Florence Lebert

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease

Objective: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. Background: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. Methods: 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 Aβ were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. Results: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 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. Conclusions: 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.

Poststroke dementia Incidence and relationship to prestroke cognitive decline

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.

Frontotemporal Dementia: A Randomised, Controlled Trial with Trazodone

Behavioural troubles due to frontotemporal dementia (FTD) are difficult to treat. The serotonergic system is associated with frontal lobes, the degeneration of which contributes to FTD. Trazodone increases the extracellular 5-HT levels in the frontal cortex. In a randomised, double-blind, placebo-controlled cross-over study, we investigated the effect of trazodone. There was a significant decrease in the Neuropsychiatry Inventory (NPI) total score with trazodone (p = 0.028) in the 26 evaluable patients. A decrease of more than 50% in the NPI score was observed in 10 patients with trazodone. This improvement was mainly based on the improvement of 4 items of the scale (irritability, agitation, depressive symptoms and eating disorders). The Mini-Mental State Examination was not modified and trazodone was well tolerated. Results of this first placebo-controlled trial suggest that trazodone is an effective treatment for the behavioural symptoms of FTD.

Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer’s disease

ObjectiveTo determine the spatiotemporal mapping of tau pathologies and insoluble pools of A&bgr; in aging and sporadic AD, and their contribution to the physiopathologic, clinical, and neuropathologic features. MethodsThe 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 A&bgr; 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. ResultsIn AD, there is a constellation of amyloid phenotypes, extending from cases with exclusively aggregated A&bgr; 42 to cases with, in addition, large quantities of insoluble A&bgr; 40 species. Five other points were observed: 1) There was no spatial and temporal overlap in the distribution of these two insoluble A&bgr; species in cortical brain areas. 2) In contrast to solubilized A&bgr; 40 aggregates composed essentially of monomers and dimers, solubilized A&bgr; 42 was essentially observed as dimers and multimers. 3) A&bgr; 42 aggregates were observed at the early stages of tau pathology, whereas the insoluble A&bgr; 40 pool was found at the last stages. 4) During the progression of the disease, A&bgr; aggregates increase in quantity and heterogeneity, in close parallel to the extension of tau pathology. 5) There was no spatial overlap between A&bgr; aggregation that is widespread and heterogeneously distributed in cortical areas and tau pathology that is progressing sequentially, stereotypically, and hierarchically. ConclusionsThese observations demonstrate that A&bgr; 42 aggregation, and not A&bgr; 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 ß-precursor protein (APP) and tau pathologies in cortical brain areas demonstrates that neurodegeneration is not a direct consequence of extracellular A&bgr; neurotoxicity. Hence, there is a synergetic effect of APP dysfunction, revealed by A&bgr; aggregation, on the neuron-to-neuron propagation of tau pathology.

Prediction of pathology in primary progressive language and speech disorders

Objective: Frontotemporal lobar degeneration (FTLD) encompasses a variety of clinicopathologic entities. The antemortem prediction of the underlying pathologic lesions is reputed to be difficult. This study sought to characterize correlations between 1) the different clinical variants of primary progressive language and speech disorders and 2) the pathologic diagnosis. Methods: The latter was available for 18 patients having been prospectively monitored in the Lille Memory Clinic (France) between 1993 and 2008. Results: The patients were diagnosed with progressive anarthria (n = 5), agrammatic progressive aphasia (n = 6), logopenic progressive aphasia (n = 1), progressive jargon aphasia (n = 2), typical semantic dementia (n = 2), and atypical semantic dementia (n = 2). All patients with progressive anarthria had a tau pathology at postmortem evaluation: progressive supranuclear palsy (n = 2), Pick disease (n = 2), and corticobasal degeneration (n = 1). All patients with agrammatic primary progressive aphasia had TDP-43-positive FTLD (FTLD-TDP). The patients with logopenic progressive aphasia and progressive jargon aphasia had Alzheimer disease. Both cases of typical semantic dementia had FTLD-TDP. The patients with atypical semantic dementia had tau pathologies: argyrophilic grain disease and corticobasal degeneration. Conclusions: The different anatomic distribution of the pathologic lesions could explain these results: opercular and subcortical regions in tau pathologies with progressive anarthria, the left frontotemporal cortex in TDP-43-positive frontotemporal lobar degeneration (FTLD-TDP) with agrammatic progressive aphasia, the bilateral lateral and anterior temporal cortex in FTLD-TDP or argyrophilic grain disease with semantic dementia, and the left parietotemporal cortex in Alzheimer disease with logopenic progressive aphasia or jargon aphasia. These correlations have to be confirmed in larger series.

