Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates.

BACKGROUND: It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD). SUMMARY: The present postmortem 7.0-tesla MRI study investigates the anatomical distribution of cortical microbleeds (CoMBs) in LBD brains with and without associated Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). CoMBs predominated in the frontal section of the LBD brains and were associated to severe white matter lesions. No differences were observed when LBD brains with and without AD and CAA were compared. KEY MESSAGES: In LBD, there is a specific distribution of CoMBs that is different from that in other neurodegenerative diseases. The increase of frontal CoMBs is not due to the frequently associated AD and CAA features but due to the LBD itself.

My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer's disease.

Theory of mind reasoning-the ability to understand someone else's mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else's mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer's disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else's mental perspective requires two distinct processes: inferring someone else's belief and inhibiting one's own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer's disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer's disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimer's disease had a predominant deficit in inferring someone else's belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting one's own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone else's beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia.

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

[From Pick's disease to frontotemporal dementia]. / De la maladie de Pick aux démences fronto-temporales.

Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.

The gendered consequences of the COVID-19 lockdown on unpaid work in Swiss dual earner couples with children.

This article assesses the gendered impact of COVID-19 measures on changes in time that Swiss dual earner couples spent on unpaid work during the pandemic, focusing on families with children. Overcoming some of the methodological shortcomings of previous studies, high-quality representative panel data allow us to examine the change in time invested in housework and childcare before and during the pandemic, and test theoretical assumptions as to the mechanisms underlying the observed patterns. Gender inequalities are explained by the couple's work division prior to, and at the onset of, the pandemic and interpreted in the light of key theoretical approaches (economics of the family, bargaining and time availability, doing gender). Our results imply that in particular changes in the time availability of the partner are relevant for changes in time spent on housework, while in case of care work, the own time availability matters more. Moreover, we also found that the respondents' economic bargaining power within the couple matters both for housework and care work. Finally, the implemented COVID-19 measures neither led to an increase in patriarchal power structures nor did they foster an increase in equality for unpaid work among women and men. Instead, the results show that changes in time availability due to short-time, remote or overtime working schemes determined changes in time spent on unpaid care to a larger extent than gender alone.

Characteristics of Bipolar Patients with Cognitive Impairment of Suspected Neurodegenerative Origin: A Multicenter Cohort.

Bipolar disorder is associated with an increased risk of dementia with aging. Little is known regarding this association, limiting appropriate diagnosis and management. We aimed to describe the characteristics of bipolar patients with late cognitive impairment for whom the hypothesis of an underlying neurodegenerative disease had been raised. We performed a retrospective multicenter study, recruiting bipolar patients over 50 years old from five French tertiary memory centers who had undergone cerebrospinal fluid (CSF) biomarker assessment for Alzheimer's disease (AD). Clinical, neuropsychological, and paraclinical characteristics were analyzed and 78 patients were included. The mean age at the onset of cognitive impairment was 62.4 years (±9.2). The mean MMSE score was 22.8 (±4.5), the mean FAB was 11.7 (±3.9), and the mean FCRST was 15.8 (±7.4)/36.8 (±9.7) (free/total recall). A total of 48.6% of the patients displayed cognitive fluctuations, and 38.2% showed cognitive improvement during follow-ups; and 56.3% of the patients showed Parkinsonism, of which 12.7% had never received antipsychotics. Among patients who underwent DAT-scans, 35.3% displayed dopaminergic denervation; 10.3% of patients had CSF AD biological signature ("A+ T+" profile), while 56.4% had other abnormal CSF profiles. Thus, clinical presentation was dominated by executive dysfunction, episodic memory impairment, fluctuating cognition, and a high frequency of Parkinsonism. Specifically, high frequency of delusional episodes suggests limited tolerance of psychotropic drugs. Most patients had abnormal CSF biomarker profiles, but only a minority displayed AD's specific biomarker signature. Therefore, while our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies rather than a common degenerative mechanism in the pathophysiology of this condition.

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network.

BACKGROUND: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator. METHODS: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE). RESULTS: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients. CONCLUSIONS: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.

[Caring for "young" Alzheimer's patients in a home for dependent elderly people]. / Accompagner un malade Alzheimer "jeune" en Ehpad.

Alzheimer's disease can affect people under the age of 60, considered as "young" patients. In France, the disease affects 8 000 such people today. Caring for them at home is sometimes impossible and the 2008-2012 Alzheimer plan comprises a measure to reflect on requirements with regard to medico-social establishments. For the last ten years, a residential home for dependent elderly people in the north of France has regularly taken in "young" residents with Alzheimer's disease and reports, via a study, on their characteristics and their needs.

