 02), involved coregistration of each SPECT image to the MR scan, followed by a spatial normalisation to the Montreal Neurological Institute standard brain and a smoothing of each SPECT image. Group effects and correlation were assessed using two sample t-tests and linear regression respectively. Atrophy difference between the two groups was assessed by voxel-based morphometry of each MR scan using two sample t-tests. RESULTS: MMSE values were significantly different between AD and controls. Relative to controls, a significant decrease in [(123)I]-IBVM binding (47-62%) was apparent in AD subjects in cingulate cortex and parahippocampal-amygdaloïd complex. These patterns appeared to be independent of atrophied areas. CONCLUSION: These results strongly suggest that a cholinergic degeneration occurs in the early stage of AD and could be involved in the impairment of the cognitive functions. Imaging of cholinergic neurons used here could be effective in identifying potential cholinergic treatment responders.

Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study.

OBJECTIVE: To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). BACKGROUND: Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. METHODS: A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. RESULTS: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). CONCLUSIONS: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.

[Cued and uncued memory tests: norms in elderly adults from the 3 Cities epidemiological study]. / Test de rappel libre/rappel indicé à 16 items: normes en population générale chez des sujets âgés issues de l'étude des 3 Cités.

INTRODUCTION: The free and cued reminding test is often considered to be essential in the neuropsychological examination of elderly people consulting Memory Clinics. One of the reasons is that this test maximizes learning by inducing deep semantic processing and by controlling encoding and retrieval conditions. The aim of this study was to produce age, sex and educational level-adjusted normative data for this test. METHODS: These data were collected as part of the Three-City (3C) Study, a French population-based study on aging. RESULTS: The subsample of subjects analysed for this study included 1 458 non-institutionalised and non-demented elderly adults aged 65 and over. Norms were calculated according to age (65-70, 70-74, 74-78, 78-90), sex and educational level of the subjects (primary level versus and secondary or university level). CONCLUSION: The interest of this work is to provide to clinicians normative scores on the free and cued reminding test which can be used as an aid to interpret a patient's performance on a test widely used to detect episodic memory deficits in aging.

Restriction in complex activities of daily living in MCI: impact on outcome.

OBJECTIVE: To describe the restriction in instrumental activities of daily living (IADL) in mild cognitive impairment (MCI) and to assess the impact of IADL restriction on the progression to dementia and on MCI reversibility. METHODS: The study sample included 1,517 participants of the PAQUID cohort, visited at 8- and 10-year follow-ups. Subjects classified as having MCI had no dementia but a cognitive deficit according to five neuropsychological tests. Four IADL (telephone, transports, medication, finances) were assessed and considered restricted if at least two of them were not performed at the highest level of performance. Cross-sectional and longitudinal analyses were conducted. RESULTS: A total of 285 subjects were classified as having MCI at baseline, and 15.2% developed dementia within 2 years. MCI subjects were more frequently IADL restricted (34.3%) than controls (5.4%) but less than those with dementia (91.1%). The IADL-restricted MCI subjects were more likely to develop dementia over 2 years (30.7%) than the nonrestricted ones (7.8%). In multivariate analyses, the odds ratio for dementia was 7.4 (CI: 3.3 to 16.5) in the IADL-restricted MCI and 2.8 (CI: 1.3 to 6.0) in the non-IADL-restricted MCI compared with the non-IADL-restricted controls. IADL restriction also lowered the chance of reversibility to normal, observed in 10.7% of the restricted MCI and 34.7% of the nonrestricted MCI. CONCLUSIONS: Inclusion of instrumental activities of daily living restriction in the criteria of mild cognitive impairment improves the prediction of dementia and the stability of this status over time. Conversely, its exclusion results in inappropriate selection of subjects with a low probability of short-term progression to dementia.

[Validity of the five-word screening test for Alzheimer's disease in a population based study]. / Le test des 5 mots: validité dans la détection de la maladie d'Alzheimer dans la population générale.

