Publications by authors named "Olivier Piguet"

231 Publications

Neural correlates of fat preference in frontotemporal dementia: translating insights from the obesity literature.

Ann Clin Transl Neurol 2021 May 11. Epub 2021 May 11.

ARC Centre of Excellence of Cognition and its Disorders, Sydney, NSW, Australia.

Objective: Alterations in eating behaviour are one of the diagnostic features of behavioural variant frontotemporal dementia (bvFTD). It is hypothesised that underlying brain network disturbances and atrophy to key structures may affect macronutrient preference in bvFTD. We aimed to establish whether a preference for dietary fat exists in bvFTD, its association with cognitive symptoms and the underlying neural mechanisms driving these changes.

Methods: Using a test meal paradigm, adapted from the obesity literature, with variable fat content (low 20%, medium 40% and high 60%), preference for fat in 20 bvFTD was compared to 16 Alzheimer's disease (AD) and 13 control participants. MRI brain scans were analysed to determine the neural correlates of fat preference.

Results: Behavioural variant FTD patients preferred the high-fat meal compared to both AD (U = 61.5; p = 0.001) and controls (U = 41.5; p = 0.001), with 85% of bvFTD participants consistently rating the high-fat content meal as their preferred option. This increased preference for the high-fat meal was associated with total behavioural change (Cambridge Behavioural Inventory: r  = 0.462; p = 0.001), as well as overall functional decline (Frontotemporal Dementia Rating Scale: r  = -0.420; p = 0.03). A preference for high-fat content in bvFTD was associated with atrophy in an extended brain network including frontopolar, anterior cingulate, insular cortices, putamen and amygdala extending into lateral temporal, posteromedial parietal and occipital cortices.

Conclusions: Increased preference for fat content is associated with many of the canonical features of bvFTD. These findings offer new insights into markers of disease progression and pathogenesis, providing potential treatment targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51369DOI Listing
May 2021

Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia.

Brain 2021 Apr 12. Epub 2021 Apr 12.

The University of Sydney, Brain and Mind Centre, Sydney, New South Wales, Australia.

Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer's disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer's disease, and 51 healthy older control participants. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer's disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular cortices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab032DOI Listing
April 2021

Beyond language impairment: Profiles of apathy in primary progressive aphasia.

Cortex 2021 Jun 16;139:73-85. Epub 2021 Mar 16.

The University of Sydney, Brain & Mind Centre, Sydney, NSW, Australia; The University of Sydney, School of Psychology, Sydney, NSW, Australia. Electronic address:

Primary progressive aphasia (PPA) is characterised by predominant language and communication impairment. However, behavioural changes, such as apathy, are increasingly recognised. Apathy is defined as a reduction in motivation and goal-directed behaviour. Recent theoretical models have suggested that apathy can be delineated into multiple dimensions: executive apathy (i.e., deficits in maintaining goals and organisation), emotional apathy (i.e., emotional blunting and indifference) and initiation apathy (i.e., reduced self-initiation). Whether the nature of apathy differs between clinical variants of PPA, and across early and late disease stages, remains to be established. Here, carers/informants of 20 semantic variant PPA (svPPA), 15 non-fluent variant PPA (nfvPPA), 16 logopenic variant PPA (lvPPA) and 25 healthy older controls completed the Dimensional Apathy Scale to quantify executive, emotional and initiation apathy. Voxel-based morphometry was used to identify associations between dimensions of apathy and regions of grey matter intensity decrease. Our behavioural results showed greater executive and initiation apathy in late svPPA than in late nfvPPA patients, while late svPPA had greater emotional apathy than both late nfvPPA and late lvPPA groups. Executive and initiation apathy were significantly higher than premorbid levels in all PPA subtypes, while elevated emotional apathy was only seen in early and late svPPA. Distinct neural correlates were identified across apathy dimensions. Executive apathy correlated with grey matter intensity of the left dorsolateral prefrontal and inferior parietal cortices; emotional apathy with the left medial prefrontal, insular and cerebellar regions; and initiation apathy with right parietal areas. Our findings are the first to reveal evidence of the dimensional nature of apathy in PPA, with different clinical signatures observed for each subtype. From a clinical standpoint, these results will inform the development of targeted interventions for specific aspects of apathy which emerge in PPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2021.02.028DOI Listing
June 2021

Dementia in Latin America: Paving the way toward a regional action plan.