Does amnesia specifically predict Alzheimer's pathology? A neuropathological study.

Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.

Implicit sensitivity to disgust-inducing stimuli in self-neglect FTD patients.

BACKGROUND: Among behavioral and socioemotional changes occurring before cognitive decline at the early stages of frontotemporal dementia, the patients often manifest with self-neglect and some criteria of Diogene syndrome. Despite the lack of accurate behavior regarding disgust, are they still sensitive to the emotional content of disgust-inducing words or scenes? METHODS: Eleven patients with frontotemporal dementia, 11 healthy controls, and 34 young adults performed a lexical decision task, where some of the words conveyed an emotional content and a number comparison task while they were presented with emotion-inducing pictures. They were not instructed to identify the emotional content of the words and pictures. RESULTS: Contrary to the healthy controls paired for age, the patients provided delayed responses for disgust-inducing words in the lexical decision task and in presence of disgust-inducing pictures in the number comparison task. CONCLUSIONS: Although they manifest with self-neglect and inaccurate behavior regarding dirt, the patients were still sensitive to disgust, provided that this sensitivity was tested implicitly, suggesting that they above all suffer from inabilities in matching the appropriate social behavior with such emotions.

[Is frontotemporal dementia a disease of identity?]. / Démence frontotemporale : une maladie aussi de l'identité ?

Patients with frontotemporal dementia (FTD) have major behavioral troubles and a loss of insight. These factors contribute to reduce self-awareness and recognition of identify of others and by others. Autobiographical amnesia, loss of insight and executive dysfunctions are the major reasons of vulnerable "self" in FTD. Mind representation deficits, decrease of perception of emotions and semantic amnesia contribute to reduced recognition of the relative's identity. Alterations of body expressions, social disinhibition, changes in social and religious values decrease the recognition of patient's identity by the relatives. Different psychological components of identity are modified by the FTD such as feeling of unity, of consistency, of temporality and of affiliation. The fact that brain lesions of FTD are focalized can contribute to understand the biological knowledge of "identity". To know the neurological substrate of alterations of identity, this can help to improve the empathy of the suffering caregivers for the patient.

[Frontotemporal dementia: behavioral story of a neurological disease]. / Démence frontotemporale : histoire comportementale d'une maladie neurologique.

The very slow progression of behavioral disorders, initially isolated at the onset of frontotemporal dementia, easily results in their neglect, all the more so since the patients are anosognosic. In absence of cognitive decline, these patients, whatever carrying a neurological disease, are frequently led towards psychiatrists. Many psychiatric disorders may be evoked: depression, mania, compulsive obsessive disorder, psychopathy, alcoholic addiction, bulimia, schizophrenia, or Diogene syndrome. However, the diagnosis can often be easily corrected by a detailed clinical analysis. The knowledge of the 3 behavioral symptoms included in the diagnostic criteria can help to recognize frontotemporal dementia, even when imaging and neuropsychological data show mild abnormalities. In the last few years, various neuropsychological, biological and environmental mechanisms have been proposed to explain the behavioral disorders. These disorders are very difficult to tolerate by the caregivers because the patients appear to be asocial and show no affect. A detailed information of the changes related to the disease is important for the caregivers to accept the behavioral changes and to cope with them. However, over time, the occurrence of mutism may lead caregivers to regret the period of behavioral disorders.

Young onset demented patients in French cognitive-behavioral specialized units.

The number of patients with young onset dementia (YOD) (first symptoms beginning before the age of 60 years) is estimated around 5,000 in France. On account of the usual severity of behavioral symptoms in these patients, the need for cognitive-behavioral specialized unit (UCC) is expected. To determine the number and characteristics of YOD patients cared for in UCC in France during the year 2013. A specific questionnaire was sent to the 84 French UCC. The questionnaire was completed by 55 UCC (65%), whose 33 received 179 YOD patients. The diagnosis was Alzheimer's disease in 50% of the cases and frontotemporal dementia in 30%. The main reasons for the hospitalization in UCC were the severity of behavioral symptoms in 86% of cases, the need to alleviate the caregiver burden in 31% and the waiting for a place in a nursing home in 23%. Mean duration of hospitalization was 40.4 ± 20.5 days. At the end of hospitalization 51% of the patients returned to their original living accomodation and 39% entered into a nursing home. The main reason of YOD patients hospitalization reject was the care team's fear in the UCC without experience. The severity of the behavioral troubles was the major issue while the necessary ethical reflection raised by the YOD patients management was a positive aspect. The teams rated how ready do they feel about taking care of YOD patients on a scale from 0 to 100, the median was 35. The welcoming of YOD patients in UCC is necessary, however the severity of the behavioral troubles and the care teams fear prompt to set up specific education and to increase of the number of staff for YOD patients management.

