A simple score to predict survival with dementia in the general population.

BACKGROUND/AIMS: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. METHODS: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based, long-term cohort study, the Three City Study. - RESULTS: Among the 3,777 subjects enrolled in the Paquid Study, 454 incident cases of dementia were included in this study. After a 5-year follow-up period, 319 (70.3%) were deceased. The score was constructed from three independent prognostic variables (gender, age at diagnosis and number of ADL restricted). The discriminant ability of the score was good with a c index of 0.754. Sensitivity was 64.7% and specificity 76.3%. In the validation cohort, the discriminant ability of the prognostic score with c statistics was 0.700. Sensitivity was 26.3% and specificity 95.4%. CONCLUSIONS: The prognostic factors selected in the predictive model are easily assessable, so this simple score could provide helpful information for the management of dementia, particularly to identify patients with duration of the disease greater than 5 years.

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

[The new 2011 recommendations of the National Institute on Aging and the Alzheimer's Association on diagnostic guidelines for Alzheimer's disease: Preclinal stages, mild cognitive impairment, and dementia]. / Les nouvelles recommandations 2011 du National Institute on Aging et de l'Alzheimer's Association sur le diagnostic de la maladie d'Alzheimer : stades précliniques, mild cognitive impairment et démence.

BACKGROUND: Criteria for the clinical diagnosis of Alzheimer's disease (AD) were established in 1984, and they needed to be updated and revised, in vue of the scientific knowledge acquired over the last decades. METHODS: The National Institute on Aging (NIA) and the Alzheimer's Association (AA) sponsored a series of advisory round table meetings to establish a revision of diagnostic and research criteria for AD. The workgroups reviewed the biomarker, epidemiological, and neuropsychological evidence, and proposed conceptual frameworks as well as operational research criteria based on the prevailing scientific evidence to date. RESULTS: Three preclinical stages of AD were proposed: asymptomatic amyloidosis, asymptomatic amyloidosis+neurodegeneration, amyloidosis+neurodegeneration+subtle cognitive decline. The preclinical workgroup developed recommendations to determine the factors, which best predict the risk of progression from normal cognition to mild cognitive impairment (MCI) and AD dementia. It is necessary to refine these models with longitudinal clinical research studies. The workgroups on MCI and AD dementia sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. The symptomatic predementia phase of AD was referred to as MCI due to AD. Core clinical and cognitive criteria of MCI were proposed, the final set of criteria for MCI due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Criteria for all-cause dementia and for AD dementia were presented. Dementia caused by AD were classified in: probable AD dementia, possible AD dementia, and probable or possible AD dementia with evidence of the AD pathophysiological process, for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis. CONCLUSIONS: In the revised criteria, a conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes. The core clinical criteria of the recommendations regarding MCI due to AD and AD dementia are intended to guide diagnosis in the clinical setting whereas the recommendations of the preclinical AD workgroup are intended purely for research purposes and do not have any clinical implications. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

Validity of the free and cued selective reminding test in predicting dementia: the 3C study.

OBJECTIVE: We assessed the validity of the Free and Cued Selective Reminding Test (FCSRT) in predicting dementia 2 and 5 years after initial evaluation in a population-based cohort over age 65 years participating in the French 3 Cities (3C) study. METHODS: The FCSRT was administered at baseline along with demographics, cognitive and functional scales, and a memory-complaint questionnaire. Two and 5 years later, subjects were assessed for dementia using a 2-stage design. We calculated the sensitivity, specificity, and positive and negative predictive values of various cutoff FCSRT scores in dementia prediction. RESULTS: Among 1,761 participants at the Bordeaux 3C center, 98 were excluded because of existing dementia, leading to 1,663 candidate participants. Among them, 1,464 underwent FCSRT and other mental status testing. Of these, 1,299 subjects were reassessed at 2 years, and 1,160 were seen 5 years later. At 2 years, 23 subjects had developed dementia; by 5 years, 60 additional subjects showed dementia. With optimized cutoff scores, the subtests of free and total recall from the FCSRT showed good sensitivity and fair specificity for the diagnosis of dementia, and the negative predictive values were high. However, positive predictive values were low: many subjects with low scores for free and total recall on FCSRT remained free of dementia at 5 years. CONCLUSIONS: In a population-based setting, despite good sensitivity, low Free and Cued Selective Reminding Test (FCSRT) scores must be interpreted with caution. Those subjects, who often do not have memory complaints, may have unrecognized poor memory status. High FCSRT scores are useful to rule out dementia.