INTRODUCTION: In general medicine lack of time impairs screening for Alzheimer's disease (AD). The five word test (FWT) enables rapid assessment of verbal episodic memory in accordance with Grober and Buschke neuropsychological concept. The main steps of the FWT are: induce specific semantic processing, control of encoding to avoid attention deficits, free and cued recall. Cued recall helps to distinguish a recall impairment from storage impairment which is evocative of AD. OBJECTIVE: Evaluate FWT total score (sum of free and cued recalls), FWT total weighed score which give a higher coefficient for free recalls than cued recalls and present the ability of these two scores for AD screening. METHOD: Evaluation performed with 4116 subjects (of whom 73 MA) aged from 65 years and more, randomly selected in two French towns for the "Three Cities" Study, a population-based cohort. RESULTS: The total score was more specific than sensitive with a maximal sensitivity (Se) at 63 percent with specificity (Sp) at 91.1 percent. The total weighed score significantly increased Se (83.6 percent) with control of specificity (84.9 percent) and positive predictive value (9.1 percent). CONCLUSION: The FWT allows quick screening of patients for whom further neuropsychological evaluation is needed to diagnose AD. The ability of is simple test to screen for AD is improved by a simple weighting procedure: the total weighted score.

Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis.

OBJECTIVES: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging. METHODS: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted. RESULTS: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases. CONCLUSIONS: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.

[Normative data for the MMSE, the Benton visual retention test, the Isaacs's set test, the digit symbol substitution test and the Zazzo's cancellation task in subjects over the age 70: results from the PAQUID Study]. / Normes pour le MMSE, le test de rétention visuelle de Benton, le set test d'Isaacs, le sous-test des codes de la WAIS et le test de barrage de Zazzo chez des sujets âgés de 70 ans et plus: données de la cohorte PAQUID.

UNLABELLED: Introduction. The aim of this study was to produce norms for the Mini-Mental State Examination, the Benton visual retention test, Isaacs's set test, the digit symbol substitution test and Zazzo's cancellation task (short 8-line version), in elderly people. METHODS: Data was collected in a representative sample of 1780 subjects aged 70 years and older, followed-up for five years after inclusion in the PAQUID study. Only individuals who did not have characteristics likely to alter their cognitive performance were considered. RESULTS: Descriptive statistics (median, tenth percentile, first and third quartile) were used to define gender-, age- and education-specific norms. CONCLUSIONS: These norms can be used by clinicians to interpret a patient's performance on several widely used cognitive tests according to the scores obtained by individuals of the same age, gender and educational level.

Incidence and outcome of mild cognitive impairment in a population-based prospective cohort.

OBJECTIVE: To estimate the age-specific incidence rate of mild cognitive impairment (MCI) according to sex and educational level and to explore the course of MCI, particularly its progression to AD, in a population-based cohort. METHODS: A community-based cohort of nondemented elderly people (Personnes Agées QUID [PAQUID]) was followed longitudinally for 5 years. MCI was defined as memory complaints with objective memory impairment, without dementia, impairment of general cognitive functioning, or disability in activities of daily living. Incidence rates were calculated using the person-years method. A descriptive analysis at the different follow-up times was performed to study the course of MCI. RESULTS: At baseline, there were 58 prevalent cases of MCI (2.8% of the sample). During a 5-year follow-up, 40 incident cases of MCI occurred in 1,265 subjects at risk. The global incidence rate of MCI was 9.9/1,000 person-years. MCI was a good predictor of AD with an annual conversion rate of 8.3% and a good specificity, but it was very unstable over time: Within 2 to 3 years, only 6% of the subjects continued to have MCI, whereas >40% reverted to normal. CONCLUSIONS: Conventionally defined MCI has reasonable predictive value and specificity for AD. However, MCI was very unstable across time in this study. Furthermore, the definition of MCI seems to be too restrictive and should probably be extended to other categories of individuals also at high risk of developing AD.

The disablement process: a conceptual framework for dementia-associated disability.

