Different apathy clinical profile and neural correlates in behavioral variant frontotemporal dementia and Alzheimer's disease

Objectives

Apathy is one of the most common and disabling syndromes of dementia. Clinical apathy expression and neuroanatomical basis of apathy seem to differ between behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), although evidence is scarce and poorly understood. Our main purposes were to compare the clinical apathy profile from patients with bvFTD and AD and analyze the relationship between apathy and brain metabolism measured using positron emission tomography imaging with ¹⁸F fluorodeoxyglucose (FDG‐PET).

Methods

Forty‐two bvFTD, 42 AD, and 30 healthy volunteers without cognitive or behavioral complaints were included. Apathy was defined using Robert's 2009 diagnostic criteria, and specific apathy characteristics were assessed with the Lille Apathy Rating Scale. All participants underwent FDG‐PET brain scan to provide data for voxel‐based morphometric analysis.

Results

Multivariate analysis showed that subjects affected by bvFTD displayed greater impairment of emotional apathy and self‐awareness in comparison with AD sample. Additionally, FDG‐PET imaging analyses revealed that apathy was associated with different neuroanatomical substrates in each dementia group: left lateral prefrontal, medial frontal/anterior cingulate, lateral orbitofrontal and anterior insular cortices in bvFTD, and right anterior cingulate in AD.

Conclusions

These results support that apathy is a complex syndrome, with different clinical expressions across different pathological conditions. Those differences in qualitative aspects of apathy seem to be associated with differences in the damage sites, as shown by our FDG‐PET imaging analysis. Our findings provide a better knowledge about pathophysiology of apathy in dementia, which could have practical implications for therapeutic management. Copyright © 2017 John Wiley & Sons, Ltd.     

Functional neuroanatomical associations of working memory in early‐onset Alzheimer's disease

Objective

To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early‐onset Alzheimer's disease.

Background

Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible.

Methods

Twenty‐four patients with predominantly early‐onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1‐weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region‐of‐interest approach.

Results

Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left‐sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers.

Conclusions

Our findings support the hypothesis that working memory changes in early‐onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.     

Increased cerebral FDG‐PET uptake in type 1 diabetes patients with impaired awareness of hypoglycaemia

Approximately 20% of type 1 diabetes (T1D) patients have an impaired awareness of hypoglyceamia (IAH). IAH represents a risk factor for severe and recurrent hypoglycaemic events, which can lead to brain damage. Because no effective treatments are currently available to prevent IAH in this population, characterising the set of brain alterations associated with IAH may reveal novel preclinical diagnostic or therapeutic strategies. Using state‐of‐the art neuroimaging techniques, we compared ¹⁸F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) uptake at rest between 10 T1D patients with IAH and nine patients with normal awareness of hypoglycaemia (NAH). T1D‐IAH patients showed a pattern of increased FDG‐PET uptake with respect to NAH patients (P < .05 corrected). Topographically, glucose metabolism was increased in the frontal and precuneus regions. Importantly, within the IAH group, this abnormal hypermetabolism correlated with IAH severity. This hypermetabolic state appeared to be unrelated to compensatory mechanisms as a result of reduced grey matter density or a neuroinflammatory state. We observed an abnormal increase in FDG‐uptake in T1D patients with IAH in brain regions strongly related to cognition. Because this hypermetabolic state correlated with IAH severity, its biological characterisation could reveal new preventive or therapeutic strategies. A possible mechanism could be that glucose transport is increased in hypoglycaemia unawareness to compensate for recurrent hypoglycaemia, although this need to be confirmed in further research.     

Using machine learning to quantify structural MRI neurodegeneration patterns of Alzheimer's disease into dementia score: Independent validation on 8,834 images from ADNI,AIBL, OASIS,and MIRIAD databases

Biomarkers for dementia of Alzheimer's type (DAT) are sought to facilitate accurate prediction of the disease onset, ideally predating the onset of cognitive deterioration. T1‐weighted magnetic resonance imaging (MRI) is a commonly used neuroimaging modality for measuring brain structure in vivo, potentially providing information enabling the design of biomarkers for DAT. We propose a novel biomarker using structural MRI volume‐based features to compute a similarity score for the individual's structural patterns relative to those observed in the DAT group. We employed ensemble‐learning framework that combines structural features in most discriminative ROIs to create an aggregate measure of neurodegeneration in the brain. This classifier is trained on 423 stable normal control (NC) and 330 DAT subjects, where clinical diagnosis is likely to have the highest certainty. Independent validation on 8,834 unseen images from ADNI, AIBL, OASIS, and MIRIAD Alzheimer's disease (AD) databases showed promising potential to predict the development of DAT depending on the time‐to‐conversion (TTC). Classification performance on stable versus progressive mild cognitive impairment (MCI) groups achieved an AUC of 0.81 for TTC of 6 months and 0.73 for TTC of up to 7 years, achieving state‐of‐the‐art results. The output score, indicating similarity to patterns seen in DAT, provides an intuitive measure of how closely the individual's brain features resemble the DAT group. This score can be used for assessing the presence of AD structural atrophy patterns in normal aging and MCI stages, as well as monitoring the progression of the individual's brain along with the disease course.     