[Semantic and letter fluency tasks: normative data in an elderly population of 70 years old and over from the PAQUID cohort]. / Fluences verbales sémantiques et littérales: normes en population générale chez des sujets âgés de 70 ans et plus issus de la cohorte PAQUID.

INTRODUCTION: Verbal fluency tasks are frequently used in neuropsychological examinations. The aim of this study was to produce norms for a normal elderly population in semantic (colors, animals, fruits, city names) and letter fluency (letters "L" and "P") tasks performed in 60 seconds. METHODS: These data were collected as part of the PAQUID cohort, a French population-based study on aging conducted in Gironde and Dordogne. RESULTS: The sub-sample analyzed included 1730 non-institutionalized and non-demented subjects. Norms were calculated according to age (70-74 years, 75-79 years, >or=80 years), sex and educational level (no diploma, primary degree, secondary degree and higher). For each task, the number of correct words produced and repetition errors were analyzed. CONCLUSION: The contribution of this work is to provide clinicians with normative scores for semantic and letter fluency tasks helpful for interpreting the performances of elderly patients consulting for cognitive disorders.

A 15-year population-based cohort study of the incidence of Parkinson's disease and dementia with Lewy bodies in an elderly French cohort.

OBJECTIVE: To provide global and age-related incidence over 65 years of Parkinsonian syndromes (PS), Parkinson's disease (PD) and suspected dementia with Lewy bodies (DLB). METHODS: A 15-year prospective population-based elderly cohort study in South-Western France (PAQUID). RESULTS: Incidences found were: 557.7/100,000 person-years for PS, 263 per 100 000 person-years for PD and 112 per 100,000 person-years for suspected DLB. The incidence of all PS, PD and suspected DLB was greater in men. The age-specific incidence of PD decreased over 85, while that of DLB continuously increased, even in the oldest individuals. CONCLUSIONS: The authors provide new data on PD and suspected DLB incidence in a large population-based French cohort of subjects aged over 65 and followed up for 15 years. PD incidence decreased in the oldest old contrary to that of suspected DLB cases and Alzheimer's disease.

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.

[Semantic dementia: reflexions of a French working group for diagnostic criteria and constitution of a patient cohort]. / Démence sémantique: réflexions d'un groupe de travail pour des critères de diagnostic en français et la constitution d'une cohorte de patients.

Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de réflexion sur les évaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.

[Update on vascular dementias]. / Mise au point sur les démences vasculaires.

The concept of vascular dementia greatly evolved since Hachinski's description of multi-infarct dementia. Vascular dementias are reviewed with emphasis on current diagnostic criteria, elusive natural history, neuroradiological aspects, difficult epidemiological features and intriguing links with Alzheimer's disease. The recent proposed shift from vascular dementias to a broader definition of "vascular cognitive disorders", including non demented subjects with "vascular cognitive impairment", is described, followed by a brief review of current treatments.

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.

Early prevention at public health issue.

Alzheimer's Disease and related disorders have recently become a priority in France and two consecutive governmental plans have been undertaken in 2001-2004 and 2004-2007. The number of prevalent cases was estimated to be 850,000 in France with an incidence of 220,000 cases. Only 50% of these cases were actually diagnosed and about 32% were treated by antidementia drugs. If the incidence and the duration of the disease do not change, the number of cases will increase to 1,200,000 in 2020 and 2,100,000 cases in 2040. In absence of curative treatment, the prevention way is necessary if one wishes to control this phenomena. The development of Memory Clinics and "Centres de Mémoires de Ressources et de Recherche" in all regions in France is one of the important measures to develop primary and secondary prevention in subjects with cognitive complaints or MCI. Several factors could be the basis of this prevention 1) Vascular risk factors (High Blood Pressure, Diabetes, Obesity, Hypercholesterolemiae, Tobacco consumption) ; 2) physical exercise ; 3) Stimulating cognitive activities ; 4) Nutrition ; 5) depressive disorders and loneliness.

Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment.

We investigated the efficacy and safety of rivastigmine alone and combined with memantine in Alzheimer's disease patients previously failing on donepezil or galantamine. This was a prospective, open-label, multicentre study. After stopping donepezil or galantamine, patients received rivastigmine 3-12 mg/day for 16 weeks. Non-responders to rivastigmine monotherapy at week 16 received memantine 5-20 mg/day plus rivastigmine for 12 weeks. The primary efficacy parameter was response (Mini-Mental State Examination equal or better than at week 16) to dual therapy at week 28. Secondary criteria were changes on cognitive and behavioural scales. Two hundred and two patients were included. Ninety-three (46.3%) patients responded to rivastigmine monotherapy. Of 86 patients receiving additional memantine for another 12 weeks, 67 (77.9%) responded. Combination therapy caused no apparent safety concerns. When patients fail on donepezil or galantamine, switching to rivastigmine may improve cognition and behaviour. Should they continue to deteriorate, the addition of memantine may be beneficial.

Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil.

BACKGROUND: Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is a specific, reversible inhibitor of AChE, while rivastigmine is a slowly reversible (pseudoirreversible) dual cholinesterase (ChE) inhibitor, with brain-regional specificity for the cerebral cortex and hippocampus. According to the European Marketing Authorisations, the clinical benefit of ChE inhibitors should be reassessed on a regular basis and discontinuation should be considered when evidence of a therapeutic effect is no longer present. However, substantial differences in the pharmacological and pharmacokinetic profiles of the available ChE inhibitors suggest that it may be desirable to switch between ChE inhibitors if patients fail to show efficacy, deteriorate or are unable to tolerate their initially prescribed medication. DESIGN: This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons). RESULTS: At the end of the study, 56.2% of patients were responders to rivastigmine, as assessed using a global function scale (the Clinicians' Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of patients, respectively. Rivastigmine was generally well tolerated, the most common adverse events being nausea and vomiting, consistent with reports from previous clinical studies. The occurrence of side-effects or lack of efficacy with donepezil treatment was not a predictor of similar problems when treated with rivastigmine. CONCLUSION: Rivastigmine treatment appears to be beneficial in AD patients who have previously failed to benefit from, or were unable to tolerate treatment with, donepezil.

Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled study with MRI correlates.

The relative rarity of primary progressive (PP) and transitional progressive (TP) multiple sclerosis has meant that little documentation of cognitive function in such patients is currently available. The aim of this study was to investigate the cognitive skills of patients with PP and TP multiple sclerosis relative to matched healthy controls, and to examine the relationship of this impairment to MRI parameters. Sixty-three patients (43 PP, 20 TP) were individually matched with healthy controls, who undertook the same cognitive tasks as the patient group. The neuropsychological assessment comprised Rao's brief repeatable battery, a reasoning test, and a measure of depression. Patients also underwent T1- and T2-weighted brain MRI. These patients were taken from a larger cohort (158 PP, 33 TP) in whom it had been demonstrated that the re were no significant differences between the mean scores of the PP and TP groups on any of the cognitive variables. The 63 patients were therefore taken as one group for comparison with the healthy controls. These patients performed significantly worse than the controls in tests of verbal memory, attention, verbal fluency and spatial reasoning. An impairment index was constructed and applied to the patient data. This correlated modestly with T2-lesion load (r = 0.45, P = 0.01), T1-hypointensity load (r = 0.45, P = 0.01) and cerebral volume (r = -0.35, P = 0.01). Thus, PP and TP multiple sclerosis patients demonstrate significant cognitive dysfunction when compared with matched healthy controls. The relationship between this impairment and MRI parameters is moderate, suggesting that cognitive dysfunction in PP and TP multiple sclerosis has a complex and multifactorial aetiology, which is not adequately explained by pathology as demonstrated on conventional MRI.

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.

[Adverse seizure reactions after electroconvulsive therapy. Study of personal cases and review of the literature]. / Crises comitiales indésirables après électroconvulsivothérapie. Etude cas-témoins et revue des données de la littérature.

