Alzheimer Disease: Pasquier F

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Pasquier F. · No affiliation provided · Rev Neurol (Paris). · Pubmed #18805307 No free full text.

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Leys D, Pasquier F. · No affiliation provided · Stroke. · Pubmed #15073393 links to  free full text

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Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, Blum D, Delacourte A, Pasquier F, Vanmechelen E, Schraen-Maschke S, Buée L. · Inserm, U837, place de Verdun, 59045 Lille, France. · Expert Rev Proteomics. · Pubmed #18466052 No free full text.

Abstract: Microtubule-associated Tau proteins belong to a family of factors that polymerize tubulin dimers and stabilize microtubules. Tau is strongly expressed in neurons, localized in the axon and is essential for neuronal plasticity and network. From the very beginning of Tau discovery, proteomics methods have been essential to the knowledge of Tau biochemistry and biology. In this review, we have summarized the main contributions of several proteomic methods in the understanding of Tau, including expression, post-translational modifications and structure, in both physiological and pathophysiological aspects. Finally, recent advances in proteomics technology are essential to develop further therapeutic targets and early predictive and discriminative diagnostic assays for Alzheimer's disease and related disorders.

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Pasquier F, Boulogne A, Leys D, Fontaine P. · Department of Neurology, EA 2691, Memory Clinic, Lille, France. · Diabetes Metab. · Pubmed #17110895 links to  free full text

Abstract: Alzheimer's disease (AD) and diabetes mellitus (DM) are two of the most common and devastating health problems in the elderly. They share a number of common features amongst which high prevalence after 65 years, important impact of patient's quality of life, substantial health care costs. Reviews on the epidemiological studies on cognitive impairment in patients with DM found evidence of cross-sectional and prospective associations between type 2 DM and moderate cognitive impairment, on memory and executive functions. There is also evidence for an elevated risk of both vascular dementia and AD in patients with type 2 DM, albeit with strong interaction of other factors such as hypertension, dyslipidaemia and ApoE genotype. DM is an independent predictor of post-stroke dementia. DM being an atherogenic risk factor, it may increase the risk of dementia through associations with stroke, causing vascular dementia. In addition, vascular reactivity may be adversely affected by advanced glycosylation end products resulting in more subtle perfusion abnormalities. Cerebrovascular disease may exacerbate AD through direct interactions between the two pathological processes or through cognitive impairment secondary to cerebrovascular disease "unmasking" AD at an earlier stage than it would otherwise become apparent. The increased risk of AD may also be mediated by the exacerbation of B-amyloid neurotoxicity by advanced glycosylation end products identified in the matrix of neurofibrillary tangles and amyloid plaques in AD brains, or associations with insulin functions. Decreased cholinergic transport across the blood-brain barrier observed in diabetic animals may exacerbate cognitive impairment in AD. Many interventions could reduce the cognitive decline associated with DM, yet not enough are taken into account so far.

Helmer C, Pasquier F, Dartigues JF. · Inserm U.593, Université de Bordeaux II, 146, rue Léo Saignat, 33076 Bordeaux Cedex, France. · Med Sci (Paris). · Pubmed #16527211 No free full text.

Abstract: Alzheimer's disease and related disorders (dementia) are a major public health problem due to the number of cases in the general population, the projections for the future, and the consequences of these diseases. We can estimate that about 850 000 cases of dementia were present in France in 2005 and this number will increase to 1,200,000 in 2020 and 2,100,000 in 2040 if the incidence and the duration of the disease did not change. The development of prevention is therefore necessary. Four ways of prevention are credible. The most important is the treatment of vascular risk factors and particularly hypertension. Other ways are nutritional factors, stimulating leisure activities and depression.

Bombois S, Lebert F, Vellas B, Pasquier F. · Centre mémoire de ressource et de recherche, EA 2691, CHRU de Lille, 59037 Lille. · Rev Prat. · Pubmed #16396232 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder with a decline in memory and cognitive abilities. During the past 20 years, research on AD has increased the knowledge of the physiopathological mechanisms leading to the disease. The major hallmarks of AD are amyloid plaques and neurofibrillary tangles, associated with a prevalent and early cholinergic deficit and an excitotoxicity with inflammation. These pathological mechanisms represent current and future therapeutic targets. cholinesterase inhibitors were the first therapeutic class that has consistently shown a clinical efficacy and safety in patients with mild to moderate ad. more recently glutamate receptor antagonists have been shown effective in the management of patients with moderate to severe AD. These two therapeutic classes could improve cognitive functions, slow the progression of the cognitive decline, prevent some behavioural changes and delay institutionalisation. However, AD represents a problem of public health and preventive and curative strategies have to be proposed.

Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. · Stroke department, Department of Neurology, University of Lille II, EA 2691, Rue Emile Laine, Lille, France. · Lancet Neurol. · Pubmed #16239182 No free full text.

Abstract: Dementia is one of the major causes of dependency after stroke. The prevalence of poststroke dementia (PSD)-defined as any dementia occurring after stroke-is likely to increase in the future. In community-based studies, the prevalence of PSD in stroke survivors is about 30% and the incidence of new onset dementia after stroke increases from 7% after 1 year 48% after 25 years. Having a stroke doubles the risk of dementia. Patient-related variables associated with an increased risk of PSD are increasing age, low education level, dependency before stroke, prestroke cognitive decline without dementia, diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias, congestive heart failure, silent cerebral infarcts, global and medial-temporal-lobe atrophy, and white-matter changes. Stroke-related variables associated with an increased risk of PSD are stroke severity, cause, location, and recurrence. PSD might be the result of vascular lesions, Alzheimer pathology, white-matter changes, or combinations of these. The cause of PSD differs among studies in relation to the mean age of patients, ethnicity, criteria used, and time after stroke. In developed countries, the proportion of patients with presumed Alzheimer's disease among those with PSD is between 19% and 61%. Patients with PSD have high mortality rates and are likely to be functionally impaired. These patients should be treated according to the current guidelines for stroke prevention.

Lebert F, Pasquier F. · Centre de la Mémoire, Centre Médical des Monts de Flandre, Bailleul. · Rev Neurol (Paris). · Pubmed #13679730 No free full text.

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Pasquier F, Fukui T, Sarazin M, Pijnenburg Y, Diehl J, Grundman M, Miller BL. · CHRU Clinique Neurologie, Lille. France. · Ann Neurol. · Pubmed #12833367 No free full text.

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Delacourte A, Sergeant N, Wattez A, Maurage CA, Lebert F, Pasquier F, David JP. · Unité Inserm 422, 1, Place de Verdun, 59045 Lille cedex, France. · Exp Gerontol. · Pubmed #12470843 No free full text.

Abstract: Tauopathy is a concept to describe different genetic or metabolic dysfunctions of tau proteins that generate most of the known dementing disorders. Tauopathy is a degenerating process that also affects the entorhinal formation, and then the hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to APP dysfunction, a similar tauopathy process in observed in neocortical areas, well correlated to cognitive impairment. One important gap of knowledge is the relationship between tauopathy in the hippocampal formation, ageing, AD, and cognitive impairment. Here we show that the multidisciplinary analysis of numerous brains from non-demented and demented patients suggests the following observations: tauopathy of the hippocampal formation in humans is age-related but not an age-dependent process, also independent of AD, but amplified by APP dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be another type of pathological dysfunction of tau proteins, and a therapeutic target to delay AD. Relevant animal models are desperately needed to address this issue.

Dartigues JF, Helmer C, Dubois B, Duyckaerts C, Laurent B, Pasquier F, Touchon J. · Unité INSERM 330, Université de Bordeaux II, Bordeaux. · Rev Neurol (Paris). · Pubmed #11976590 No free full text.

Abstract: Alzheimer's Disease is a major Public Health problem for many reasons. First, it is a frequent disease since, in France, the prevalence was estimated at about 400.000 cases, and the annual incidence at 100.000 cases. The frequency of the disease increases, in particular due to the ageing of the population. This disease has major consequences on the life of the patient and his/her caretaker. The cost of the disease is important, estimated at about 50 milliards of French francs. Pharmaceutical treatment and other interventions are possible in particular to delay the nursing home placement. On the other hand, this disease is often ignored, under-diagnosed, underestimated and exposed to inequality in resorting to care. In summary, Alzheimer's Disease (AD) has all the criteria required for a major public health problem. In spite of this observation, AD is not yet considered as a priority for health authorities, although attitudes are changing.

