Jacques Touchon

Classification criteria for mild cognitive impairment: a population-based validation study.

Objective: To evaluate the predictive validity and temporal stability of diagnostic criteria for mild cognitive impairment (MCI). Background: MCI has been proposed as a nosologic entity referring to elderly persons with subclinical cognitive deficits due to incipient dementia. Classification criteria, which have been derived from small, selected clinical groups, are currently disputed, and have not yet been assessed within the general population. Methods: Subjects meeting current criteria for MCI and also age-associated cognitive decline (AACD—a similar concept that is assumed to be related to normal cognitive aging processes rather than incipient dementia) were identified within each of three waves of a longitudinal population study, which included a standardized neurologic examination. Results: In the general population, the prevalence of MCI was estimated to be 3.2% and AACD 19.3%. MCI was a poor predictor of dementia within a 3-year period, with an 11.1% conversion rate. Subjects with MCI also constituted an unstable group, with almost all subjects changing category each year. Discriminant function analysis failed to isolate a homogeneous clinical group. Subjects classified as AACD, contrary to the theoretical assumptions underlying the disorder, represented a more stable group, with a 28.6% conversion rate to dementia over 3 years (relative risk = 21.2). Conclusion: MCI criteria perform poorly when applied to a representative population sample. The authors propose modifications to current diagnostic criteria to increase their capacity to detect incipient dementia.

Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study

Abstract Objective To assess the potential of anticholinergic drugs as a cause of non-degenerative mild cognitive impairment in elderly people. Design Longitudinal cohort study. Setting 63 randomly selected general practices in the Montpellier region of southern France. Participants 372 people aged > 60 years without dementia at recruitment. Main outcome measures Anticholinergic burden from drug use, cognitive examination, and neurological assessment. Results 9.2% of subjects continuously used anticholinergic drugs during the year before cognitive assessment. Compared with non-users, they had poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks but not on tasks of reasoning, immediate and delayed recall of wordlists, and implicit memory. Eighty per cent of the continuous users were classified as having mild cognitive impairment compared with 35% of non-users, and anticholinergic drug use was a strong predictor of mild cognitive impairment (odds ratio 5.12, P = 0.001). No difference was found between users and non-users in risk of developing dementia at follow-up after eight years. Conclusions Elderly people taking anticholinergic drugs had significant deficits in cognitive functioning and were highly likely to be classified as mildly cognitively impaired, although not at increased risk for dementia. Doctors should assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering administration of acetylcholinesterase inhibitors.

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. GLOSSARY: AD = Alzheimer disease; AUC = area under the curve; CDR = Clinical Dementia Rating; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised; FCSRT = Free and Cued Selective Recall Reminding Test; IADL = Instrumental Activities of Daily Living; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; ROC = receiver operating characteristic; WAIS = Wechsler Adult Intelligence Scale.

Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial

BACKGROUND Prevention strategies are urgently needed to tackle the growing burden of Alzheimers disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract for the reduction of incidence of Alzheimers disease in elderly adults with memory complaints. METHODS In the randomised, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, we enrolled adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France. We randomly allocated participants in a 1:1 ratio according to a computer-generated sequence to a twice per day dose of 120 mg standardised ginkgo biloba extract (EGb761) or matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed-up for 5 years by primary-care physicians and in expert memory centres. The primary outcome was conversion to probable Alzheimers disease in participants who received at least one dose of study drug or placebo, compared by use of the log-rank test. This study is registered with ClinicalTrials.gov, number NCT00276510. FINDINGS Between March, 2002, and November, 2004, we enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of ginkgo biloba extract and 1414 received at least one dose of placebo. By 5 years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimers disease (1·2 cases per 100 person-years) compared with 73 participants in the placebo group (1·4 cases per 100 person-years; hazard ratio [HR] 0·84, 95% CI 0·60-1·18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups. 76 participants in the ginkgo group died compared with 82 participants in the placebo group (0·94, 0·69-1·28; p=0·68). 65 participants in the ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1·12, 95% CI 0·77-1·63; p=0·57). Incidence of other haemorrhagic or cardiovascular events also did not differ between groups. INTERPRETATION Long-term use of standardised ginkgo biloba extract in this trial did not reduce the risk of progression to Alzheimers disease compared with placebo. FUNDING Ipsen.