[Treatment of Alzheimer's disease]. / Traitement pharmacologique de la maladie d'Alzheimer.

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.

DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia.

BACKGROUND: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. OBJECTIVE: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. METHODS: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. RESULTS: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. CONCLUSION: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.

Tau aggregation in the hippocampal formation: an ageing or a pathological process?

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.

Influence of prestroke dementia on early and delayed mortality in stroke patients.

Causes of early and delayed death after stroke differ. It has been suggested that delayed mortality rate was increased in patients with post-stroke dementia. Prestroke dementia is frequent: its influence on survival in stroke patients has never been evaluated. The aim of this study was to evaluate the influence of prestroke dementia on early and delayed mortality rate after stroke. In a cohort of 202 consecutive stroke patients aged >or= 40 years admitted between November 1995 and May 1996 in a primary care center, the prevalence of prestroke dementia was determined using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) with a cut-off of 104. Patients were followed-up for 3 years. Statistics were performed using life-table methods. Of 202 patients, 33 had prestroke dementia. Of 142 survivors at month-6, 44 were demented, of them 15 having prestroke and 29 new-onset post-stroke dementia. No patient was lost to follow-up. The risk of death at month-6 was higher in patients with prestroke dementia (RR 2.7; 95 % CI: 1.6-4.8). However, independent predictors of early death were age, severity of the deficit at admission, type and etiology of stroke. The risk of delayed death was higher in patients with prestroke dementia (RR 4.97; 95 % CI: 1.76-13.98) as in patients with new-onset post-stroke dementia (RR 6.24; 95 % CI: 2.67-14.57), compared with non-demented patients. The mortality rate did not differ between patients with prestroke and new-onset post-stroke dementia. Dementia at month-6 was an independent predictor of delayed death (RR 5.7; 95 % CI: 2.4-13.4), with age and stroke recurrence. Causes of death did not differ between demented and non-demented patients. Dementia adversely influences vital outcome in stroke patients, perhaps partly because the therapeutic approach differs between demented and non-demented patients.

[Serotonin reuptake inhibitors in depression of Alzheimer's disease and other dementias]. / Inhibiteurs de la recapture de la sérotonine dans la dépression de la maladie d'Alzheimer et autres démences.

RATIONALE IN ALZHEIMER'S DISEASE: Selective serotonine uptake inhibitors (SSRI) have demonstrated their effectiveness for symptomatic treatment of depression, as well as for behavioral and psychological disorders in dementia patients, particularly in Alzheimer's disease. TOLERANCE: SSRI are particularly well tolerated, particularly in comparison with tricyclic antidepressants. Nausea and vomiting may be a problem in old demented patients. Safety studies have shown that tolerance is not modified in patients with Alzheimer's disease. DRUG INTERACTIONS AND PHARMACOKINETICS: Fluoxetine and paroxetine have an inhibiting effect on metabolism of cholinesterase inhibitors which should be avoided. The compounds have a short half-life and non-active metabolites should be preferred. TRAZODONE: Studies conducted in patients with Alzheimer's disease, mixed type dementia, or fronto-temporal dementia have shown the efficacy of trazodone for diverse types of symptoms: sadness, emotional disorders, irritability, fear, psychomotor instability, delirant ideas. Efficacy of SSRI in patients with Lewy body dementia remains to be confirmed.

[Treatment of frontotemporal dementia]. / Traitement des démences frontotemporales.

Frontotemporal dementia (FTD) is the most neglected dementia by pharmacological research. Nevertheless, FTD can be now diagnosed with a good accuracy. Serotonin deficit is found in FTD and most of FTD are tauopathies. Pharmacological agents such as trazodone have showed a positive effect on behavioral symptoms, but the cognitive symptoms can not be significantly improved and parameters to follow a long-term trial in FTD remain to be identified. The recognition of the differences between FTD and Alzheimer's disease allows to determine a specific management of FTD patients and their caregivers.