Pasquier F. · Centre de la Mémoire, Clinique Neurologique, CHRU 59037 Lille, France. · Therapie. · Pubmed #11098729 No free full text.

Abstract: Memory assessment in pharmaceutical trials has to date been mainly performed in Alzheimer's disease. North American and European Medical Evaluating Agencies recommend guidelines. Tests need to be simple and short, and sensitive enough to assess changes over a wide range of severity to avoid floor or ceiling effect. They require inter-rater reliability and face validity. They should be at least appropriate for different languages and culture, correlate well with universally accepted estimates of a function and have several parallel forms available to avoid a training effect. Memory is assessed with sub-tests of composite scales assessing a number of cognitive functions including episodic memory. The ADAS-Cog has become the standard instrument since it was used for the approval of tacrine and other cholinesterase inhibitors. Some studies have assessed more specifically different sub-systems of memory. However, autobiographical, remote or prospective memory, as well as metamemory, has not been explored in pharmaceutical trials.

Leys D, Erkinjuntti T, Desmond DW, Schmidt R, Englund E, Pasquier F, Parnetti L, Ghika J, Kalaria RN, Chabriat H, Scheltens P, Bogousslavsky J. · University of Lille, France. · Alzheimer Dis Assoc Disord. · Pubmed #10609680 No free full text.

Abstract: Although vascular dementia (VaD) is the second most frequent cause of dementia after Alzheimer disease (AD), the concept remains controversial in terms of delineation. The objective of this review is to investigate, from available literature, the role of cerebral infarcts in the pathogenesis of VaD and to identify areas of interest that need further evaluation and research. The incidence of new onset dementia is increased after stroke. Stroke subtypes, total volume of cerebral infarction and functional tissue loss, and location of the lesions are probably the major determinants of VaD. Any cause of stroke can lead to VaD. In some circumstances the causal relation between stroke and dementia is clear: (1) in young patients who are unlikely to have associated Alzheimer pathology; (2) when the cognitive functioning was normal before stroke, impaired immediately after, and does not worsen over time; (3) when the lesions are located in strategic areas; and (4) when a well-defined vasculopathy known to cause dementia is proven. However, several issues remain unsolved in VaD: lack of specificity of the diagnostic criteria; influence of white matter changes and associated Alzheimer pathology; influence of preexisting cognitive status; possibility of having VaD without stroke and the clinical relevance of silent infarcts to VaD; and best therapeutic strategy to be used to prevent VaD and to prevent stroke in patients with VaD. These questions form the basis for proposals for future research.

Desmond DW, Erkinjuntti T, Sano M, Cummings JL, Bowler JV, Pasquier F, Moroney JT, Ferris SH, Stern Y, Sachdev PS, Hachinski VC. · Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609678 No free full text.

Abstract: Dementia is common among patients with cerebrovascular disease, particularly in a setting of one or more clinically evident strokes. Prior cohort and case studies have suggested that the cognitive syndrome of vascular dementia is characterized by predominant executive dysfunction, in contrast to the deficits in memory and language function that are typical of patients with Alzheimer disease. The course of cognitive decline may also differ between those dementia subtypes, with many, but not all, patients with vascular dementia exhibiting a stepwise course of decline caused by recurrent stroke and most patients with Alzheimer disease exhibiting a gradually progressive course of decline. The findings of prior studies of the cognitive syndrome of vascular dementia must be interpreted with caution, however, because of (1) possible inaccuracies in the determination of the dementia subtype and the loss of precision that might result from pooling heterogeneous subgroups of patients with vascular dementia, (2) difficulties inherent in identifying a pattern of strengths and weaknesses in patients who are required to have memory impairment and other deficits to meet operationalized criteria for dementia, and (3) the use of limited test batteries whose psychometric properties are incompletely understood. Specific questions that should be addressed by future studies are discussed.

Pasquier F, Hénon H, Leys D. · Centre de la Mémoire, Centre Hospitalier et Universitaire de Lille. · Rev Neurol (Paris). · Pubmed #10528361 No free full text.