Most of the social and economic burden of dementia is attributable to its consequences in terms of disability. In this review, we describe the concepts defined in the disablement process model of Verbrugge and Jette [Soc Sci Med 1994;38:1-14] and show how they apply to dementia. The main pathway leads from pathology to impairments, functional limitations and disability. Pathologies (any cause of dementia) are expressed by impairments in specific cognitive processes. Functional limitations are limitations in generic cognitive tasks such as remembering a list of words or orientating oneself in time and space. They are responsible for disability in activities of daily living. Predisposing risk factors as well as introduced intraindividual and extraindividual factors speed up or slow down the main pathway. We show how the model can help in understanding the functional consequences of dementia, for better assessment and management of demented subjects.

Neuropsychologic effects of long-term exposure to pesticides: results from the French Phytoner study.

The Phytoner study investigated a possible association between neuropsychologic performances and long-term exposure to pesticides in Bordeaux vineyard workers, most of whom use fungicides. Among the 917 subjects interviewed from February 1997 to August 1998, 528 were directly exposed to pesticides through mixing and/or spraying (mean exposure duration: 22 years), 173 were indirectly exposed through contact with treated plants, and 216 were never exposed. All subjects performed neuropsychologic tests administered at home by trained psychologists. The risk of scoring a low performance on the tests was constantly higher in exposed subjects. When taking into account educational level, age, sex, alcohol consumption, smoking, environmental exposures, and depressive symptoms and when restricting analysis to subgroups, results remained significant for most tests, with odds ratios (OR) exceeding 2. These results point to long-term cognitive effects of low-level exposure to pesticides in occupational conditions. Given the frequency of pesticide use and the potential disabilities resulting from cognitive impairments, further toxicologic and epidemiologic research is needed to confirm these results and assess the impact on public health.

Occupation during life and risk of dementia in French elderly community residents.

OBJECTIVE: To determine whether principal occupation during life is a risk factor for incident Alzheimer's disease, vascular dementia, or dementia with parkinsonism. METHODS: This study was carried out from the PAQUID (Personnes Agées QUID) cohort, an epidemiological study on normal and pathological aging after 65 years in the south west of France. At baseline, 2950 non-demented people living at home were identified and re-examined 1, 3, 5, 8, and 10 years later with identical standardised neurological and neuropsychological measures. Cox proportional hazards models with delayed entry were used, taking age as the time scale and adjusting for sex, education, tobacco, and wine consumption to estimate the risk ratio (RR) of incident dementia, Alzheimer's disease, vascular dementia, and dementia with parkinsonism associated with occupational category. RESULTS: Of the 2950 subjects, 393 became demented, of whom 251 had Alzheimer's disease, 112 had vascular dementia, and 27 had dementia with parkinsonism. The risk of Alzheimer's disease was not related to a given occupation. However the risk of dementia with parkinsonism seemed to be increased in farmers in comparison with professionals and managerials, particularly among women (RR 7.47; 95%CI, 1.80-31.07). CONCLUSION: The data suggest that occupation does not change the risk of Alzheimer's disease, which seems to be more influenced by cognitive abilities in childhood and adolescence than by occupation in adult life. However, being a farmer may increase the risk of dementia with parkinsonism among women; occupation could act by the way of differences in health behaviour or in exposure to environmental factors.

[Memory, aging and risk factors. Lessons from clinical trials and epidemiologic studies]. / Mémoire, vieillissement et facteurs de risque. Leçons des essais cliniques et des études epidémiologiques.

Memory troubles associated with age justify treatment and medical attention because they lead to real disabilities in daily living even without dementia, and also because they are early predictors of dementia in Alzheimer's Disease (AD). However, the treatment of these troubles remains uncertain, badly codified and extremely variable depending on the health systems concerned. Moreover, the dominant idea of many physicians, in the general population and even in health authorities, is that it is normal to have memory troubles in the elderly. This fact explains the common attitude of therapeutic nihilism. However, recent progress in the treatment of AD demonstrates that this disease should not be considered as an irremediable phenomenon. Moreover, on the basis of the follow up of an elderly cohort, it is possible to determine subjects at high risk of dementia where preventive interventions could be undertaken.

