Characterizing sexual behavior in frontotemporal dementia

Background: Frontotemporal dementia (FTD) is characterized by a number of prominent behavioral changes. While FTD has been associated with the presence of aberrant or unusual sexual behaviors in a proportion of patients, few studies have formally investigated changes in sexual function in this disease. Objective: We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer’s disease (AD). Methods: Carers of 49 dementia patients (21 bvFTD, 11 SD, 17 AD) were interviewed using the Sexual Behavior and Intimacy Questionnaire (SIQ), a survey designed to assess changes in sexual function across multiple domains including initiating, level of affection, and aberrant or unusual sexual behavior. Results: BvFTD patients show prominent hyposexual behavior including decreased affection, initiation, and response to advances by partners, and decreased frequency of sexual relations, compared to AD and to SD patients. The greatest changes in sexual behavior compared to pre-diagnoses were found in the bvFTD group with a 90–100% decrease in initiation, response, and frequency of sexual relations. Notably, aberrant or unusual sexual behavior was reported in a minority of bvFTD and SD patients and occurred in patients who also showed hyposexual behavior toward their partner. Conclusion: Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus

Anhedonia in Semantic Dementia-Exploring Right Hemispheric Contributions to the Loss of Pleasure.

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith-Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer's disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer's patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer's disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.This study was supported in part by funding to ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases, from the National Health and Medical Research Council (NHMRC) Program grant (#1132524) and Dementia Research Team Grant (#1095127), as well as the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (CE11000102) and an NHMRC Project grant (#1121791). The authors acknowledge the technical assistance provided by the Sydney Informatics Hub, a Core Research Facility of the University of Sydney. M.I. is supported by an ARC Future Fellowship (FT160100096). A.E.W. is supported by an NHMRC Fellowship (#1110773). O.P. is supported by an NHMRC Senior Research Fellowship (GNT1103258). These funding sources were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the manuscript for publication

Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

IMPORTANCE: Abnormal eating behaviors are common in patients with frontotemporal dementia (FTD), yet their exact prevalence, severity, and underlying biological mechanisms are not understood. OBJECTIVE: To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. DESIGN, SETTING, AND PARTICIPANTS: Forty-nine patients with dementia (19 with bvFTD, 15 with semantic dementia, and 15 with Alzheimer disease) were recruited, and their eating behavior was compared with that of 25 healthy controls. The study was conducted from November 1, 2013, through May 31, 2015, and data analyzed from June 1 to August 31, 2015. MAIN OUTCOMES AND MEASURES: Patients participated in an ad libitum breakfast test meal, and their total caloric intake and food preferences were measured. Changes in eating behavior were also measured using the Appetite and Eating Habits Questionnaire (APEHQ) and the Cambridge Behavioral Inventory (CBI). Sucrose preference was tested by measuring liking ratings of 3 desserts of varying sucrose content (A: 26%, B: 39%, C: 60%). Voxel-based morphometry analysis of whole-brain 3-T high-resolution brain magnetic resonance imaging was used to determine the gray matter density changes across groups and their relations to eating behaviors. RESULTS: Mean (SD) ages of patients in all 4 groups ranged from 62 (8.3) to 66 (8.4) years. At the ad libitum breakfast test meal, all patients with bvFTD had increased total caloric intake (mean, 1344 calories) compared with the Alzheimer disease (mean, 710 calories), semantic dementia (mean, 573 calories), and control groups (mean, 603 calories) (P < .001). Patients with bvFTD and semantic dementia had a strong sucrose preference compared with the other groups. Increased caloric intake correlated with atrophy in discrete neural networks that differed between patients with bvFTD and semantic dementia but included the cingulate cortices, thalami, and cerebellum in patients with bvFTD, with the addition of the orbitofrontal cortices and nucleus accumbens in patients with semantic dementia. A distributed network of neural correlates was associated with sucrose preference in patients with FTD. CONCLUSIONS AND RELEVANCE: Marked hyperphagia is restricted to bvFTD, present in all patients with this diagnosis, and supports its diagnostic value. Differing neural networks control eating behavior in patients with bvFTD and semantic dementia and are likely responsible for the differences seen, with a similar network controlling sucrose preference. These networks share structures that control cognitive-reward, autonomic, neuroendocrine, and visual modulation of eating behavior. Delineating the neural networks involved in mediating these changes in eating behavior may enable treatment of these features in patients with complex medical needs and aid in our understanding of structures that control eating behavior in patients with FTD and healthy individuals.This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746 to MK and JH) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021 to OP and JH) and other grants/sources (NHMRC project grant #1003139). We are grateful to the research participants involved with the ForeFront research studies. RA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. MI is an ARC Discovery Early Career Researcher Award Fellow Ahmed et al. (#DE130100463). OP is an NHMRC Career Development Research Fellow (#1022684). ISF is supported by the Wellcome Trust, Medical Research Council, European Research Council, NIHR Cambridge Biomedical Research Centre and The Bernard Wolfe Endowment.This is the author accepted manuscript. The final version is available from American Medical Association at http://dx.doi.org/10.1001/jamaneurol.2015.4478

