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The purpose of this review is to provide an update on the role of tau beyond the stabilization of microtubules and on the clinical, pathological, diagnostic and therapeutic aspects of tauopathies.Beyond its function as a microtubule-associated tau protein, tau is also involved in gene regulation, signal transduction and metabolism. Experimental models allow for the development of new diagnostic and therapeutic tools. Tauopathies encompass different disorders that may manifest with various clinical syndromes. Differential diagnosis with other proteinopathies is still challenging. Cerebrospinal fluid biomarkers and radiotracers were extensively studied in the last year. Although diagnostic accuracy remains deceiving in non-Alzheimer's disease tauopathies, positron emission tomography tau tracers could be used to monitor disease progression.Despite the advent of novel therapeutic approaches and the increasing number of clinical trials in tauopathies, accurate clinical diagnosis is still an unmet need and better tau biomarkers are still desperately needed. Although primary taupathies are rare and heterogeneous disorders, their combined prevalence and the importance of tau disorder in Alzheimer's disease and secondary tauopathies makes research on tauopathy a priority - because it could benefit many patients.

Objective: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. Methods: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). Results: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. Conclusion: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

We aimed to evaluate the influence of prestroke cognitive impairment (PSCI) on outcomes in stroke patients treated with IV recombinant tissue plasminogen activator (rtPA).OPHELIE-COG was a prospective observational multicenter study conducted in French and Japanese patients treated with IV rtPA for cerebral ischemia. The preexisting cognitive status was evaluated by the short version of the Informant Questionnaire on Cognitive Decline in the Elderly. PSCI was defined as a mean score3. The primary endpoint was a favorable outcome (modified Rankin Scale [mRS] score 0-1) after 3 months. Secondary endpoints were symptomatic intracerebral hemorrhage (sICH), mRS scores 0-2, and mortality at 3 months. We performed a pooled analysis with Biostroke and Strokdem.Of 205 patients, 62 (30.2%) met criteria for PSCI. They were 11 years older (p0.001). Although they had more sICH and were less frequently independent after 3 months, they did not differ for any endpoint after adjustment for age, baseline NIH Stroke Scale score, and onset-to-needle time: sICH (odds ratio [OR] 2.78; 95% confidence interval [CI] 0.65-11.86), mRS 0-1 (OR 0.82; 95% CI 0.41-1.65), mRS 0-2 (OR 0.62; 95% CI 0.28-1.37), death (OR 0.40; 95% CI 0.08-2.03). The pooled analysis found no association of PSCI with any endpoint.Ischemic stroke patients with PSCI should receive rtPA if they are eligible. This conclusion cannot be extended to severe cognitive impairment or severe strokes.This study provides Class IV evidence that in patients with PSCI presenting with acute ischemic stroke, IV rtPA improves outcomes.

This study aims to determine the distribution and to quantify microbleeds (MBs) in postmortem brains of patients with Alzheimer disease (AD) on T2*-weighted gradient-echo 7.0 T magnetic resonance imaging. Twenty-eight AD brains were compared with 5 controls. The AD brains were subdivided further: 18 without and 10 with additional severe cerebral amyloid angiopathy (AD-CAA). The distribution and the number of cortical focal signal intensity losses, representing MBs, were assessed on coronal sections at the frontal, the central, and the occipital level of a cerebral hemisphere. MBs prevailed in the central sections (P=0.005) of AD brains without CAA, whereas in AD-CAA brains, they were more frequent in all coronal sections (P≤0.002). They prevailed in the deep cortical layers of the AD brains and of the controls (P≤0.03). They were significantly increased in all cortical layers of the AD-CAA brains (P≤0.04), compared with the controls. MBs prevalence in brains of AD patients had a different topographic distribution according to the absence or presence of severe CAA.