Abstract: Stroke significantly increases the risk of dementia in subjects aged 55 years or more. Twenty to 25 p. 100 of patients are demented 5 years after a stroke. Age and supratentorial location of the vascular lesion are risk factors for post-stroke dementia. Volume, left side of the lesion, large middle cerebral artery infarction, lesions of the frontal lobe, second stroke, diabetes, aphasia, clinical features expressing the severity of the stroke event in the acute phase, mitral valve prolapse, atrial fibrillation, depression, concomitant hypoxic/ischemic disorders, and white matter changes have also been found as predictors of dementia. There are many different mechanisms of vascular pathology that may lead to dementia: ischemic or hemorrhagic lesions, large vessel disease including multi-infarct and strategic single infarct, small-vessel disease including lacunes and white matter changes, hypoperfusion.... Post-stroke dementia may not be due only to vascular lesion. Some post-stroke dementias have a progressive onset and course. The cognitive decline may pre-exist to the stroke, even when a dementia is not diagnosed. This suggests a degenerative process. Alzheimer's disease is frequent in ages when the majority of strokes occur. Alzheimer's and vascular diseases share common risk factors such as age, APOE4, hypertension, and smoking. Patients with low MMS scores and AD patients are at risk for stroke. Moreover, white matter changes are associated with stroke and Alzheimer's disease and may contribute to the cognitive decline. Many post-stroke dementias could be multifactorial. Even when vascular lesions and degenerative changes (mainly Alzheimer changes) are not severe enough, no their own, to be the cause of dementia, their summation may reduce the preclinical stage of the degenerative process.

Leys D, Pasquier F. · Service de neurologie et pathologie neurovasculaire, Hôpital Roger Salengro. · Rev Neurol (Paris). · Pubmed #10528360 No free full text.

Abstract: Arterial hypertension is the leading risk factor for all stroke subtypes. However, its relationship with cognitive decline and dementia is more complex than a simple causal relationship. Cognitive functions are worse in patients with arterial hypertension, especially when the level of education is lower, age higher and arterial hypertension more severe. Arterial hypertension is an independent factor of cognitive decline. It also leads to white matter changes which contribute to the cognitive decline. Longitudinal studies have shown that a higher blood pressure at the age of 70 years is associated with an increased risk of dementia (vascular or Alzheimer) 10 to 15 years later, but blood pressure spontaneously decreases as dementia occurs. Treatments of arterial hypertension decrease the incidence of stroke, but clinical trials are still necessary to determine if they also decrease the incidence of dementia. Preliminary results obtained in elderly subjects with systolic arterial hypertension, support this hypothesis.

Pasquier F. · Department of Neurology, Memory Clinic, Centre Hospitalier Régional et Universitaire, Lille, France. · J Neurol. · Pubmed #9987708 No free full text.

Abstract: Neuropsychology contributes greatly to the diagnosis of dementia. Cognitive deficits can be detected several years before the clinical diagnosis of dementia. The neuropsychological profile may indicate the underlying neuropathology. Neuropsychological assessment at an early stage of dementia has two goals: (a) to determine a memory disorder, not always associated with a memory complaint, and (b) to characterize the memory disorder in light of the cognitive neuropsychology and to assess other cognitive (and noncognitive) functions toward integrating the memory disorder in a syndrome. We review the global tools, the memory tests that describe the memory profile and indicate the underlying pathology, the assessment of other cognitive functions, and the neuropsychological patterns of typical Alzheimer's disease, frontotemporal dementia, primary progressive aphasia, semantic dementia, Lewy body dementia, subcortical dementia, and vascular dementia. These patterns must be interpreted in the light of the history, rate of progression, imaging results, and nature of existing behavioral disturbances. Moreover, there may be overlap between two or more pathologies, which complicates the diagnostic process. Follow-up of patients is necessary to improve diagnostic accuracy.

Mormont E, Laurier-Grymonprez L, Baisset-Mouly C, Pasquier F. · Service de Neurologie, Cliniques Universitaires UCL de Mont-Godinne, Yvoir, Belgique. · Rev Neurol (Paris). · Pubmed #13679718 No free full text.