Alzheimers Dement 2021 02 20;17(2):295-313. Epub 2020 Nov 20.

Hospital Geral de Fortaleza, University of Fortaleza, Brazil.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984223PMC
February 2021

Heterogeneity of behavioural and language deficits in FTD-MND.

J Neurol 2021 Feb 20. Epub 2021 Feb 20.

The University of Sydney, The Faculty of Medicine and Health, Sydney, NSW, Australia.

Objective: To comprehensively examine the clinical presentation of patients diagnosed with frontotemporal dementia-motor neuron disease (FTD-MND) compared to FTD subtypes. To clarify the heterogeneity of behavioural and language deficits in FTD-MND using a data-driven approach.

Methods: Patients with FTD-MND (n = 31), behavioural variant FTD (n = 119), non-fluent variant primary progressive aphasia (n = 47), semantic variant primary progressive aphasia (n = 42), and controls (n = 127) underwent comprehensive clinical, cognitive and behavioural assessments. Two-step cluster analysis examined patterns of behavioural and language impairment. Voxel-based morphometry and tract-based spatial statistics were used to investigate differences across the subgroups that emerged from cluster analysis.

Results: More than half of FTD-MND patients initially presented with variable combinations of deficits (e.g., mixed behaviour/cognitive, mixed behaviour/cognitive/motor deficits), with 74% of them meeting criteria for FTD-MND within 24 months with a median of 12 months. The frequency and severity of behavioural and language abnormalities in FTD-MND lie between that seen in the three FTD phenotypes. Cluster analysis identified three patterns of behavioural and language impairment in FTD-MND. The three FTD-MND subgroups demonstrated different profiles of white matter tract disruption, but did not differ in age at onset, disease duration or patterns of cortical atrophy.

Conclusions: While highly heterogeneous, in terms of behavioural and language deficits, and disease severity, the presentation of FTD-MND may be distinct to that of FTD. Distinct white matter degeneration patterns may underpin heterogeneous clinical profiles in FTD-MND. FTD presenting with mixed behavioural-language disturbances should be monitored closely for at least 12-24 months for the emergence of MND symptoms/signs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-021-10451-7DOI Listing
February 2021

Clinical and Biological Correlates of White Matter Hyperintensities in Patients With Behavioral-Variant Frontotemporal Dementia and Alzheimer Disease.

Neurology 2021 03 17;96(13):e1743-e1754. Epub 2021 Feb 17.

From the School of Psychology (K.H., O.P., R.L.-R.), Brain and Mind Centre (K.H., O.P., J.K., C.D.-S., G.M.H., J.R.H., R.L.-R.), Central Clinical School (J.K., C.D.-S., G.M.H., J.R.H.), The University of Sydney; and the School of Medical Sciences (J.K., C.D.-S., G.M.H., J.R.H.), University of New South Wales, Sydney, Australia.

Objective: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses.

Methods: A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed.

Results: Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD.

Conclusion: Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011638DOI Listing
March 2021

Predictors of survival in frontotemporal lobar degeneration syndromes.

J Neurol Neurosurg Psychiatry 2021 Jan 13. Epub 2021 Jan 13.

Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-324349DOI Listing
January 2021

Problem-focused coping underlying lower caregiver burden in ALS-FTD: implications for caregiver intervention.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jan 13:1-8. Epub 2021 Jan 13.

Brain & Mind Centre, The University of Sydney, Camperdown, Australia.

: Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder which includes cognitive and behavioral symptoms akin to frontotemporal dementia (FTD). Despite the necessity of caregiver intervention to assist with the management of cognitive and behavioral symptoms, there has been a lack of research on the topic. A focus on caregiver coping may offer a promising foundation to guide the development of interventions as part of ALS care. Accordingly, the aim of the present study was to examine the relationships between caregiver coping, psychological morbidity and burden of care in the context of ALS cognitive and behavioral symptoms. : Fifty-five patient-caregiver dyads were recruited from specialized ALS and FTD clinics. Specific coping strategies were examined using the COPE Inventory/Brief COPE and psychological morbidity and burden were assessed using the Depression, Anxiety, and Stress Scale-21 and Zarit Burden Interview. The relationship between coping, psychological morbidity and burden of care were analyzed using univariate and multivariate methods. : High-burden caregivers were more likely to be caring for patients with a diagnosis of ALS-FTD ( =.0001). Caregivers used problem-focused strategies (particularly planning) more frequently ( = 71.4, SD = 15.3) compared to emotion-focused ( = 60.8, SD = 12.3) and dysfunctional coping strategies ( = 42.2, SD = 8.6). A diagnosis of ALS-FTD (=.0001) and problem-focused strategies (=.024) emerged as significant predictors of caregiver burden. Caregiver anxiety, depression and stress were not predictive of caregiver burden (=.151). : Timely provision of caregiver support optimizing problem-focused coping strategies as part of multidisciplinary ALS care, particularly for caregivers of ALS-FTD patients may mitigate caregiver burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1867180DOI Listing
January 2021

Behavioural Variant Frontotemporal Dementia: Recent Advances in the Diagnosis and Understanding of the Disorder.

Adv Exp Med Biol 2021 ;1281:1-15

School of Psychology and Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia.

Frontotemporal dementia (FTD), particularly the behavioural variant (bvFTD) form, has fascinated researchers. Recent years have seen an increasing interest in aspects of bvFTD that extend beyond the initial focus on cognitive changes and frontal executive dysfunction. Changes have been identified in aspects including fundamental changes in physiology and metabolism, and cognitive domains such as episodic memory. Work on social cognition has emphasised the importance of a breakdown in interpreting and expressing emotions, while the overlap between psychiatric disorders and bvFTD has been brought into focus by the finding of high rates of psychotic features in carriers of the c9orf72 gene expansion. We review these aspects in the chapter " Behavioural variant frontotemporal dementia: Recent advances in diagnosis and understanding of the disorder" and also potential markers of disease progression and early diagnosis that may aid in the development of treatment options, which have thus far eluded us.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-030-51140-1_1DOI Listing
February 2021

Longitudinal cognitive and functional changes in primary progressive aphasia.

J Neurol 2021 May 8;268(5):1951-1961. Epub 2021 Jan 8.

School of Psychology, The University of Sydney, Sydney, Australia.

Objective: The variants of primary progressive aphasia (PPA) are predominantly diagnosed on the basis of specific profiles of language impairments. Deficits in other cognitive domains and their evolution over time are less well documented. This study examined the cognitive profiles of the PPA variants over time and determined the contribution of cognition on functional capacity.

Methods: Longitudinal performance on the Addenbrooke's Cognitive Examination-III (ACE-III) total and cognitive subdomains were investigated in 147 PPA individuals (41 logopenic [lv-PPA], 44 non-fluent [nfv-PPA], and 62 semantic variants [sv-PPA]). The relative contribution of ACE-III subdomain scores to overall functional capacity over time was identified using mixed and hierarchical regression modelling.

Results: The annual rate of global ACE-III decline was twice that in lv-PPA than in nfv-PPA and sv-PPA, despite lv-PPA performing intermediate to the other variants at baseline assessment. Notably, attention and visuospatial subdomains declined faster in lv-PPA than in nfv-PPA and sv-PPA; and memory impairment was more severe in lv-PPA than in nfv-PPA at all time points. Functional decline was comparable across PPA variants; however, the contribution of cognition on functional capacity varied across variants and over time.

Conclusion: The cognitive profiles of the PPA variants are distinct at baseline and over time. Crucially, cognitive decline in lv-PPA was more widespread and pervasive than in nfv-PPA and sv-PPA. Our findings also demonstrate the complex interplay between cognition and functional capacity. This study underscores the importance of routinely assessing cognition and functional capacity in PPA to improve diagnostic accuracy and provide targeted support services.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10382-9DOI Listing
May 2021

The interplay of emotional and social conceptual processes during moral reasoning in frontotemporal dementia.

Brain 2021 Apr;144(3):938-952

The University of Sydney, Brain and Mind Centre, Camperdown, Australia.