Introduction: Memory impairment caused by bilateral hippocampal primitive brain tumor is rarely reported. Clinical and MRI features can mimic paraneoplastic limbic encephalitis (PLE), and the differential diagnosis between these 2 entities may be difficult. Case Report: We report the case of a 42-year-old woman presenting with amnesia without neurologic focal signs at clinical examination. The neuroimaging features consisted of bilateral limbic hyperintensities on T2-weighted and FLAIR brain MRI. Despite exhaustive biologic and radiologic investigations, no specific etiology was found. The diagnosis of paraneoplastic limbic encephalitis was suspected, although antineuronal antibodies were negative and no cancer was detected after the first evaluation. Eight months after onset, the memory complaint of the patient increased along with disability in activities of the daily living, the neurologic examination slightly changed with frontal neurologic signs and the brain MRI showed a new cystic lesion in the left hippocampus with enhancement after contrast administration. The left temporal tumor was resected and the neuropathological examination was consistent with gliomatosis cerebri with a focal high grade astrocytoma. Conclusions: This case highlights the need to consider the possibility of infiltrative gliomatosis in patients presenting with features of paraneoplastic limbic encephalitis.

Background and Purpose— Patients with mild cognitive impairment (MCI) have an increased risk of dementia. The identification of predictors of conversion to dementia is therefore important. The aim of our study was to test the hypothesis that subcortical hyperintensities (SH) are associated with an increased rate of conversion to dementia in MCI patients. Methods— This was an observational study on consecutive MCI patients attending a memory clinic. We assessed SH on a baseline MRI scan, using a semiquantitative rating scale. A multivariable Cox regression model was used to test the association of SH with conversion to dementia. Results— We included 170 MCI patients. The median duration of follow-up was 3.8 years. During this period, 67 patients (39.4%, 95% CI: 32.1 to 46.8%) developed dementia: Alzheimer disease (AD) in 29 patients, dementia with Lewy bodies in 19, mixed dementia in 8, vascular dementia in 7, fronto-temporal dementia in 2, and primary progressive aphasia in 2. SH were not associated with the risk to develop dementia as a whole, including AD. However, the risk to develop vascular or mixed dementia increased significantly with increasing amounts of SH at baseline (HR=1.14 [95% CI: 1.06 to 1.24]), especially periventricular hyperintensities (HR=2.71 [95% CI: 1.60 to 4.58]), independently of medial temporal lobe atrophy, age, gender, vascular risk factors, education, and cognitive functions at baseline. Conclusion— The risk of vascular or mixed dementia, but not of other types of dementia, was significantly increased in MCI patients with a large amount of subcortical hyperintensities at baseline.

A precise diagnosis of the cause of dementia during life is needed for proper management, in order to explain the symptoms to the patient and to the close relatives, and to give appropriate indications on the prognosis and possibly on the genetic risk. Frontotemporal dementia remains under-diagnosed and often misdiagnosed for Alzheimer's disease, the most common cause of dementia. More and more studies explore the differences between the two syndromes.Progress in neuropsychological testing improves the ability to distinguish between syndromes and knowledge on brain functioning. More attention has been paid over these last months--or years--on emotion, insight, behavior, artistic creativity and quality of responses. Yet, biomarkers do not improve the diagnostic accuracy of trained clinicians, and do not help to distinguish between histological subtypes of frontotemporal dementia.Improvement in knowledge on cognitive and emotional impairment in frontotemporal dementia and Alzheimer's disease is essential for the management of the patient--information can be given to the patients and the families that helps them to understand and to behave in consequence.

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.

Objective: To characterize the natural history of primary progressive aphasia (PPA). Methods: Forty-nine patients (28 women) with newly diagnosed with PPA presenting to a memory disorders clinic between 1992 and 2001 were prospectively evaluated. Results: Median age at onset was 62 years (range 49 to 73 years) and at first visit was 66 years (52 to 80 years). The median duration of follow-up was 4 years (1 to 11 years). Impairments in activities of daily living developed a median of 6 to 7 (2 to 12) years post onset. Seventy-five percent of patients eventually met clinical diagnostic criteria for frontotemporal dementia (FTD), 14% met diagnostic criteria for dementia with Lewy bodies, and 8% developed signs of corticobasal degeneration; 60% of the patients died after a median course of 7 years (3 to 17 years) at a median age of 71 years (56 to 81 years). Patients showing high Mini-Mental State Examination scores, moderate aphasia, and fluent language at first visit subsequently retained greater autonomy in daily life. Conclusions: Although activities of daily living are well maintained during the first years of the disease, patients with primary progressive aphasia (PPA) may lose autonomy 6 to 7 years after onset. The majority of patients with PPA in the current study developed frontotemporal dementia.