OBJECTIVE: To determine what are the risk factors for the occurrence of unwanted seizures after an ECT session, and what is the best attitude regarding future ECT. METHOD: We have reviewed all the case reports published in the literature between 1946 and 1995 and have carried out a prospective case-control study of all incidental seizure type side effects among a group of 43 patients treated consecutively using the same procedure within the same institution in 1993. RESULTS: Results from the literature are presented in tables I to IV and results from our case-control study in tables V to VIII. Twenty seven seizure type side effects are reported in 22 published papers reporting the case of 24 patients. Most accidents occur during the first ECT and the occurrence of non convulsive seizures is greatly increased in case of coexisting EEG-monitoring. In our own study the overall incidence is 0.95%. Risk factors are neurologic disease, psychotropic medication, history of prolonged seizure during previous ECT. CONCLUSION: It appears that no unique risk factor but a summation of several risks (personal or family history of seizure, psychotropic medications, high energy level of electric stimuli) for specific subjects increases the risk for seizures after ECT. ECT can be resumed if necessary after occurrence of a post ECT seizure with addition of anti-epileptic medication.

Dementia in Parkinson's disease: a population-based study in ambulatory and institutionalized individuals.

We examined the frequency of dementia and depressive symptomatology in 60 Parkinson's disease (PD) patients, identified in a large representative sample of the population, aged 65 years and older, living at home or in institutions in Gironde, France. Dementia, diagnosed according to DSM-III-R criteria, was present in 17.6%, and depressive symptomatology, assessed by the Center for Epidemiologic Studies-Depression Scale, was present in 32.7%. The frequency of dementia in PD increased strongly with age and was higher in institutionalized PD patients than in those living at home. PD was significantly associated with dementia for individuals living at home (odds ratio = 8.2, adjusted for age and symptoms of depression.

Validity of the International Headache Society criteria for migraine. GRIM. Groupe de Recherche Interdisciplinaire sur la Migraine.

For general practitioners and in epidemiological studies, migraine poses diagnostic problems. It is a polymorphous disease, with diagnosis based on a subjective description of symptoms. The International Headache Society (IHS) proposed a set of rigorous criteria for the diagnosis of migraine. We studied its validity on 171 outpatients of headache clinics and on 96 headache sufferers detected during an annual checkup for workers. The criteria showed an excellent specificity, however sensitivity in both samples was < 50%. This lack of validity could be due to IHS criteria being too restrictive. We therefore elaborated and validated our own diagnostic tool, based on the IHS criteria, to a sensitivity of 95% and a specificity of 78%. We propose our tool for epidemiological studies.

[The Paquid research program on the epidemiology of dementia. Methods and initial results]. / Le programme de recherche Paquid sur l'épidémiologie de la démence. Méthodes et résultats initiaux.

Paquid is an epidemiological study designed to gather and follow up a cohort of 4,000 elderly subjects (65 years and older) living at home in order to study normal and pathological brain aging. These subjects were randomly chosen in the general population of 75 communities of South-Western France. We present the results of the data collected from 2,792 subjects on the prevalence and the correlates of clinically diagnosed dementia. The DSM III criteria for dementia were met by 101 subjects (3.62 p. 100). These cases were reviewed by a neurologist to confirm the diagnosis and to determine the cause of dementia using the NINCDS-ADRDA criteria. Forty-three subjects were classified as probable Alzheimer's disease; 8 as possible Alzheimer's disease; 5 as vascular dementia; 5 as Parkinson's disease with dementia; 2 as alcoholic dementia; 2 as "dementified psychosis"; and 1 unclassified. Fifteen patients refused to be examined by the neurologist, 18 were false-positives, and 2 died before the neurologists visit. Using the NINCDS-ADRDA criteria, the prevalence of dementia was as low as 1.6 p. 100. The prevalence of probable Alzheimer's disease decreased dramatically as educational level increased, lung 5.4 p. 100 for subjects with no education, 1.7 p. 100 for subjects with grade school level, 0.4 p. 100 for subjects with high school level and 0.4 p. 100 for subjects with university degrees. The relationship between dementia and educational level is still controversial in the literature. In this study the sample was large and randomly selected; all the demented cases fulfilled the NINCDS-ADRDA criteria. This suggests that educational level is indeed an important correlate of dementia in the French elderly community.