Differences in structural covariance brain networks between behavioral variant frontotemporal dementia and Alzheimer's disease

Disease‐specific patterns of gray matter atrophy in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) overlap with distinct structural covariance networks (SCNs) in cognitively healthy controls. This suggests that both types of dementia target specific structural networks. Here, we study SCNs in AD and bvFTD. We used structural magnetic resonance imaging data of 31 AD patients, 24 bvFTD patients, and 30 controls from two centers specialized in dementia. Ten SCNs were defined based on structural covariance of gray matter density using independent component analysis. We studied group differences in SCNs using F‐tests, with Bonferroni corrected t‐tests, adjusted for age, gender, and study center. Associations with cognitive performance were studied using linear regression analyses. Cross‐sectional group differences were found in three SCNs (all P < 0.0025). In bvFTD, we observed decreased anterior cingulate network integrity compared with AD and controls. Patients with AD showed decreased precuneal network integrity compared with bvFTD and controls, and decreased hippocampal network and anterior cingulate network integrity compared with controls. In AD, we found an association between precuneal network integrity and global cognitive performance (P = 0.0043). Our findings show that AD and bvFTD target different SCNs. The comparison of both types of dementia showed decreased precuneal (i.e., default mode) network integrity in AD and decreased anterior cingulate (i.e., salience) network integrity in bvFTD. This confirms the hypothesis that AD and bvFTD have distinct anatomical networks of degeneration and shows that structural covariance gives valuable insights in the understanding of network pathology in dementia. Hum Brain Mapp 37:978–988, 2016. © 2015 Wiley Periodicals, Inc .     

European Association of Nuclear Medicine and European Academy of Neurology recommendations for the use of brain 18F‐fluorodeoxyglucose positron emission tomography in neurodegenerative cognitive impairment and dementia: Delphi consensus

Background and purpose

Recommendations for using fluorodeoxyglucose positron emission tomography (FDG‐PET) to support the diagnosis of dementing neurodegenerative disorders are sparse and poorly structured.

Methods

Twenty‐one questions on diagnostic issues and on semi‐automated analysis to assist visual reading were defined. Literature was reviewed to assess study design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiver operating characteristic curve, and positive/negative likelihood ratio of FDG‐PET in detecting the target conditions. Using the Delphi method, an expert panel voted for/against the use of FDG‐PET based on published evidence and expert opinion.

Results

Of the 1435 papers, 58 papers provided proper quantitative assessment of test performance. The panel agreed on recommending FDG‐PET for 14 questions: diagnosing mild cognitive impairment due to Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) or dementia with Lewy bodies (DLB); diagnosing atypical AD and pseudo‐dementia; differentiating between AD and DLB, FTLD or vascular dementia, between DLB and FTLD, and between Parkinson's disease and progressive supranuclear palsy; suggesting underlying pathophysiology in corticobasal degeneration and progressive primary aphasia, and cortical dysfunction in Parkinson's disease; using semi‐automated assessment to assist visual reading. Panellists did not support FDG‐PET use for pre‐clinical stages of neurodegenerative disorders, for amyotrophic lateral sclerosis and Huntington disease diagnoses, and for amyotrophic lateral sclerosis or Huntington‐disease‐related cognitive decline.

Conclusions

Despite limited formal evidence, panellists deemed FDG‐PET useful in the early and differential diagnosis of the main neurodegenerative disorders, and semi‐automated assessment helpful to assist visual reading. These decisions are proposed as interim recommendations.     

Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders

Apathy is a neurocognitive syndrome of reduced goal-directed behaviour and is an important cause of disability in neurodegenerative disorders. Frontal–subcortical dysfunction is thought to be important in apathy, but the contribution of individual brain regions to different aspects of the apathy syndrome is poorly understood. We aimed to test the hypotheses that apathy in two distinct neurodegenerative disorders would be associated with frontal lobe atrophy and that reduced initiative and emotional blunting would be associated with distinct patterns of atrophy in functionally relevant brain areas. Seventeen patients with progressive supranuclear palsy (PSP) and 17 patients with Alzheimer’s disease (AD) underwent structural MRI scanning at 3 T to provide data for voxel based morphometric analysis. Apathy was defined using Robert’s 2009 diagnostic criteria and specific symptoms were assessed with the Apathy Inventory. Patients with and without apathy were matched for important demographic and clinical characteristics. Apathy was associated with atrophy of the ventromedial orbitofrontal cortex and left insula in both AD and PSP. Reduced initiative was specifically associated with atrophy of the anterior cingulate and ventrolateral orbitofrontal cortex whilst emotional blunting was specifically associated with atrophy of the left insula. These findings provide further support for the role of medial frontal regions and insular cortex in apathy and suggest that behavioural and emotional aspects of the apathy syndrome may have distinct neuroanatomical bases.     

Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study.

OBJECTIVE: Apathy is one of the most common late-life neuropsychiatric syndromes. The objective of our study was to examine the neuroanatomical correlates of apathy in older subjects with and without geriatric major depression (MDD). METHODS: Eighty-four subjects (43 patients with MDD and 41 normal comparison subjects) underwent comprehensive neuropsychiatric examination, physical examination, and high-resolution magnetic resonance imaging (MRI) brain scans on a 1.5T GE MRI scanner. Apathy was assessed using the Apathy Evaluation Scale. MRI image analyses included cortical surface extraction, tissue segmentation, and cortical parcellation methods to measure the gray and white matter volumes in two prefrontal subregions: the anterior cingulate and orbitofrontal cortex. RESULTS: The depressed group had smaller orbitofrontal gray matter volumes compared to the age-matched normal comparison group. The severity of apathy was associated with the decreased gray matter volume in the right anterior cingulate gray matter volumes using partial correlation and regression analyses after controlling for age, sex, and diagnosis. CONCLUSION: Apathy and depression were associated with different anatomical correlates in the prefrontal regions implicated in the regulation of cognition and emotion. Our findings offer new understanding of the neuroanatomical characteristics of apathy and depression in late life, and have broad implications for the neurobiology of behavior.     

Structural correlates of apathy in Alzheimer's disease

BACKGROUND: Apathy is the most common noncognitive symptom in Alzheimer's disease (AD). The structural correlates of apathy in AD have not yet been described. METHODS: We analyzed magnetic resonance imaging data of 35 AD patients with and without apathy. RESULTS: There was a significant linear association between apathy severity and cortical gray matter atrophy in the bilateral anterior cingulate [Brodmann area (BA) 24; r = 0.39-0.42, p = 0.01] and left medial frontal cortex (BA 8 and 9; r = 0.4, p < 0.02). Left mean cingulate cortical thinning predicted the presence/absence of apathy at the trend level of significance. CONCLUSION: Our study demonstrates a strong association between apathy and the integrity of medial frontal regions in AD.     

Positron emission tomography metabolic correlates of apathy in Alzheimer disease

BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.     

Neuropathologic correlates of apathy in Alzheimer's disease

Apathy is the most commonly observed behavioral disturbance in Alzheimer's disease (AD) and has been suggested to be frontally mediated. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed for 8 brain regions in 29 subjects with definite AD. Neuropsychiatric Inventory (NPI) for autopsied subjects was obtained from questioning of caregivers of subjects included in the study. Chronic apathy and total NPI composite scores correlated with anterior cingulate NFT counts (r = 0.518, p = 0.01, and r = 0.438, p = 0.032). This analysis suggests that chronic apathy in AD correlates with a greater anterior cingulate NFT burden and that chronic behavioral changes are more reflective than acute changes of disease pathology.     

Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and alzheimer's disease

Conflicting evidence exists regarding the integrity of episodic memory in the behavioral variant of frontotemporal dementia (bvFTD). Recent converging evidence suggests that episodic memory in progressive cases of bvFTD is compromised to the same extent as in Alzheimer's disease (AD). The underlying neural substrates of these episodic memory deficits, however, likely differ contingent on dementia type. In this study we sought to elucidate the neural substrates of episodic memory performance, across recall and recognition tasks, in both patient groups using voxel‐based morphometry (VBM) analyses. We predicted that episodic memory dysfunction would be apparent in both patient groups but would relate to divergent patterns of neural atrophy specific to each dementia type. We assessed episodic memory, across verbal and visual domains, in 19 bvFTD, 18 AD patients, and 19 age‐ and education‐matched controls. Behaviorally, patient groups were indistinguishable for immediate and delayed recall, across verbal and visual domains. Whole‐brain VBM analyses revealed regions commonly implicated in episodic retrieval across groups, namely the right temporal pole, right frontal lobe, left paracingulate gyrus, and right anterior hippocampus. Divergent neural networks specific to each group were also identified. Whereas a widespread network including posterior regions such as the posterior cingulate cortex, parietal and occipital cortices was exclusively implicated in AD, the frontal and anterior temporal lobes underpinned the episodic memory deficits in bvFTD. Our results point to distinct neural changes underlying episodic memory decline specific to each dementia syndrome. Hum Brain Mapp 35:1422–1435, 2014. © 201 Wiley Periodicals, Inc.     

Why Do They Just Sit? Apathy as a Core Symptom of Alzheimer Disease

Objective

Apathy is common in Alzheimer disease (AD) and has a far-reaching impact on patients’ clinical course and management needs. However, it is unclear if apathy is an integral component of AD or a manifestation of depression in cognitive decline. This study aims to examine interrelationships between apathy, depression, and function.

Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel‐based morphometry

Apathy is generally defined as a disorder of motivation and is considered one of the most common neuropsychiatric disturbances in Parkinson's disease (PD). Only few studies addressed the neuroanatomical correlates of apathy in PD. The aim of this article was to determine the structural correlates of apathy in PD patients. Fifty‐five PD patients underwent a neuropsychiatric and neuropsychological examination, and a 3 T magnetic resonance imaging scan was acquired. A voxel‐based multiple regression analysis was used to calculate correlation between gray matter density and severity measures of apathy. Apathy correlates with decreased cognitive functioning and more depressive symptoms but not with more severe motor symptoms. High apathy scores were correlated with low gray matter density values in a number of cortical brain areas: the bilateral precentral gyrus (BA 4, 6), the bilateral inferior parietal gyrus (BA 40), the bilateral inferior frontal gyrus (BA 44, 47), the bilateral insula (BA 13), the right (posterior) cingulate gyrus (BA 24, 30, 31), and the right precuneus (BA 31). Apathy in PD correlates with reduced gray matter density in a number of brain regions. The involvement of the cingulate gyrus and inferior frontal gyrus is in line with the results of earlier studies addressing apathy in patients with Alzheimer's disease or depressive disorder. Further studies addressing the pathogenesis of apathy are needed. © 2010 Movement Disorder Society.     

Bupropion improved apathy in behavioral variant frontotemporal dementia: a case report

ABSTRACT

Apathy is a common neurobehavioral sign in cases of behavioral variant frontotemporal dementia. However, there is still no established sustained effective treatment. We present the case of a 65-year-old man with behavioral variant frontotemporal dementia who suffered from severe apathy, but his apathy improved after a 10-month period of bupropion treatment. His single photon emission computed tomography report also showed slight improvement. To the best of our knowledge, such a case with imaging evidence has never been reported. Further studies to correlate the effects of bupropion on apathy in behavioral variant frontotemporal dementia patients are clearly needed.     

Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis

Alzheimer's disease (AD) is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. These behavioral disorders contribute to the clinical heterogeneity of the disease and probably express different pathophysiological processes. Apathy is one of the most frequent behavioral disorders in AD. The aim of this study was to evaluate brain perfusion of AD patients with and without apathy (as determined by the Neuropsychiatric Inventory) compared with that in healthy elderly subjects. A total of 15 AD patients without apathy (AD/NA; mean age 76.6) and 15 AD patients with apathy (AD/A; mean age 77.6) were studied. Brain perfusion was measured by 99mTc-labeled bicisate (ECD) single-photon emission tomography (ECD SPECT). The images of the two AD subgroups were compared by means of statistical parametric mapping (SPM 99) to corresponding images of 11 healthy elderly control subjects (obtained from the Society of Nuclear Medicine database). Compared with the healthy elderly subjects, the apathy-free AD subgroup had significantly lower perfusion of inferior temporal regions (left fusiform gyrus, left parahippocampal area) and occipital regions (left gyrus lingualis). The apathy subgroup had significantly decreased perfusion of the left anterior cingulate, the right inferior and medial gyrus frontalis, the left orbitofrontal gyrus and the right gyrus lingualis. The differences in the brain areas with reduced perfusion between the apathy-free subjects (mainly the posterior regions) and the apathetic subjects (mainly the anterior regions) indicate that behavioral disorders such as apathy participate in the heterogeneity of brain perfusion in AD.     