Clinical profiles of late‐onset semantic dementia,compared with early‐onset semantic dementia and late‐onset Alzheimer's disease

Background: Semantic dementia (SD) has been recognized as a representative of dementia with presenile onset; however, recent epidemiological studies have shown that SD also occurs in the elderly. There have been few studies about the differences of clinical profiles between early‐onset SD (EO‐SD) and late‐onset SD (LO‐SD). Age‐associated changes in the brain might cause some additional cognitive and behavioural profiles of LO‐SD in contrast to the typical EO‐SD cases. The aim of the present study was to clarify the characteristics of neuropsychological, and behavioural and psychological symptoms of dementia (BPSD) profiles of LO‐SD patients observed in screening tests in comparison with EO‐SD patients and late‐onset Alzheimer's disease (LO‐AD) patients as controls. Methods: Study participants were LO‐SD (n = 10), EO‐SD (n = 15) and LO‐AD (n = 47). We examined the Mini‐Mental State Examination (MMSE), the Raven's Coloured Progressive Matrices (RCPM), the Short‐Memory Questionnaire (SMQ), the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Results: Both SD groups scored significantly lower than the LO‐AD patients in ‘naming’ of the MMSE. In the ‘construction’ score of the MMSE and the RCPM score, however, the LO‐SD patients as well as the LO‐AD patients were significantly lower than the EO‐SD patients. In the SMQ score, ‘euphoria’ and ‘disinhibition’ scores of the NPI, the SRI total and subscale scores, both SD groups were significantly higher, whereas in the ‘delusion’ score of the NPI, both SD groups were significantly lower than the LO‐AD patients. Conclusions: Visuospatial and constructive skills of LO‐SD patients might be mildly deteriorated compared with EO‐SD patients, whereas other cognitive and behavioural profiles of LO‐SD are similar to EO‐SD. Age‐associated changes in the brain should be considered when we diagnose SD in elderly patients.     

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration—[18F]FDG‐PET

In Parkinson's disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [¹⁸F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinson's disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty‐two Parkinson's patients (10 demented) and seven controls underwent FDG‐PET. A metabolic index (mean relative uptake in typically affected regions) was calculated for each patient and compared with scores for cognition [Minimental State Examination (MMSE)], motor performance [Unified Parkinson's Disease Rating Scale (UPDRS III)” and behavior (Neuropsychiatric Inventory). In stepwise linear regression analysis, MMSE (P < 0.001) score showed the only significant effect. Estimated sensitivity and specificity for DSM‐IV diagnosis of dementia were high for the metabolic index (MI), with 91 and 100%. Taken together, the presented data indicate that cerebral hypometabolism in Parkinson's disease is primarily associated with cognitive impairment. © 2009 Movement Disorder Society     

Behavioural disturbances in psychiatric inpatients with dementia of the Alzheimer's type in Taiwan

This report studied behavioural disturbances in psychiatric inpatients with dementia of the Alzheimer's type (DAT) in Taiwan. The sample consisted of 75 inpatients with DAT who were consecutively admitted to the geropsychiatric ward. Their behavioural disturbances were obtained from semistructured interviews with families and ward observation. There were eight main behavioural disturbances: getting lost, repetitive phenomena, sleep disturbance, aggression, wandering, hyperphagia, hoarding behaviour, and inappropriate sexual behaviour. Number of behavioural disturbances, wandering, hyperphagia and sleep disturbance were significantly associated with the severity of cognitive impairment. © 1997 John Wiley & Sons, Ltd.     