Objective: To determine the spatiotemporal mapping of tau pathologies and insoluble pools of Aβ in aging and sporadic AD, and their contribution to the physiopathologic, clinical, and neuropathologic features. Methods: The authors studied 130 patients of various ages and different cognitive status, from nondemented controls (n = 60) to patients with severe definite AD (n = 70) who were followed prospectively. Insoluble Aβ 42 and 40 species were fully solubilized and quantified in the main neocortical areas, with a new procedure adapted to human brain tissue. Tau pathology staging was determined in 10 different brain areas, using Western blots. Results: In AD, there is a constellation of amyloid phenotypes, extending from cases with exclusively aggregated Aβ 42 to cases with, in addition, large quantities of insoluble Aβ 40 species. Five other points were observed: 1) There was no spatial and temporal overlap in the distribution of these two insoluble Aβ species in cortical brain areas. 2) In contrast to solubilized Aβ 40 aggregates composed essentially of monomers and dimers, solubilized Aβ 42 was essentially observed as dimers and multimers. 3) Aβ 42 aggregates were observed at the early stages of tau pathology, whereas the insoluble Aβ 40 pool was found at the last stages. 4) During the progression of the disease, Aβ aggregates increase in quantity and heterogeneity, in close parallel to the extension of tau pathology. 5) There was no spatial overlap between Aβ aggregation that is widespread and heterogeneously distributed in cortical areas and tau pathology that is progressing sequentially, stereotypically, and hierarchically. Conclusions: These observations demonstrate that Aβ 42 aggregation, and not Aβ 40, is the marker that is close to Alzheimer etiology. It should be the main target for the early biological diagnosis of AD and modeling. Furthermore, the spatial mismatch between amyloid s-precursor protein (APP) and tau pathologies in cortical brain areas demonstrates that neurodegeneration is not a direct consequence of extracellular Aβ neurotoxicity. Hence, there is a synergetic effect of APP dysfunction, revealed by Aβ aggregation, on the neuron-to-neuron propagation of tau pathology.

Objective: To evaluate the 3-year incidence of poststroke dementia (PSD) and the influence of prestroke cognitive decline. Methods: The authors evaluated prestroke cognitive functions in 202 consecutive stroke patients ≥40 years old using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), with a cut-off of 104 for the diagnosis of dementia. Six months and then annually after stroke, dementia was reassessed. The diagnosis of dementia was based on the International Classification of Diseases, 10th revision criteria in survivors who underwent a visit with a neurologist, or on the IQCODE score obtained by telephone contact with the family in survivors who did not. Statistics were performed using life-table methods. Results: Thirty-three patients were excluded because of prestroke dementia. In the 169 remaining patients, the cumulative proportion of patients with dementia was 28.5% at the end of the follow-up period, with most of PSD occurring during the first 6 months. Using multivariate analysis, independent predictors of PSD were aging, preexisting cognitive decline, severity of deficit at admission, diabetes mellitus, and silent infarcts. Leukoaraiosis was an independent predictor of PSD when prestroke cognitive decline was not taken into account. The presumed etiology of dementia was vascular dementia (VaD) in two-thirds of patients and AD in one-third. Conclusions: The risk of PSD is high, and increased in patients with prestroke cognitive decline, with about one-third of patients meeting the criteria for AD and two-thirds meeting the criteria for VaD. These results confirm that, in stroke patients, an underlying degenerative pathology may play a role in the development of PSD.