Addenbrooke’s Cognitive Examination III: Psychometric Characteristics and Relations to Functional Ability in Dementia

Objectives: The Addenbrooke’s Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE- III cutoff scores for the detection of dementia, and explored its relationship with functional ability. Methods: Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability. Results: Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia. Conclusions: This study represents one of the largest and most clini- cally diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018, 24, 854–863

Altered High Density Lipoprotein Composition in Behavioral Variant Frontotemporal Dementia

Frontotemporal dementia (FTD) is a common cause of early onset dementia with behavioral variant FTD (bvFTD) being the most common form. bvFTD is characterized clinically by behavioral and personality changes, eating abnormalities, and pathologically, by systemic lipid dysregulation that impacts on survival. As lipoprotein metabolism is at the core of lipid dysregulation, here, we analyzed the composition, both proteins and lipids, of the two major lipoprotein classes in blood – high density lipoproteins (HDLs) and low density lipoproteins (LDLs). Fasted plasmas from bvFTD and Alzheimer’s disease (AD) patients and controls were fractionated using fast protein liquid chromatography (FPLC) and samples analyzed by lipid assays, ELISA and western blotting. We found that apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) levels in HDLs were decreased in bvFTD compared to controls, whereas apolipoprotein B (apoB) levels in LDLs were unaltered. We also found that cholesterol and triglyceride levels in FPLC fractions were altered in bvFTD compared to controls. The apoB:apoA-I ratio and the standard lipid ratios were significantly increased in bvFTD compared to AD and controls. Furthermore, we found that plasma apolipoprotein C-I and paraoxonase 1 levels were significantly altered in bvFTD and AD, respectively, compared controls. This study represents the first apolipoprotein analysis of bvFTD, and our results suggest altered HDL function and elevated cardiovascular disease risk in bvFTD

Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

SEE FINGER DOI101093/AWW312 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Abnormal eating behaviour and metabolic parameters including insulin resistance, dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study, it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia, 13 with Alzheimer's disease and 16 (age- and sex-matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate, activity levels, and resting, active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia, resting (P = 0.001), stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects, and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke's Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex, insula, and amygdala, regions previously suggested to be involved exclusively in social and emotion processing in frontotemporal dementia. These neural correlates overlap the network involved in eating behaviour in frontotemporal dementia, suggesting a complex interaction between eating behaviour, autonomic function and energy homeostasis. As such the present study suggests that increased heart rate and autonomic changes are prevalent in behavioural variant frontotemporal dementia, and are associated with changes in energy expenditure. An understanding of these changes and neural correlates may have potential relevance to disease progression and prognosis.National Health and Medical Research Council of Australia (Grant IDs: 1037746, 1003139, 1022684), Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (Grant ID: CE110001021), Royal Australasian College of Physicians (PhD scholar), MND Australia (PhD scholar), Wellcome Trust, Medical Research Council, European Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, The Bernard Wolfe Endowment, Swiss National Science Foundation (Grant IDs: PBLAP3-145870, P3SMP3-155318)This is the author accepted manuscript. The final version is available from Oxford University Press via https://doi.org/10.1093/brain/aww26

Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism.

Metabolic changes incorporating fluctuations in weight, insulin resistance, and cholesterol concentrations have been identified in several neurodegenerative disorders. Whether these changes result from the neurodegenerative process affecting brain regions necessary for metabolic regulation or whether they drive the degenerative process is unknown. Emerging evidence from epidemiological, clinical, pathological, and experimental studies emphasises a range of changes in eating behaviours and metabolism in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS, metabolic changes have been linked to disease progression and prognosis. Furthermore, changes in eating behaviour that affect metabolism have been incorporated into the diagnostic criteria for FTD, which has some clinical and pathological overlap with ALS. Whether the distinct and shared metabolic and eating changes represent a component of the proposed spectrum of the two diseases is an intriguing possibility. Moreover, future research should aim to unravel the complex connections between eating, metabolism, and neurodegeneration in ALS and FTD, and aim to understand the potential for targeting modifiable risk factors in disease development and progression.This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746 to GH, MK and JH) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021 to OP and JH) and other grants/sources (NHMRC project grant #1003139). We are grateful to the research participants involved with the ForeFront research studies. RA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. MI is an ARC Discovery Early Career Researcher Award Fellow (#DE130100463). OP is an NHMRC Career Development Research Fellow (#1022684). GH is a NHMRC Senior Principal Research Fellow (#1079679). L.M.I. is a NHMRC Senior Research Fellow (#1003083).This is the author accepted manuscript. The final version is available from Elsevier at http://dx.doi.org/10.1016/S1474-4422(15)00380-4

Mouse models of frontotemporal dementia: a comparison of phenotypes with clinical symptomatology

Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effect of Fibrin Glue on the Biomechanical Properties of Human Descemet's Membrane

10.1371/journal.pone.0037456PLoS ONE75