Cooperative social behaviour in humans hinges upon our unique ability to make appropriate moral decisions in accordance with our ethical values. The complexity of the neurocognitive mechanisms underlying moral reasoning is revealed when this capacity breaks down. Patients with the behavioural variant of frontotemporal dementia (bvFTD) display striking moral transgressions in the context of atrophy to frontotemporal regions supporting affective and social conceptual processing. Developmental studies have highlighted the importance of social knowledge to moral decision making in children, yet the role of social knowledge in relation to moral reasoning impairments in neurodegeneration has largely been overlooked. Here, we sought to examine the role of affective and social conceptual processes in personal moral reasoning in bvFTD, and their relationship to the integrity and structural connectivity of frontotemporal brain regions. Personal moral reasoning across varying degrees of conflict was assessed in 26 bvFTD patients and compared with demographically matched Alzheimer's disease patients (n = 14), and healthy older adults (n = 22). Following each moral decision, we directly probed participants' subjective emotional experience as an index of their affective response, while social norm knowledge was assessed via an independent task. While groups did not differ significantly in terms of their moral decisions, bvFTD patients reported feeling 'better' about their decisions than healthy control subjects. In other words, although bvFTD patients could adjudicate between different courses of action in the moral scenarios, their affective responses to these decisions were highly irregular. This blunted emotional reaction was exclusive to the personal high-conflict condition, with 61.5% of bvFTD patients reporting feeling 'extremely good' about their decisions, and was correlated with reduced knowledge of socially acceptable behaviour. Voxel-based morphometry analyses revealed a distributed network of frontal, subcortical, and lateral temporal grey matter regions involved in the attenuated affective response to moral conflict in bvFTD. Crucially, diffusion-tensor imaging implicated the uncinate fasciculus as the pathway by which social conceptual knowledge may influence emotional reactions to personal high-conflict moral dilemmas in bvFTD. Our findings suggest that altered moral behaviour in bvFTD reflects the dynamic interplay between degraded social conceptual knowledge and blunted affective responsiveness, attributable to atrophy of, and impaired information transfer between, frontal and temporal cortices. Delineating the mechanisms of impaired morality in bvFTD provides crucial clinical information for understanding and treating this challenging symptom, which may help pave the way for targeted behavioural interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa435DOI Listing
April 2021

Cerebellar contributions to cognition in corticobasal syndrome and progressive supranuclear palsy.

Brain Commun 2020 16;2(2):fcaa194. Epub 2020 Nov 16.

Central Sydney Medical School and Brain and Mind Centre, The University of Sydney, Sydney, Australia.

Mounting evidence suggests an association between cerebellar atrophy and cognitive impairment in the main frontotemporal dementia syndromes. In contrast, whether cerebellar atrophy is present in the motor syndromes associated with frontotemporal lobar degeneration (corticobasal syndrome and progressive supranuclear palsy) and the extent of its contribution to their cognitive profile remain poorly understood. The current study aimed to comprehensively chart profiles of cognitive impairment in relation to cerebellar atrophy in 49 dementia patients (corticobasal syndrome = 33; progressive supranuclear palsy = 16) compared to 33 age-, sex- and education-matched healthy controls. Relative to controls, corticobasal syndrome and progressive supranuclear palsy patients demonstrated characteristic cognitive impairment, spanning the majority of cognitive domains including attention and processing speed, language, working memory, and executive function with relative preservation of verbal and nonverbal memory. Voxel-based morphometry analysis revealed largely overlapping patterns of cerebellar atrophy in corticobasal syndrome and progressive supranuclear palsy relative to controls, primarily involving bilateral Crus II extending into adjacent lobules VIIb and VIIIa. After controlling for overall cerebral atrophy and disease duration, exploratory voxel-wise general linear model analysis revealed distinct cerebellar subregions differentially implicated across cognitive domains in each patient group. In corticobasal syndrome, reduction in grey matter intensity in the left Crus I was significantly correlated with executive dysfunction. In progressive supranuclear palsy, integrity of the vermis and adjacent right lobules I-IV was significantly associated with language performance. These results are consistent with the well-established role of Crus I in executive functions and provide further supporting evidence for vermal involvement in cognitive processing. The current study presents the first detailed exploration of the role of cerebellar atrophy in cognitive deficits in corticobasal syndrome and progressive supranuclear palsy, offering insights into the cerebellum's contribution to cognitive processing even in neurodegenerative syndromes characterized by motor impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753056PMC
November 2020

Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia.