Data‐driven approaches for tau‐PET imaging biomarkers in Alzheimer's disease

Previous positron emission tomography (PET) studies have quantified filamentous tau pathology using regions‐of‐interest (ROIs) based on observations of the topographical distribution of neurofibrillary tangles in post‐mortem tissue. However, such approaches may not take full advantage of information contained in neuroimaging data. The present study employs an unsupervised data‐driven method to identify spatial patterns of tau‐PET distribution, and to compare these patterns to previously published “pathology‐driven” ROIs. Tau‐PET patterns were identified from a discovery sample comprised of 123 normal controls and patients with mild cognitive impairment or Alzheimer's disease (AD) dementia from the Swedish BioFINDER cohort, who underwent [¹⁸F]AV1451 PET scanning. Associations with cognition were tested in a separate sample of 90 individuals from ADNI. BioFINDER [¹⁸F]AV1451 images were entered into a robust voxelwise stable clustering algorithm, which resulted in five clusters. Mean [¹⁸F]AV1451 uptake in the data‐driven clusters, and in 35 previously published pathology‐driven ROIs, was extracted from ADNI [¹⁸F]AV1451 scans. We performed linear models comparing [¹⁸F]AV1451 signal across all 40 ROIs to tests of global cognition and episodic memory, adjusting for age, sex, and education. Two data‐driven ROIs consistently demonstrated the strongest or near‐strongest effect sizes across all cognitive tests. Inputting all regions plus demographics into a feature selection routine resulted in selection of two ROIs (one data‐driven, one pathology‐driven) and education, which together explained 28% of the variance of a global cognitive composite score. Our findings suggest that [¹⁸F]AV1451‐PET data naturally clusters into spatial patterns that are biologically meaningful and that may offer advantages as clinical tools.     

A white-matter disease in dementia of Alzheimer's type – clinical and neuropathological correlates

A correlative neuropathological-clinical study was undertaken in order to analyse the possible clinical effects of the selective incomplete white-matter infarctions (SIWI) frequently found in dementia of Alzheimer's type (DAT). The cases studied represent DAT with and without concomitant SIWI, non-Alzheimer dementia with SIWI and cerebrovascular dementia, including multi-infarct dementia and Binswanger's disease. The structural grey and white matter changes were examined and the clinical symptoms and signs were analysed. The occurrence of cardiovascular disease and abnormal blood pressure was studied as well. The results show that cardiovascular disease and systemic hypotension occur frequently in cases with SIWI and they are considered of pathogenetic importance for SIWI. Symptoms and signs of a non-focal cerebrovascular/ischaemic type, mainly vertigo, fainting and a fluctuating course, are associated with SIWI. In DAT and SIWI, the clinical picture of DAT is altered accordingly, compared to DAT with normal white matter.     

Anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) is present in the sera of patients with dementia of Alzheimer’s type in Asian

Satoh K, Kawakami A, Shirabe S, Tamai M, Sato A, Tsujihata M, Nagasato K, Eguchi K. Anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) is present in the sera of patients with dementia of Alzheimer’s type in Asian.
Acta Neurol Scand. 2010: 121: 338–341.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – In the hippocampi of Alzheimer’s disease (AD) patients, aberrant expression of citrullinated proteins and peptidylarginase 2 (PADI2) has been identified. We explored the functional roles of these proteins by means of detection of serum anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) in patients with dementia of Alzheimer’s type (DAT). Methods – Sera were obtained from 42 patients with DAT, 30 patients with other neurological disorders and 42 healthy controls. Gender ratio and age were comparable among the three groups. The level of anti‐CCP antibody in sera was examined by ELISA. Findings – Anti‐CCP antibody was not found in the 30 patients with other neurological disorders, and only one of the 42 healthy controls (2.4%) was positive. However, surprisingly, anti‐CCP antibody was clearly detected in eight of the 42 DAT patients. Interpretation – Anti‐CCP antibody appears to be a simple and early serologic biomarker for DAT among dementia patients. Additionally, our data imply that citrullinated proteins accumulated in the astrocytes of AD patients acquire neo‐antigenicity, inducing anti‐CCP antibody production.     

Gender differences in healthy aging and Alzheimer's Dementia: A 18F‐FDG‐PET study of brain and cognitive reserve

Cognitive reserve (CR) and brain reserve (BR) are protective factors against age‐associated cognitive decline and neurodegenerative disorders. Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD). We investigated gender differences in brain metabolic activity and resting‐state network connectivity, as measured by ¹⁸F‐FDG‐PET, in healthy aging and AD, also considering the effects of education and occupation. The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282). In HE, males showed more extended age‐related reduction of brain metabolism than females in frontal medial cortex. We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic‐affective and executive networks in HE females. In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo‐parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks. Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females. The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors. Hum Brain Mapp 38:4212–4227, 2017. © 2017 Wiley Periodicals, Inc.