A cognitive screening battery for dementia in the elderly.

The objective of this study is to propose a screening instrument for dementia based on a reduced number of neuropsychological tests. The sample consists in the pooled data of the five follow-up visits of the Paquid cohort study on cerebral aging: the estimation sample included 2792 subjects (8830 observations) and the validation sample included 985 subjects (2643 observations). Among scores significantly associated with dementia, we retained only those that increased the specificity of the model for a sensitivity of one. Seven neuropsychological tests and the MMSE subscores were considered. The most discriminant combination of tests included the MMSE and the subscores "orientation to time" and "recall three objects," the Benton Visual Retention Test, and Isaacs' Set Test of verbal fluency. The specificity of this screening instrument was 0. 77 for a sensitivity of 1.

Deterioration of controlled processes in the preclinical phase of dementia: a confirmatory analysis.

Preclinical deficits in dementia have recently been investigated in the PAQUID cohort by means of a principal component analysis (PCA) performed from various test scores. According to the interpretation of the first PCA factor, which was found to be an independent predictor of dementia 2 years later, the authors suggested that cognitive deficits occurring in the preclinical phase of dementia may reflect the deterioration of controlled processes. Because this hypothesis relies essentially on the interpretation of PCA factors, the present study was designed to test it within the same cohort. The analyses were focused on one of the tests administered to the subjects, the Wechsler Paired Associate Test (WPAT) divided into two subscores in order to provide a measure of controlled processes of memory functioning (i.e. retrieval of unrelated pairs) as well as of more automatic processes (i.e. retrieval of related pairs). The results showed that the future demented subjects, although significantly impaired compared to elderly controls, were able to increase their performance across trials. More importantly, a new PCA including the subscores of the WPAT showed that the unrelated pair scores were strongly correlated to factor 1, which remained the only factor associated with subsequent dementia, whereas the related pair scores were rather correlated to factor 2. Therefore, these results confirm our previous PCA interpretation, lending more weight to our hypothesis of a preclinical impairment of controlled processes in dementia.

Marital status and risk of Alzheimer's disease: a French population-based cohort study.

OBJECTIVE: To analyze the relationship between marital status and risk of AD or dementia. METHODS: This study was carried out from the Personnes Agées QUID (PAQUID) cohort, an epidemiologic study on normal and pathologic aging after age 65 years. The PAQUID cohort began in 1988. Individuals were followed up at 1, 3, and 5 years, with an active detection of dementia. Marital status was divided into four categories: widowed, never married, divorced or separated, and the reference category, married or cohabitant. The longitudinal relationship between marital status and risk of incident AD or dementia was analyzed by a Cox model with delayed entry. RESULTS: Among the 3,675 individuals initially not demented, 2,106 were married or cohabitants, 1,287 were widowers, 179 were never married, and 103 were divorced or separated. Among the 2,881 individuals reevaluated at least once for the risk of dementia during the 5-year follow-up, 190 incident cases of dementia were identified, including 140 with AD. The relative risks (RRs) of dementia (RR = 1.91, p = 0.018) and of AD (RR = 2.68, p<0.001) were increased for the never-married individuals compared with those who were married or cohabitants. This excess of risk was specifically associated with AD. Adjustment for other risk factors of dementia (education, wine consumption), or for factors reflecting social environment, leisure activities, and depression, did not modify the risk of AD for never-married individuals (RR = 2.31, p = 0.02). CONCLUSIONS: We confirmed an association between marital status and AD, with an excess risk observed among never-married individuals. This association may provide clues about the pathogenesis of AD.

Neuropsychological correlates of self-reported performance in instrumental activities of daily living and prediction of dementia.

