The topography of cortical microbleeds in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance study.

INTRODUCTION: Cerebrovascular lesions are rare in frontotemporal lobar degeneration (FTLD), in contrast to other neurodegenerative diseases. Cortical microbleeds (CoMBs) are frequent in Alzheimer's disease, in particular in cases associated with cerebral amyloid angiopathy. The present study investigates the gyral topographic distribution of CoMBs in post-mortem FTLD brains with 7.0-tesla magnetic resonance imaging. MATERIAL AND METHODS: The distribution of CoMBs in 11 post-mortem FTLD brains and in 12 control brains was compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean values of CoMBs were determined in twenty-two different gyri. The findings were correlated to those separately observed on neuropathological examination. RESULTS: As a whole there was a trend of more CoMBs in the prefrontal section of FTLD as well as of the control brains. CoMBs were significantly increased in the superior frontal gyrus and the insular cortex (p ≤ 0.001) and also in the inferior frontal gyrus and the superior temporal gyrus (p ≤ 0.01). CONCLUSIONS: CoMBs in FTLD are only increased in the regions mainly affected by the neurodegenerative lesions. They probably do not reflect additional cerebrovascular disease.

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.

Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease.

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.

[Dementia following bipolar disorder]. / Syndrome démentiel dans les suites d'une bipolarité.

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.

Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies.

The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated alpha-synuclein, tau, and Abeta species. All sporadic cases of DLB were associated with abundant deposits of Abeta x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and Abeta accumulation. The constant and abundant Abeta x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.

[Treatment of dementia with Lewy bodies]. / Prise en charge thérapeutique de la démence à corps de Lewy.

Dementia with Lewy bodies (DLB) is known for its partial resistance and hypersensitivity to some treatments, but DLB is treatable with cholinesterase inhibitors, sometimes better than in Alzheimer's disease. Cholinesterase inhibitors have a symptomatic effect on cognition and behavior. Nevertheless, new antipsychotics are sometimes also useful to manage psychotic symptoms. Although DLB patients respond less well to levodopa than patients with Parkinson's disease, 75 percent of DLB patients improve with levodopa, which is the best-tolerated dopaminergic agent. Nonpharmacological strategies include speech therapy, physiotherapy, psychotherapy, and educational support groups for care givers.

[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary group of experts, including geriatricians, neurologists, epidemiologists, psychiatrists, pharmacologists, and public health specialists developed consensus recommendations about care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians, and specialists, based on the knowledge currently available (2005). The aim of care at all stages is to mitigate the quality-of-life of patient, caregiver, and family insofar as possible, combining care and future planning until the end of life. Management, to take into account problems including nutritional status, behavior disorders, and ability (or inability) to perform activities of daily living, must be global, multidisciplinary, and coordinated and must optimize use of local medical and social resources. The group also stressed the importance of clinical research to improve knowledge of disease course and assess management strategies and recommended specific area for research.

[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary team including geriatritians, neurologists, epidemiologists, psychiatrists, pharmacologists and public health specialists developed a consensus on care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians and specialists based on knowledge available in 2005. At all stages of the disease, the objective of care is to improve as much as possible quality-of-life for the patient and his/her family, including a life project until the end of life. It is always possible to do something for these patients and their family: nutritional status, behavior disorders, and incapacities to deal with basic activities of daily life have to be taken in consideration. Resource allocation and proximity care have to be targeted. Research areas necessary to improve the care of patients with severe dementia has been selected.

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 >/==" BORDER="0">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.

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

OBJECTIVE: To determine the spatiotemporal mapping of tau pathologies and insoluble pools of Abeta 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 Abeta 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 Abeta 42 to cases with, in addition, large quantities of insoluble Abeta 40 species. Five other points were observed: 1) There was no spatial and temporal overlap in the distribution of these two insoluble Abeta species in cortical brain areas. 2) In contrast to solubilized Abeta 40 aggregates composed essentially of monomers and dimers, solubilized Abeta 42 was essentially observed as dimers and multimers. 3) Abeta 42 aggregates were observed at the early stages of tau pathology, whereas the insoluble Abeta 40 pool was found at the last stages. 4) During the progression of the disease, Abeta aggregates increase in quantity and heterogeneity, in close parallel to the extension of tau pathology. 5) There was no spatial overlap between Abeta 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 Abeta 42 aggregation, and not Abeta 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 Abeta neurotoxicity. Hence, there is a synergetic effect of APP dysfunction, revealed by Abeta aggregation, on the neuron-to-neuron propagation of tau pathology.

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 > or =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.

Memory impairment differs in frontotemporal dementia and Alzheimer's disease.