Abstract: It may be difficult to distinguish Lewy body dementia (LBD) from Alzheimer's disease (AD) especially at an early stage. Clinical diagnostic criteria for LBD still lack sensitivity. We compared memory performance in early AD and LBD to identify features that may help to distinguish these two conditions. Patients with Mini Mental State scores equal or above 18 were consecutively selected retrospectively from the University Out-patient Memory Clinic database. Probable LBD and AD were respectively diagnosed according to the international consensus criteria and the NINCDS-ADRDA criteria. Short-term memory was assessed with the digit span subtest of the Wechsler Memory Scale and the Corsi block-tapping test. Long term verbal memory was assessed with a French version of the Grober and Buschke test. Long-term visual memory was tested with the recall of four geometric figures of the CERAD battery. There was no difference between the two groups in short-term or long-term visual memory. Except for the immediate and first free recalls, DCL patients performed significantly better than AD patients in all subtests of the Grober and Buschke test. The more striking differences were seen with the third total and delayed total recall. These results highlight the differences of memory impairment pattern in early LBD and AD. Episodic verbal memory is better in LBD patients who benefit more from cues, reflecting the subcortical component of the disease. Such neuropsychological data should be validated prospectively and further be part of the diagnostic criteria.

Lebert F, Lys H, Haëm E, Pasquier F. · EA2691, centre de la mémoire de ressources et de recherche, hôpital R.-Salengro, CHRU de Lille, Lille, France. · Encephale. · Pubmed #19081458 No free full text.

Abstract: INTRODUCTION: Converging evidence suggests that people with bipolar disorder (BPD) exhibit persistent cognitive impairment independently from the emotional state. In old age BPD, the cognitive decline is more severe and can fulfill the criteria of dementia. However, the characteristics of bipolar disorder dementia are still unknown. AIM OF THE STUDY: The aim of the study was to characterise the cognitive and imaging profile of the dementia following bipolar disorder. METHOD: Patients fulfilling criteria of dementia and followed-up in the memory unit for at least two years were included. Patients with substance abuse were excluded. A battery of specific (assessing verbal memory, attention, frontal executive function, construction and visuospatial impairment), and global (MMSE and Mattis dementia rating scale) neuropsychological tests, behavioural assessment using the frontotemporal behavioural scale, MRI and HMPAO-SPECT imaging were performed in all patients during euthymic state. RESULTS: We included 13 patients with bipolar disorder (9W/4M). The mean age was 70.8 years (+/-7.7). Dementia began in average 29.2 years (+/-10.1) after the onset of the bipolar disorder. The mean score of MMSE was 24.0 (+/-4.3). The mean score of the Mattis dementia rating scale was 122.5 (+/-8.9). After an average of 6.1 years (+/-2.8) of follow-up, the mean score of MMSE was 23.5 (+/-3.2). The annual MMSE score decrease was of 0.5 (+/-4.4) per year. In more than 75% of the patients, Trail-Making Test-part B, Go-nogo test, Stroop test, delayed free recall in verbal explicit long-term memory test, category fluency tasks and code test were impaired. In more than 50% of patients, free recall, delayed cued recall, clock test, visuospatial battery and temporal orientation were impaired. On the other hand, spatial orientation and recognition were within the standards. The mean of the BREF score was 10.6 (+/-3.2). A moderate frontal behavioural syndrome was observed, but never persistent hallucinations. Seven patients had been treated with lithium and seven with antipsychotics, but none during the neurological assessment. Moderate extrapyramidal signs were reported in 10 patients, of which the seven patients treated in the past with antipsychotics. MRI showed no focal atrophy and no vascular lesions. Functional imaging conducted in 10 patients always showed uptake decrease in the frontotemporal regions and sometimes in the parietal region too. After six years of follow-up, no patient fulfilled the probable criteria for the main dementia, Alzheimer disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies. CONCLUSION: The data of this study support a possible specific dementia postbipolar disorder and not only mild cognitive decline. This hypothesis could be tested in a prospective study. Such dementia could be a main differential diagnosis from long lasting frontotemporal dementia. The pathogenic process of this dementia could also be determined.

Hansmannel F, Lendon C, Pasquier F, Dumont J, Hannequin D, Chapuis J, Laumet G, Ayral AM, Galimberti D, Scarpini E, Campion D, Amouyel P, Lambert JC. · INSERM, U744, Institut Pasteur de Lille, Université de Lille, Lille, France. · Neurosci Lett. · Pubmed #18983895 No free full text.