Verbal fluency in dementia of frontal lobe type and dementia of Alzheimer type.

This study compares semantic (category) and letter-initial verbal fluency performance in dementia of frontal lobe type, dementia of Alzheimer type, and control subjects matched for age, sex, and level of education. As well as demographic characteristics, patients were matched for severity of dementia as estimated by the mini mental scale (23.2 (SD 4.9)). All patients with dementia of frontal lobe type had a frontal hypoperfusion on single photon emission computed tomography whereas patients with dementia of Alzheimer type showed mainly posterior deficits. Patients had significantly lower verbal fluency than controls but those with dementia of frontal lobe type did not differ from those with dementia of Alzheimer type in the number of words generated, intrusions, or preservations. Category fluency was more impaired than letter fluency in both dementias. No correlation between frontal index, frontal/parietal index, and fluency was found. Verbal fluency tests are sensitive tools for detecting dementia but do not seem useful in distinguishing between patients with dementia of Alzheimer type and those with dementia of frontal lobe type in early disease.

Confusional State in Stroke Relation to Preexisting Dementia, Patient Characteristics, and Outcome

BACKGROUND AND PURPOSE Acute confusional state (ACS) is frequent in hospitalized stroke patients. We previously showed that 16% of patients admitted for a stroke have preexisting dementia. The extent to which preexisting cognitive decline is associated with a risk of ACS at the acute stage of stroke remains to be systematically examined. The aim of this study was to evaluate the prevalence of ACS in acute stroke patients, to study the influence of preexisting cognitive decline and other patient characteristics, and to evaluate the influence of ACS on outcome. METHODS We diagnosed ACS using DSM-IV criteria and the Delirium Rating Scale with a cutoff of 10 in 202 consecutive stroke patients aged 40 years or older (median age, 75 years; range, 42 to 101 years). Cognitive functioning before stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly. RESULTS Forty-nine stroke patients (24.3%; 95% CI, 18.3% to 30.2%) had an ACS during hospitalization. Using logistic regression analysis, we found preexisting cognitive decline (P=0.006) and metabolic or infectious disorders (P=0.008) to be independent predictors of ACS. Functional, but not vital, prognosis was worse in patients with ACS at discharge and 6 months after stroke. CONCLUSIONS ACS occurs in one fourth of stroke patients older than 40 years. Its occurrence requires inquiry for a preexisting cognitive decline, which usually remains unrecognized in the absence of a systematic evaluation.

The clinical picture of frontotemporal dementia: diagnosis and follow-up.

Frontotemporal dementia (FTD) was diagnosed in 74 outpatients with a standardized assessment including neuropsychological tests, behavioural scale, structural and functional imaging. Clinical characteristics were consistent with the literature data. The cohort was followed for 2–6 years to determine the reliable variable for evaluating the progression of FTD. Every fourth patient died after a mean duration of 7 years. At first, FTD manifests itself in behavioural changes with relatively stable global cognition although language, verbal fluency and memory tests were reliable tools to follow the progression of the disease. Below 18 of Mini-Mental State Examination, mutism and apathy prevented from neuropsychological testing within the next 6 months. Behavioural disorders evolved with time but restlessness and hyperorality were long-lasting. Imaging showed the progression of a consistent pattern of anterior abnormalities with frequent leukoaraiosis.

Depressive symptoms after stroke and relationship with dementia A three-year follow-up study

Objective: To determine frequency, determinants, and time course of poststroke depressive symptoms (DS) and their relationship with dementia. Methods: Two hundred two consecutive stroke patients were prospectively evaluated for DS, followed up over a 3-year period. Patients with Montgomery and Asberg Depression Rating Scale (MADRS) scores of ≥7 were considered as having DS. The severity of the neurologic deficit, functional outcome, and dementia were quantified with the Orgogozo Scale, modified Rankin Scale, Informant Questionnaire on Cognitive Decline in the Elderly, and an extensive battery of neuropsychological tests. Results: DS were present in 43% of survivors after 6 months, 36% after 12 months, 24% after 24 months, and 18% after 36 months. The severity of the neurologic deficit at admission was the only independent predictor of DS at month 6. DS at month 6 were more frequent in patients with previous depression, dementia, and right superficial lesions. Younger age and right superficial lesions were the two variables independently associated with the presence of DS at month 36. The time course of the various DS differed, sadness remaining frequent 3 years after stroke (50%), whereas slowness, psychic slowness, lack of energy, and concentration difficulties remained frequent at month 36 in patients with dementia. Conclusion: DS are frequent after stroke. Their time course varies and depends on the cognitive status; this variation contributes to differences among previous studies on poststroke depression.

Frontotemporal behavioral scale.

Summary: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.