This study examines the relationships between performance on neuropsychological tests and 4 instrumental activities of daily living (IADL) associated with an increased risk of dementia, in 1,792 nondemented elderly people included in the Personnes Agées Quid (PAQUID) study. There was a decline of neuropsychological performance on each test with increasing IADL dependency, in particular between Grades 1 and 2. Performances of the independent participants were very homogeneous. Each IADL had different specific associations with the neuropsychological tests. A principal component analysis showed three main factors explaining 49.6% of variance. The first factor was the common cognitive component of both instrumental tasks and neuropsychological tests. The second factor was specific to three IADL, whereas use of transportation had its main loading on the third factor. Only the first factor was predictive of the risk of incident dementia, suggesting that the predictive value of the 4 IADL was explained by their cognitive component.

Functional impairment in instrumental activities of daily living: an early clinical sign of dementia?

OBJECTIVE: To estimate the predictive value of four IADLs on 3- and 5-year incident dementia. DESIGN: Prospective cohort study. SETTING: A community survey in 37 randomly selected parishes. SUBJECTS: A random sample of French community dwellers aged 65 and older included in the PAQUID study followed-up at 3 (1582 subjects) and 5 years (1283 subjects). MAIN OUTCOME MEASURES: Incidence of dementia at 3 and 5 years, diagnosed by two-step screening: (1) MMS and DSM-III-R; (2) diagnosis of dementia confirmed by a neurologist. RESULTS: A score summing up the number of dependencies at baseline on four IADLs is a predictor of 3-year but not of 5-year incident dementia. Increase in the level of dependence between baseline and 3-year follow-up is associated with an increased risk of incident dementia at 5-year follow-up. CONCLUSION: These four IADLs can help to identify older subjects at high risk of dementia who should then undergo neuropsychological testing.

Analysis of error types in the trial making test evidences an inhibitory deficit in dementia of the Alzheimer type.

Several studies have reported low performances of patients with dementia of the Alzheimer Type (DAT) on the Trial Making Test (TMT), however, these studies were not designed to identify specific operations underlying this impairment. To better understand the attentional disorder in DAT, we analyzed the performances of patients with DAT and matched elderly adults on the TMT, with a detailed analysis of error types. The analysis showed that 67% of patients' errors were related to an inhibitory deficit versus only 24% in normal elderly adults. Therefore, it was suggested that inefficient inhibitory mechanisms are responsible, to a large extent, for the poor TMT performance of patients with DAT, supporting the hypothesis of an inhibitory dysfunction in DAT.

Cognitive process in preclinical phase of dementia.

Several recent prospective studies have demonstrated the existence of a preclinical stage of dementia, identifiable by neuropsychological assessment showing impairments with a great variety of cognitive tests. However, test scores are often colinear, largely because common cognitive components are involved in different tests; in spite of an apparent heterogeneity, it is still possible that a common cognitive component may be responsible for the deterioration shown in different tests in the preclinical phase. We studied the cognitive performances of 1159 elderly residents in the PAQUID (Personnes Agées quid) cohort, at a fixed lag time of 2 years before the clinical diagnosis of dementia. Seven neuropsychological tests were administered (Mini-Mental Status Examination, Benton Visual Retention Test, Wechsler Paired-Associates Test, Isaacs Set Test, Zazzo's Cancellation Task, Digit Symbol Substitution Test and Wechsler Similarities Test). Among the initially non-demented 1159 subjects, 25 developed a dementia 2 years later, of whom 16 were classified as cases of Alzheimer's disease. In order to dissect the multicolinearity of the tests we used a multivariate approach with principal component analysis (PCA). The patients' loading on each of the first four PCA factors were subsequently correlated with the risk of dementia and Alzheimer's disease 2 years later. The logistic regression with backward stepwise selected only the first factor as an independent predictor of dementia or Alzheimer's disease. Analysis shows that there are good reasons to suspect that the first PCA factor represents a general factor corresponding to aspects of control in the tasks used. Our results therefore seem to show that preclinical deficits in dementia and Alzheimer's disease reflect the deterioration of a general cognitive factor, which may be interpreted as the disturbance of central, control processes.