Background and Purpose —MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Methods —Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using κ statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Results —Interrater reliability was good for MRI (κ=0.67) and moderate for CT (κ=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. Conclusions —We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

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.

Summary: 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.

At autopsy, frontotemporal dementia (FTD) account for up to 20% of degenerative dementia cases, although FTDs are underrecognized in memory clinics. FTDs are confused with Alzheimer disease (AD) or vascular dementia (VaD). These misdiagnosis may affect the results of AD pharmacological trials. The first manifestations of FTD are behavioral abnormalities. The aim of this study was to assess a behavioral scale of frontal lobe dysfunction and to determine a behavioral cutoff to diagnose early FTD and distinguish it from AD and VaD. The score of the behavioral frontotemporal lobe dysfunction assessment scale was higher in FTD than in other dementias (p < 0.0001). With a cutoff of 3 points on the scale, FTD patients were diagnosed with a specificity of 95% and sensitivity of 91%. Noncognitive symptoms known to be institutionalization factors could contribute to differences between etiologies of mild dementia.

Background and Purpose— Subcortical hyperintensities (SH) have not been systematically evaluated in mild cognitive impairment (MCI). We sought to describe their frequency and distribution, and to test their association with cognitive characteristics in MCI patients. Methods— We performed standardized neuropsychological tests and an MRI scan in 170 consecutive MCI patients. Medial temporal lobe atrophy and SH, including periventricular, lobar white matter, basal ganglia and infratentorial hyperintensities, were assessed with visual semiquantitative scales. Results— The median age was 68.1 years (range: 45.5 to 87.0), and the median Mini-Mental State Examination score 28.0 (range: 26.0 to 30.0). MCI subtypes were amnestic single domain (21.2%), amnestic multiple domain (52.3%), nonamnestic single domain (21.8%), and nonamnestic multiple domain (4.7%). SH were found in 157 patients (92.6%); periventricular hyperintensities (80.6%) and lobar white matter hyperintensities (83.5%) were the most prominent locations. There was no association between SH and MCI subtypes. Executive dysfunction was independently associated with SH (odds ratio=2.53, 95% CI: 1.20 to 5.32), periventricular hyperintensities (odds ratio=2.51, 95% CI: 1.13 to 5.55), and white matter hyperintensities (odds ratio=2.08, 95% CI: 1.01 to 4.25). Conclusions— The prevalence of SH is high in MCI patients, irrespective of MCI subtypes. SH (especially periventricular hyperintensities, and lobar white matter hyperintensities) are associated with executive dysfunction.

Recent progress in diagnostic criteria of non-Alzheimer degenerative dementias is reviewed. These dementias comprise frontotemporal dementias (including hereditary dementias), primary progressive aphasia and anarthria, corticobasal degeneration, progressive supranuclear palsy and dementia with Lewy bodies. The approach of studying these diseases has changed considerably with genetic and biochemical analyses. A molecular classification is suggested and the clinical significance of this classification is discussed.

Editors' Note: Based on his experience, Dr. Verslegers disagrees with “Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache,” which presented arguments to use sumatriptan injections on a daily basis in refractory patients with cluster headache. Instead, he suggests that ergotamine should be employed when classical treatments fail. Drs. Leone and Proietti Cecchini, authors of the study, argue that ergots are less specific than triptans, have more side effects such as nausea and vomiting, increase the risk of cardiovascular events, and can lead to ergotism when taken frequently. The authors also suggest that neurostimulation procedures can be beneficial in treating intractable chronic cluster headache. Commenting on “Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage,” Bertoux et al. point to the issue …

White matter lesions (WML) are frequently found on magnetic resonance imaging (MRI) scans in stroke patients, in patients with cognitive decline or dementia, and in healthy—usually elderly—subjects who have vascular risk factors, especially arterial hypertension.1 However, many neurologists in their clinical practice have seen elderly subjects with a long history of improperly treated arterial hypertension who have only few WML. They have met also middle-aged subjects, with less severe, more recent, and properly treated arterial hypertension with already extensive WML. These clinical findings suggest that not all hypertensive subjects have similar risks of WML. Genetic factors may explain differences in the susceptibility of the cerebral white matter to arterial hypertension: (1) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is clearly identified as a genetic disease due to a mutation in the Notch 3 gene, in which severe WML occur at an early stage of the disease in young subjects, even in the absence of vascular risk factors;2 (2) …