Abstract: Expression of ornithine transcarbamylase (OTC) is strongly induced in the brain of individuals suffering from Alzheimer's Disease (AD). Association studies in a population from northern France have revealed that two SNPs -389 G/A (rs5963409) and -241 A/G (rs5963411) located in the promoter of the OTC gene are associated with the risk of developing AD. In the present work, these association studies were extended to a population of 2113 AD cases and 1580 controls from northern France, western France, the United Kingdom and Italy. The rs5963409 minor allele was weakly but significantly associated with an increased risk of developing AD (OR=1.19, p=0.004). This association was independent of age and ApoE status. Our results support that the OTC gene may be a minor genetic determinant of AD.

Bruandet A, Richard F, Bombois S, Maurage CA, Deramecourt V, Lebert F, Amouyel P, Pasquier F. · INSERM, U744, Lille, France. · J Neurol Neurosurg Psychiatry. · Pubmed #18977819 No free full text.

Abstract: OBJECTIVE: Vascular dementia (VaD) and Alzheimer disease with cerebrovascular disease (AD+CVD) are the leading causes of dementia after Alzheimer disease alone (AD). Little is known about the progression of either VaD or AD+CVD. The aim of this study was to compare demographic features, cognitive decline and survival of patients with VaD, AD+CVD and AD alone attending a memory clinic. METHODS: This study included 970 patients who were followed at the Lille-Bailleul memory clinic, France. Cognitive functions were measured with the Mini Mental State Examination (MMSE) and the Dementia Rating Scale (DRS). Survival rate was analysed with a left-truncated Cox model. Analyses were adjusted for age, sex, education, hypertension, diabetes and baseline MMSE and DRS. RESULTS: Of 970 patients, 141 had VaD, 663 AD alone and 166 AD+CVD. The latter were significantly older than AD or VaD patients at onset (71 (SD 7) vs 69 (9) and 68 (9) years, p = 0.01) and at first visit (75 (6) vs 73 (8) and 72 (8) years, p = 0.0002). Baseline MMSE and DRS evaluations were highest for VaD compared with AD alone or AD+CVD patients (p<0.006). Cognitive decline during follow-up was slowest for VaD, intermediate for AD+CVD and fastest for AD alone (p = 0.03). After adjustment, compared with AD patients, mortality risk was similar for those with VaD (relative mortality risk (RR) = 0.7 (0.5 to 1.1)) and tended to be lower for AD+CVD (RR = 0.7 (0.5 to 1.0)). The shorter the delay between first symptoms and first visit, the longer patients survived. CONCLUSION: This clinical cohort study shows that patients with VaD, AD+CVD and AD present different characteristics at baseline and during follow-up, and underlines the need to distinguish between them.

Vidal JS, Lacombe JM, Dartigues JF, Pasquier F, Robert P, Tzourio C, Alpérovitch A. · Institut National de la Santé et de la Recherche Médicale (INSERM-U708), Bordeaux, France. · Neuroepidemiology. · Pubmed #18815451 No free full text.

Abstract: BACKGROUND: Clinical studies reported that treatments for Alzheimer's disease may have an impact on behavioral and psychiatric disorders. We tested the hypothesis that memantine treatment initiation modifies psychotropic medication in real-life practice patients. METHODS: A 2-year follow-up cohort study was performed. A sample of patients treated in the general population, extracted from the database of the French national healthcare system (CNAM-TS), was examined. The sample included 4,600 memantine-treated patients (mean age 79.8 years, 69% women) randomly selected from the database of the CNAM-TS covering 69% of the French population aged 65 years and over. The follow-up rate was 95.0%. This database includes exhaustive data on drug consumption. We used interrupted time series analysis of the proportion of psychotropics users (all psychotropic drugs and specific categories) before and after onset of memantine. RESULTS: There was a 39-50% regular increase in patients treated with psychotropic drugs before memantine initiation This increasing trend stopped after memantine initiation, the proportion of psychotropic users remaining stable around 53% up to the end. The trends before and after memantine onset were significantly different (p < 0.001). CONCLUSIONS: Our results suggest a temporal relationship between the onset of memantine and the stabilization of psychotropic drugs use in this large sample of elderly patients.

Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. · Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA. · Cell. · Pubmed #18585350 links to  free full text

Abstract: Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.