Neuroimaging features in C9orf72 and TARDBP double mutation with FTD phenotype

Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.     

Apathy in rapid eye movement sleep behaviour disorder is common and under‐recognized

Background and purpose

Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population.

Methods

Eighty‐eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated.

Results

A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy.

Conclusions

Apathy is common in RBD and is underestimated by a single self‐report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.     

Lack of initiative and interest in Alzheimer's disease: a single photon emission computed tomography study

Apathy is defined as a lack of motivation. The aim of this study was to investigate the relation between two major dimensions of apathy (lack of initiative and lack of interest) and brain perfusion. in patients with Alzheimer's disease (AD). Brain perfusion was measured by single photon emission tomography (SPECT). Thirty-one AD patients were included. Lack of initiative and interest were assessed with the Apathy Inventory. Nineteen AD subjects presented a lack of initiative and interest pathological score whereas 12 AD subjects did not. The lack of initiative and interest score correlated significantly with the right frontal and the right inferior temporal lobes. The AD patients with lack of initiative and interest showed a significantly lower perfusion in the right anterior cingulate than the AD patients without lack of initiative and interest. These results derive from rather small subgroups of patients but have the interest to dismantle the complementary aspects of emotion and motivation in apathy and suggest that the latter one is more related to cingulate area.     

Cortical Thickness of the Salience Network and Change in Apathy Following Antidepressant Treatment for Late-Life Depression

ObjectiveApathy is common in late-life depression and is associated with poor response to antidepressant drugs. In depressed older adults, apathy may be characterized by neuroanatomical abnormalities of the salience network. The current study examined whether cortical thickness of select salience network structures predicted change in apathy following a 12-week treatment with escitalopram.MethodsA sample of 46 older adults with major depressive disorder received 12 weeks of escitalopram treatment at a daily target dose of 20 mg. All participants underwent a structural brain MRI scan at baseline, and cortical thickness was estimated in key cortical nodes of the salience network: the caudal anterior cingulate cortex and the insula. We measured baseline and post-treatment symptoms using the Apathy Evaluation Scale and the Hamilton Depression Rating Scale.ResultsA thicker insula at baseline predicted reduction in apathy symptoms following 12 weeks of treatment with escitalopram, even when controlling for age, baseline depression severity and change in depressive symptoms.ConclusionReduced insular thickness predicted residual apathetic symptoms following escitalopram treatment. These results converge with our previous findings of abnormal functional connectivity of the insular cortex in older depressed individuals with apathy. Older depressed adults with apathy may benefit from alternative treatment approaches or augmentative interventions that target abnormalities of the salience network.     

The effects of behavioral and psychological symptoms on caregiver burden in frontotemporal dementia,Lewy body dementia,and Alzheimer's disease: clinical experience in China

Background and aims: Caregivers of individuals with neurodegenerative diseases, including frontotemporal dementia (FTD), Lewy body dementia (DLB), and Alzheimer's disease (AD), experience high levels of psychological and physical stress, likely due to behavioral and psychological symptoms of dementia (BPSD). This study is the first to simultaneously evaluate the effects of BPSD on caregiver burden in these three types of dementia.

Method: A total of 214 dementia patients, including probable FTD (n = 82), DLB (n = 22), and AD (n = 110), as well as their primary caregivers, were assessed using psychological inventories and cognitive evaluation. The FTD group was further divided into the three established clinical variants: behavioral variant frontotemporal dementia (bvFTD, n = 51), non-fluent variant primary progressive aphasia (nfvPPA, n = 15), and semantic variant primary progressive aphasia (svPPA, n = 16). Cognitive impairment and neuropsychiatric symptoms were assessed using the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test, and Neuropsychiatric Inventory (NPI), respectively. Caregiver burden was assessed using the Zarit Burden Inventory (ZBI).