The aim of this study was to assess short-term and long-term explicit memory and implicit memory in frontotemporal dementia (FTD; frontal variant) and to compare FTD and Alzheimer's disease (AD) patients with similar severity of dementia. Fifteen FTD patients [mean age: 68 years; Mini-Mental State (MMS): 24], 30 probable AD patients (mean age: 72 years; MMS: 23) and 12 healthy subjects participated in the study. The three groups were comparable in terms of gender and educational level. Short-term memory was assessed with the digit span and Corsi block-tapping tests. Explicit verbal memory was assessed with the Grober and Buschke test, and implicit memory with a verbal priming task and a fragmented picture test. FTD patients demonstrated a genuine memory deficit with impaired digit span, encoding deficit and retrieval strategy difficulties, but preserved implicit verbal and visual priming. Memory patterns differed in AD and FTD: short-term memory and free recall were similarly decreased in FTD and AD but cues provided more benefit to FTD than to AD; encoding was more impaired and the forgetting rate was faster in AD than in FTD; priming was lower in AD than in FTD. AD patients with clinical and imaging frontal lobe dysfunction tended to have lower memory performance and to differ even more from FTD patients than AD patients without frontal lobe dysfunction.

[Management of behavioral disorders in dementia patients]. / Prise en charge des troubles du comportement dans les démences.

Behavioral disorders are major manifestations of Alzheimer's disease and other forms of dementia. They are associated with caregiver distress, increase the likelihood of institutionalization and may be associated with more rapid cognitive decline. The first step of treatment strategy is an assessment of these disorders. Treatment of behavioral signs is an etiological treatment. Acute behavioral signs are often related to an unknown somatic disease. Chronic signs are often symptoms of the neurological dementia and can be reduced, especially by serotonergic agents and anticonvulsivants. The new antipsychotics are a good alternative to classic neuroleptics known for their frequent cognitive side effects in demented patients. Anticholinesterasic drugs can positively influence noncognitive signs. The treatment of behavioral and psychological symptoms of dementia (BPSD) involves a number of specific interventions including cognitive stimulation which has shown effectiveness on both cognitive functions and quality of life. Prevention of BPSD includes safety measures such as evaluation of suicidality and violence, vigilance regarding neglect and abuse, planning for legal issues due to the patient's incapacity. Families or caregivers should be provided with counseling, education and support. The treatment of BPSD is part of a global and multimodal care which involves general practioners, nurses, social workers, physiotherapists, neuropsychologists, speech therapists, memory centers, psychogeriatric and geriatric units, and respite care units, nursing homes and long-term care facilities. The coordination of the professionals is a critical aspect of providing effective care for patients with Alzheimer's disease.

[Clinical and paraclinical diagnosis in psychiatry]. / Le diagnostic clinique et paraclinique en psychiatrie.

Alzheimer's disease patient can be addressed sometimes in psychiatry. At the early stage of the disease, the reason can be depressive symptoms or paranoiac reactions. Later, agitation associated with psychotic symptoms is the principal reason of hospitalization in psychiatry. The knowledge of the management of dementia has dramatically progressed, by example, antidepressant agents are not used as a diagnostic method. Psychiatric and behavioral assessment, neuropsychological tests, assessment of activities of daily life are very useful during the first consultation. Before the second consultation with the neuropsychological assessment, the stop of negative treatment, the treatment of depressive mood and the CT-scan must be realized. When the patient is hospitalized for agitation, the global assessment must be conducted after the hospitalization during consultation or day-hospital. Now, the psychiatrist must treat not only behavioral signs but specifically the disease too.

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.

Perception of emotion in frontotemporal dementia and Alzheimer disease.

Frontotemporal dementia (FTD) is the second cause of degenerative dementia. Behavioral changes occur before the cognitive decline and remain the major feature. A poor perception of emotion could account for some behavioral symptoms. The aim of this study was to assess the perception of emotion in patients with FTD and to compare it with that of patients with Alzheimer disease (AD). Fifty subjects performed the tests: 20 patients with probable AD, 18 patients with FTD, and 12 matched controls. The two patient groups did not differ in age, sex, severity of dementia, duration of the disease, and language tests. Subjects had to recognize and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise, and contempt) on a set of 28 faces presented on slides. The three groups were equally able to distinguish a face displaying affect from one not displaying affect. Naming of emotion was worse in patients with FTD than in patients with AD (correct answers 46% vs. 62%; p = 0.0006) who did not differ significantly from controls (72%). Anger, sadness, and disgust were less recognized in FTD than in AD patients who did not differ from controls, whereas fear and contempt were poorly recognized in both groups of patients compared with controls. These findings argue for different neural substrates underlying the recognition of various basic emotions. Behavioral disorders in FTD may be partly due to an impaired interpretation of the emotional environment.

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 Abeta 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.