Objective: To evaluate the frequency of c9ORF72 repeat expansion in french FTLD and FTLD-ALS patients and to describe the associated clinical phenotypes, imaging and brain pathological characteristics. Background c9ORF72 was recently identified as a major gene implicated in FTLD/ALS spectrum of disease. Its genetic contribution remains to be established in different geographic populations. Design/Methods: c9ORF72 repeat expansion was searched for by repeat-primed PCR in 600 french probands with frontal variant FTD (fvFTD, n=330), FTLD with amyotrophic lateral scelrosis (FTLD-ALS, n=210), primary progressive aphasia (PPA, n=40) and progressive supranuclear palsy (PSP, n=20). Half patients had a family history of FTLD or ALS, half were sporadic cases. Brain post-mortem examination was performed in 18 patients. Results: A GGGGCC repeat expansion was identified in 140 unrelated probands. The frequency of the expansion was 15% in the patients with bvFTD (8% in sporadic cases, 20% in familial bvFTD)and 43% in the patients with FTLD-ALS (15% in sporadic cases; 64% in familial forms). No expansion was identified in the PPA patients. Most patients had a bvFTD; only two patients presented with semantic dementia or progressive non fluent aphasia both associated with ALS at onset. The detailed clinical phenotypes, SPECT imaging characteristics and pathology of 60 c9ORF72 expansion carriers will be presented. Conclusions: c9ORF gene is the most frequent cause of familial FTLD before PGRN gene. The frequency of mutation is much higher in the population with FTLD-ALS. Less than 30% of familial FTLD/FTLD-ALS are unexplained by the eight known FTLD genes. Disclosure: Dr. Le Ber has nothing to disclose. Dr. Camuzat has nothing to disclose. Dr. Guillot-Noel has nothing to disclose. Dr. Guedj has nothing to disclose. Dr. Hannequin has nothing to disclose. Dr. Wargon has nothing to disclose. Dr. Couratier has nothing to disclose. Dr. Deramecourt has nothing to disclose. Dr. Berger has nothing to disclose. Dr. Viennet has nothing to disclose. Dr. Pasquier has nothing to disclose. Dr. Lacomblez Aurousseau has nothing to disclose. Dr. Salachas has nothing to disclose. Dr. Martinaud has nothing to disclose. Dr. Golfier has nothing to disclose. Dr. Puel has nothing to disclose. Dr. Vercelletto has nothing to disclose. Dr. Didic has nothing to disclose. Dr. Sauvee has nothing to disclose. Dr. Sellal has nothing to disclose. Dr. Thomas-Anterion has nothing to disclose. Dr. Campion has nothing to disclose. Dr. Michel has nothing to disclose. Dr. Dubois has received personal compensation for activities with Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen as a consultantDr. Dubois has received personal compensation for serving on the advisory board of Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen.Dr. Dubois has received research support from Novartis and Sanofi-Aventis. Dr. Camu has nothing to disclose. Dr. Seilhean has nothing to disclose. Dr. Meininger has received personal compensation for activities with Servier and GlaxoSmithKline. Dr. Habert has nothing to disclose. Dr. Duyckaerts has nothing to disclose. Dr. Brice has nothing to disclose.

To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD.The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment.The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively.NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired.The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

To the Editor: Kokmen et al. [1] found a 50% increase in the incidence of Alzheimer's disease (AD) one year after a first ischemic stroke. This finding supports the hypothesis that most cases of dementia recognized after an ischemic stroke are of neurodegenerative origin rather than the direct consequence of the infarcts. However, retrospective studies may underestimate the incidence rate of dementia; preexisting cognitive disorders may be unrecognized by families and general practitioners in the absence of a …