Results: FTD patients had higher NPI and ZBI scores than DLB and AD patients, whose scores were similar. Logistic regression analysis revealed that the factors influencing caregiver burden for each group were: FTD: total NPI scores, agitation, and aberrant motor behavior; bvFTD: total NPI scores; DLB: total NPI scores; and AD: total NPI scores, onset age, apathy, and ADL. Caregivers of bvFTD patients had the highest levels of burden, which were significantly greater than for caregivers of nfvPPA, svPPA, DLB, and AD patients.

Conclusion: BPSD was highly correlated with emotional burden in caregivers of FTD, DLB, and AD patients. The highest burden was observed in bvFTD caregivers.     

Diagnosis and assessment of apathy in Chinese patients with Alzheimer's disease

BackgroundApathy is a major component of the behavioral and psychological symptoms of Alzheimer's Disease (AD) and other types of dementia. Most researchers have reached a consensus on a new set of diagnostic criteria for apathy (DCA) recently. However, no relevant reports on apathy exist for AD patients in Asian countries yet.ObjectivesTo estimate the prevalence of apathy in Chinese AD patients.Methods83 AD patients were recruited for a cross-sectional observational study. Following the new diagnostic criteria for apathy (DCA) and DSM-IV criteria for Major Depressive Disorder (MDD), each patient was assessed successively by Mini Mental State Examination (MMSE), the Neuropsychiatric Inventory-apathy subscale (NPI-apathy), the Geriatric Depression Screening scale (GDS), and the Caregiver Burden Scale (CBS).ResultsAccording to the DCA, we found that the frequency of apathy in Chinese AD patients reached 61.4%. The DCA had very good standard validity and internal consistency. The frequency of apathy was not significantly associated with that of depression, whereas there was a significant association between apathy and more severe cognitive deficits. Caregiver burden was significantly associated with severity of apathy.ConclusionsFrom the symptoms of a group of Chinese AD patients, we summarized a set of effective methods for the diagnosis and assessment of apathy.     

A case of apathy due to frontotemporal dementia responsive to memantine

Objective: To study the effect of memantine on apathy, a common symptom of behavioral variant frontotemporal dementia (bvFTD). Design: The patient underwent an off-label trial of memantine with behavioral inventories and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans performed at baseline, 7 weeks and 6 months. Subject: The patient was a 66-year-old male whose main manifestation of bvFTD was affective, behavioral and cognitive apathy. Intervention: The patient began memantine at an oral dose of 5 mg per morning and titrated up by 5 mg per week to the maintenance dose of 10 mg PO bid. Results: Informants reported reduction of the apathy. The insula and cerebellum, both involved in the salience network, showed improved metabolism. Conclusion: Further study to correlate the effects of memantine on apathy and the salience network in bvFTD are warranted.     

Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease

Aim: Apathy is a well‐recognized symptom of Alzheimer's disease (AD). The aim of the present study was to validate the Taiwanese version of the Apathy Evaluation Scale, clinician version (AES‐C) and assess the severity of apathy in patients with AD. Methods: Comprehensive evaluations were conducted in a total of 144 AD patients. This study used a cross‐sectional comparative design. Data were collected from clinical interviews using the AES, the Mini‐Mental Status Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Clinical Dementia Rating Scale (CDR). Results: Internal consistency was indicated by Cronbach's alphas of 0.85; test–retest reliability was 0.89 over a period of 3 days. Criterion‐related validity was supported by the fact that AES‐C significantly correlated with the apathy scores of the NPI. Factor analysis indicated a three‐factor structure. Convergent validity was supported by a positive correlation between the AES‐C score and the anxiety score of the NPI. Discriminant validity was supported by the fact that the AES‐C scores did not correlate with the depression subscale of the NPI, and the correlation between the AES‐C score and the euphoria score of the NPI score was negative. Known‐group validity was supported by results showing that AD patients in a moderate stage of dementia (CDR = 2) had significantly higher scores on the AES‐C than patients with mild‐stage dementia (CDR = 1). Conclusion: The AES‐C is a reliable and valid instrument for measuring symptoms of apathy among AD patients in Taiwan.