Brain Commun 2020 17;2(2):fcaa125. Epub 2020 Oct 17.

MRC Cognition and Brain Sciences Unit, The University of Cambridge, Cambridge, UK.

Logopenic progressive aphasia is a neurodegenerative syndrome characterized by sentence repetition and naming difficulties arising from left-lateralized temporoparietal atrophy. Clinical descriptions of logopenic progressive aphasia largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits even on tasks with minimal language demands. Although non-linguistic cognitive deficits in logopenic progressive aphasia are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose the individual-level variation in cognitive performance in 43 well-characterized logopenic progressive aphasia patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected 'speech production and verbal memory' deficits which typify logopenic progressive aphasia. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably 'logopenic' patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralized temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, logopenic progressive aphasia patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralized temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in logopenic progressive aphasia, suggesting the presence of a genuine co-occurring cognitive impairment that is statistically independent of language function and disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750924PMC
October 2020

Examining prefrontal contributions to past- and future-oriented memory disturbances in daily life in dementia.

Cortex 2021 01 24;134:307-319. Epub 2020 Nov 24.

The University of Sydney, School of Psychology, Sydney, Australia; The University of Sydney, Brain and Mind Centre, Sydney, Australia. Electronic address:

Deficits in episodic memory are commonplace in dementia, yet mounting evidence indicates pervasive impairments in future-oriented thinking in these syndromes. How such impairments manifest in the daily lives of people with dementia remain unclear, as do their neural bases. This study aimed to determine the neurocognitive mechanisms of past- and future-oriented memory performance across a large sample of dementia syndromes, each of which is characterised by distinct clinical and cognitive profiles. Carer-rated memory changes in everyday life in Alzheimer's disease, behavioural-variant frontotemporal dementia, semantic dementia, progressive non-fluent aphasia, and logopenic progressive aphasia were assessed using the Prospective and Retrospective Memory Questionnaire (PRM-Q). Participants underwent neuropsychological testing and whole-brain structural MRI. Relative to Controls, past- and future-oriented memory were compromised exclusively in AD and bvFTD, with no impairments reported for the other groups. For AD, atrophy in a distributed network of prefrontal, lateral and medial temporal regions including the hippocampus, correlated with past- and future-oriented memory impairments. In contrast, lateral and medial prefrontal regions correlated with past- and future-oriented memory difficulties in bvFTD. Notably, the orbitofrontal cortex emerged as a common neural substrate implicated in memory disturbances across the AD and bvFTD groups. This study confirms the presence of episodic amnesia in bvFTD across a host of everyday activities, mirroring the profile typically observed in AD. Of note, the orbitofrontal cortex emerged as a common region implicated in past- and future-oriented memory deficits in both patient groups, underscoring a critical role for prefrontal regions in supporting complex aspects of memory function in everyday life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2020.11.003DOI Listing
January 2021

A study protocol for a phase II randomised, double-blind, placebo-controlled trial of sodium selenate as a disease-modifying treatment for behavioural variant frontotemporal dementia.

BMJ Open 2020 11 16;10(11):e040100. Epub 2020 Nov 16.

Department of Neuroscience, Monash University, Melbourne, Victoria, Australia.

Introduction: Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder often neuropathologically associated with the accumulation of abnormally hyperphosphorylated tau, for which there is currently no disease-modifying treatment. Previous work by our group has shown sodium selenate upregulates the activity of protein phosphatase 2 in the brain, increasing the rate of tau dephosphorylation. The objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying treatment for bvFTD.

Methods And Analysis: This will be a multisite, phase IIb, double-blind placebo-controlled trial of sodium selenate. One hundred and twenty participants will be enrolled across 4 Australian academic hospitals. Following screening eligible participants will be randomised (1:1) to sodium selenate (15 mg three times a day) or placebo for 52 weeks. Participants will have regular safety and efficacy visits throughout the study period. The primary study outcome will be percentage brain volume change (PBVC) as measured on MRI over 52 weeks of treatment. This will be analysed with a general linear model (analysis of covariance (ANCOVA)) with the PBVC as an output, the treatment as an input and the baseline brain volume as covariate for adjustment purposes. Secondary outcomes include safety and tolerability measures, and efficacy measures; change in cerebrospinal fluid total-tau, Addenbrooke's Cognitive Examination-III and Cambridge Behavioural Inventory-Revised scores over the 52 weeks of treatment. These will also be analysed with ANCOVA where the corresponding baseline measure will be incorporated in the model. Additional exploratory outcomes will include other imaging, cognitive and biospecimen analyses.