Risk profiles for mild cognitive impairment and progression to dementia are gender specific

Objective: To examine risk factors for mild cognitive impairment (MCI) and progression to dementia in a prospective community-based study of subjects aged 65 years and over. Methods: 6892 participants who were over 65 and without dementia were recruited from a population-based cohort in three French cities. Cognitive performance, clinical diagnosis of dementia, and clinical and environmental risk factors were evaluated at baseline and 2-year and 4-year follow-ups. Results: 42% of the population were classified as having MCI at baseline. After adjustment for confounding with logistic regression models, men and women classified as having MCI were more likely to have depressive symptomatology and to be taking anticholinergic drugs. Men were also more likely to have a higher body mass index, diabetes and stroke, whereas women were more likely to have poor subjective health, to be disabled, to be socially isolated, and to suffer from insomnia. The principal adjusted risk factors for men for progression from MCI to dementia in descending order were ApoE4 allele (OR = 3.2, 95% CI 1.7 to 5.7), stroke (OR = 2.8, 95% CI 1.2 to 6.9), low level of education (OR = 2.3, 95% CI 1.3 to 4.1), loss of Instrumental Activities of Daily Living (IADL) (OR = 2.2, 95% CI 1.1 to 4.5) and age (OR = 1.2, 95% CI 1.1 to 1.2). In women, progression is best predicted by IADL loss (OR = 3.5, 95% CI 2.1 to 5.9), ApoE4 allele (OR = 2.3, 95% CI 1.4 to 4.0), low level of education (OR = 2.2, 95% CI 1.3 to 3.6), subclinical depression (OR = 2.0, 95% CI 1.1 to 3.6), use of anticholinergic drugs (OR = 1.8, 95% CI 1.0 to 3.0) and age (OR = 1.1, 95% CI 1.1 to 1.2). Conclusions: Men and women have different risk profiles for both MCI and progression to dementia. Intervention programmes should focus principally on risk of stroke in men and depressive symptomatology and use of anticholinergic medication in women.

Revised Criteria for Mild Cognitive Impairment: Validation within a Longitudinal Population Study

Background: Mild cognitive impairment (MCI) refers to the transitional zone between normal ageing and dementia. Current criteria perform poorly within the general population setting. Revisions have been proposed based on results obtained from clinical and epidemiological studies. Objective: To evaluate revised diagnostic criteria for mild cognitive impairment (MCI-R) incorporating changes in activity level and non-mnesic cognitive functioning. Method: MCI-R subjects were recruited from a representative network of general practitioners in the south of France. A computerized neuropsychometric examination was given. At 2 years of follow-up, a diagnosis of dementia was made by a neurologist using DSM-IIIR criteria and without knowledge of the results of the cognitive testing. Rates of conversion to incident dementia were assessed by receiver operating characteristics analysis. Results: The MCI-R prevalence was found to be 16.6% using revised criteria. A significantly better prediction of transition to dementia (AUC = 0.80, sensitivity: 95%, specificity: 66%) was obtained with MCI-R than with the previous MCI criteria (AUC = 0.48, sensitivity: 5%, specificity: 91%). The predictive power was found to increase when MCI subtypes were combined. Conclusion: Incorporating the possibility of change in activity level and alteration of non-mnesic cognitive functions have been found to ameliorate the original algorithm and better define subjects converting to dementia. This definition may be applicable to both clinical and population research.

Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period

ABSTRACT Objectives: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimers disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimers disease over a 2-year period. Methods: Patients were randomly assigned to rivastigmine 3–12 mg/day or donepezil 5–10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs. Results: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT–LOCF population. However, this was not maintained in the non-ITT–LOCF populations. In secondary sub-group analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment. Conclusions: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Leisure activities and the risk of dementia in the elderly Results from the Three-City Study

Objective: There is accumulating evidence that involvement in leisure activities may be related to risk of dementia; however, there is no consensus concerning the underlying mechanism of this association. Hypothesizing that leisure activities may contribute to cognitive reserve (CR), we examined the association between leisure activities and risk of incident dementia and its subtypes within a general population sample, categorizing leisure activity as stimulating, passive, physical, and social. The possibility that these associations may be driven by other proxies of CR was also examined. Methods: Analyses were carried out on 5,698 dementia-free participants aged 65 and over included in the Three-City cohort study in Dijon and Montpellier (France) in 1999–2001. Hazard ratios (HR) were calculated for incident dementia and its subtypes (mixed/vascular dementia and Alzheimer disease) in relation to category of leisure activity. Results: Stimulating leisure activities were found to be significantly associated with a reduced risk of dementia (n = 161, HR = 0.49, 95% confidence interval [CI]: 0.31; 0.79) and Alzheimer disease (n = 105, HR = 0.39, 95% CI: 0.21; 0.71) over the 4-year follow-up 1) independently of other proxies of CR, 2) after adjusting for vascular risk factors, depressive symptoms, and physical functioning, and 3) independently of other leisure activities. Furthermore, no significant association was found with other leisure activities and dementia after controlling for the potential confounders. Conclusion: Our findings support the hypothesis that cognitively stimulating leisure activities may delay the onset of dementia in community-dwelling elders.

Effect of Music Therapy on Anxiety and Depression in Patients with Alzheimer’s Type Dementia: Randomised, Controlled Study

Background/Aims: Numerous studies have indicated the value of music therapy in the management of patients with Alzheimer’s disease. A recent pilot study demonstrated the feasibility and usefulness of a new music therapy technique. The aim of this controlled, randomised study was to assess the effects of this new music therapy technique on anxiety and depression in patients with mild to moderate Alzheimer-type dementia. Methods: This was a single-centre, comparative, controlled, randomised study, with blinded assessment of its results. The duration of follow-up was 24 weeks. The treated group (n = 15) participated in weekly sessions of individual, receptive music therapy. The musical style of the session was chosen by the patient. The validated ‘U’ technique was employed. The control group (n = 15) participated under the same conditions in reading sessions. The principal endpoint, measured at weeks 1, 4, 8, 16 and 24, was the level of anxiety (Hamilton Scale). Changes in the depression score (Geriatric Depression Scale) were also analyzed as a secondary endpoint. Results: Significant improvements in anxiety (p < 0.01) and depression (p < 0.01) were observed in the music therapy group as from week 4 and until week 16. The effect of music therapy was sustained for up to 8 weeks after the discontinuation of sessions between weeks 16 and 24 (p < 0.01). Conclusion: These results confirm the valuable effect of music therapy on anxiety and depression in patients with mild to moderate Alzheimer’s disease. This new music therapy technique is simple to implement and can easily be integrated in a multidisciplinary programme for the management of Alzheimer’s disease.

Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset

Hypocretin/orexin deficiency appears to be a consistent feature of narcolepsy with a putative autoimmune mechanism involved. We treated four hypocretin/orexin‐deficient narcolepsy patients with intravenous immunoglobulins and assessed the efficacy by repeated polysomnographies and questionnaires. Three patients received the treatment within a few months after acute onset of narcolepsy. A clear improvement in the frequency and severity of cataplexy was obtained with a benefic effect up to 7 months without any anticataplectics drugs at follow‐up. Our findings point to the importance of early diagnosis of narcolepsy, which once treated quickly may modify its long‐term outlook. Ann Neurol 2004;56:905–908