Ethics And Dissemination: The study was approved by the Human Research and Ethics Committee of the lead site as part of the Australian Multisite Ethics approval system. The results of the study will be presented at national and international conferences and published in peer-reviewed journals.

Trial Registration Number: ACTRN12620000236998 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-040100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670941PMC
November 2020

Dynamic brain fluctuations outperform connectivity measures and mirror pathophysiological profiles across dementia subtypes: A multicenter study.

Neuroimage 2021 01 2;225:117522. Epub 2020 Nov 2.

Global Brain Health Institute (GBHI), University of California San Francisco (UCSF), California, US; & Trinity College Dublin, Dublin, Ireland; National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina; Universidad de San Andrés, Buenos Aires, Argentina; Universidad Autónoma del Caribe, Barranquilla, Colombia; Center for Social and Cognitive Neuroscience (CSCN), School of Psychology, Universidad Adolfo Ibáñez, Santiago de Chile, Chile. Electronic address:

From molecular mechanisms to global brain networks, atypical fluctuations are the hallmark of neurodegeneration. Yet, traditional fMRI research on resting-state networks (RSNs) has favored static and average connectivity methods, which by overlooking the fluctuation dynamics triggered by neurodegeneration, have yielded inconsistent results. The present multicenter study introduces a data-driven machine learning pipeline based on dynamic connectivity fluctuation analysis (DCFA) on RS-fMRI data from 300 participants belonging to three groups: behavioral variant frontotemporal dementia (bvFTD) patients, Alzheimer's disease (AD) patients, and healthy controls. We considered non-linear oscillatory patterns across combined and individual resting-state networks (RSNs), namely: the salience network (SN), mostly affected in bvFTD; the default mode network (DMN), mostly affected in AD; the executive network (EN), partially compromised in both conditions; the motor network (MN); and the visual network (VN). These RSNs were entered as features for dementia classification using a recent robust machine learning approach (a Bayesian hyperparameter tuned Gradient Boosting Machines (GBM) algorithm), across four independent datasets with different MR scanners and recording parameters. The machine learning classification accuracy analysis revealed a systematic and unique tailored architecture of RSN disruption. The classification accuracy ranking showed that the most affected networks for bvFTD were the SN + EN network pair (mean accuracy = 86.43%, AUC = 0.91, sensitivity = 86.45%, specificity = 87.54%); for AD, the DMN + EN network pair (mean accuracy = 86.63%, AUC = 0.89, sensitivity = 88.37%, specificity = 84.62%); and for the bvFTD vs. AD classification, the DMN + SN network pair (mean accuracy = 82.67%, AUC = 0.86, sensitivity = 81.27%, specificity = 83.01%). Moreover, the DFCA classification systematically outperformed canonical connectivity approaches (including both static and linear dynamic connectivity). Our findings suggest that non-linear dynamical fluctuations surpass two traditional seed-based functional connectivity approaches and provide a pathophysiological characterization of global brain networks in neurodegenerative conditions (AD and bvFTD) across multicenter data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2020.117522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832160PMC
January 2021

Visuospatial short-term and working memory disturbance in the primary progressive aphasias: Neuroanatomical and clinical implications.

Cortex 2020 11 8;132:223-237. Epub 2020 Sep 8.

The University of Sydney, School of Psychology, Sydney, Australia; The University of Sydney, Brain and Mind Centre, Sydney, Australia. Electronic address:

Introduction: Primary progressive aphasia (PPA) comprises three main variants: logopenic (lv-PPA), non-fluent (nfv-PPA) and semantic variant (sv-PPA). Differentiating the language profiles of the PPA variants remains challenging, especially for lv-PPA and nfv-PPA. As such, diagnostic tools that do not rely on speech and language may offer some utility. Here, we investigated the short-term and working memory profiles of the PPA variants and typical Alzheimer's disease (AD), with a particular interest in the visuospatial system. We hypothesised visuospatial short-term and working memory would be more compromised in lv-PPA and AD than in the other PPA variants, and that this would relate to degeneration of posterior temporoparietal brain regions.

Method: Thirty-three lv-PPA, 26 nfv-PPA, 31 sv-PPA and 58 AD patients, and 45 matched healthy controls were recruited. All participants completed the WMS-III Spatial and Digit Span tasks and underwent a structural brain MRI for voxel-based morphometry analyses.

Results: Relative to Controls, Spatial Span Forward (SSF) performance was impaired in lv-PPA and AD but not in nfv-PPA or sv-PPA. In contrast, Digit Span Forward (DSF) performance was impaired in lv-PPA and nfv-PPA (to a similar level), and AD, but was relatively intact in sv-PPA. As expected, most backward span scores across both modalities were lower than forward span scores. Neuroimaging analyses revealed that SSF and SSB performance in all patients combined correlated with grey matter intensity decrease in several clusters located in temporo-parieto-occipital brain regions. Post-hoc group comparisons of these regions showed that grey matter loss was more extensive in the lv-PPA and AD groups than in the nfv-PPA and sv-PPA groups.

Conclusions: The findings suggest that the visuospatial short-term and working memory profiles of the PPA variants are separable and likely reflect their distinct patterns of temporo-parieto-occipital brain atrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2020.08.018DOI Listing
November 2020

Olfactory dysfunction in frontotemporal dementia and psychiatric disorders: A systematic review.

Neurosci Biobehav Rev 2020 11 18;118:588-611. Epub 2020 Aug 18.

The University of Sydney, Brain & Mind Centre, Sydney, Australia. Electronic address:

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease. Diagnosis of FTD, especially the behavioural variant, is challenging because of symptomatic overlap with psychiatric disorders (depression, schizophrenia, bipolar disorder). Olfactory dysfunction is common in both FTD and psychiatric disorders, and often appears years before symptom onset. This systematic review analysed 74 studies on olfactory function in FTD, depression, schizophrenia and bipolar disorder to identify differences in olfactory dysfunction profiles, focusing on the most common smell measures: odour identification and discrimination. Results revealed that FTD patients were severely impaired in odour identification but not discrimination; in contrast, patients diagnosed with schizophrenia showed impairments in both measures, while those diagnosed with depression showed no olfactory impairments. Findings in bipolar disorder were mixed. Therefore, testing odour identification and discrimination differentiates FTD from depression and schizophrenia, but not from bipolar disorder. Given the high prevalence of odour identification impairments in FTD, and that smell dysfunction predicts neurodegeneration in other diseases, olfactory testing seems a promising avenue towards improving diagnosis between FTD and psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neubiorev.2020.08.002DOI Listing
November 2020

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation.

Sci Rep 2020 08 13;10(1):13741. Epub 2020 Aug 13.

Brain and Mind Centre, The University of Sydney, Camperdown, Sydney, NSW, 2050, Australia.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that are considered to be on the same disease spectrum because of overlapping genetic, pathological and clinical traits. Changes in serum proteins in FTD and ALS are poorly understood, and currently no definitive biomarkers exist for diagnosing or monitoring disease progression for either disease. Here we applied quantitative discovery proteomics to analyze protein changes in FTD (N = 72) and ALS (N = 28) patient serum compared to controls (N = 22). Twenty three proteins were significantly altered in FTD compared to controls (increased-APOL1, C3, CTSH, EIF5A, MYH2, S100A8, SUSD5, WDR1; decreased-C1S, C7, CILP2, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, IGHV1, ITIH2, PROS1, SHBG, UMOD, VASN) and 14 proteins were significantly altered in ALS compared to controls (increased-APOL1, CKM, CTSH, IGHG1, IGKC, MYH2; decreased-C7, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, SHBG). There was substantial overlap in the proteins that were altered in FTD and ALS. These results were validated using western blotting. Gene ontology tools were used to assess functional pathways potentially dysregulated in the two diseases, and calcium ion binding and innate immunity pathways were altered in both diseases. When put together, these results suggest significant overlap in pathophysiological peripheral changes in FTD and ALS. This study represents the first proteomics side-by-side comparison of serum changes in FTD and ALS, providing new insights into under-recognized perturbed pathways and an avenue for biomarker development for FTD and ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-70687-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426269PMC
August 2020

Same needles, different haystacks: understanding early symptomatology in genetic frontotemporal dementias.

Authors:
Olivier Piguet

J Neurol Neurosurg Psychiatry 2020 09 7;91(9):905. Epub 2020 Aug 7.

School of Psychology, and Brain & Mind Centre, The University of Sydney, Sydney, New South Wales, Australia

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-323561DOI Listing
September 2020

Sleep and orexin: A new paradigm for understanding behavioural-variant frontotemporal dementia?

Sleep Med Rev 2020 12 13;54:101361. Epub 2020 Jul 13.

The University of Sydney, Brain and Mind Centre, 100 Mallett Street, Camperdown, NSW, 2050, Australia; Concord General Hospital, Hospital Road, Concord, NSW, 2139, Australia; The University of Sydney, Concord Clinical School, Medical Education Centre, Concord General Hospital, Hospital Road, Concord, NSW, 2139, Australia. Electronic address:

Behavioural variant frontotemporal dementia (bvFTD) is a complex and heterogeneous disorder with as yet unidentified unifying pathophysiological mechanism. There is emerging evidence that hypothalamic dysfunction, manifesting as disturbances in sleep and metabolism, is an integral component of neurodegeneration in bvFTD. Although sleep and metabolic disturbances and the behavioural abnormalities of bvFTD may appear disparate on the surface, there may be a common underlying hormonal mechanism involving orexin. Orexin is a hypothalamic neurotransmitter directly responsible for control of sleep and metabolism in healthy individuals and is implicated in many abnormal behaviours commonly seen in bvFTD - such as impulsive behaviour, hedonistic reinforcement and binge-consumption of ethanol. Further characterising orexin's role in pathophysiology of bvFTD could lead to a new paradigm for understanding this disease and may provide a new direction towards effective management and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.smrv.2020.101361DOI Listing
December 2020

Apathy and its impact on carer burden and psychological wellbeing in primary progressive aphasia.

J Neurol Sci 2020 09 30;416:117007. Epub 2020 Jun 30.

The University of Sydney, School of Psychology, Sydney, NSW, Australia; The University of Sydney, Brain & Mind Centre, Sydney, NSW, Australia. Electronic address:

Objective: While patients with primary progressive aphasia (PPA) typically present with predominant language impairment, behavioural symptoms, such as apathy, are often under-recognised. We aimed to systematically characterise apathy across the three recognised subtypes of PPA, plus atypical right-lateralised presentations of semantic dementia, and to evaluate the impact of apathy on carer burden and psychological wellbeing.

Methods: Baseline assessments from 114 PPA patients were included: 31 left semantic dementia (left SD) 16 right semantic dementia (right SD), 30 progressive nonfluent aphasia (PNFA) and 37 logopenic progressive aphasia (LPA). Clinician (Neuropsychiatric Inventory; NPI) and carer rated (Cambridge Behavioural Inventory; CBI, Frontal Systems Behaviour Scale; FrSBe) measures were used to quantify symptoms of apathy, and carer burden and psychological wellbeing were determined using the Zarit Burden Interview and Depression, Anxiety and Stress Scale.

Results: On the NPI, symptoms of apathy were present in 39% left SD, 56% right SD, 33% PNFA and 43% LPA patients. Multiple regression analysis revealed that 17.9% of the variance in carer burden was uniquely explained by scores on carer rated measures of apathy (CBI, FrSBe), even after accounting for diagnosis, disease duration, and cognitive and language impairment.

Conclusions: Apathy is much more common than current diagnostic criteria for PPA would suggest, though the severity of apathy is similar across patient groups. Increased awareness and routine assessments of apathy symptoms are needed, together with targeted pharmacological and behavioural interventions. Moreover, as apathy substantially contributes to carer burden in PPA, psychoeducation addressing behavioural symptoms may be beneficial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2020.117007DOI Listing
September 2020

Interactions between decision-making and emotion in behavioral-variant frontotemporal dementia and Alzheimer's disease.

Soc Cogn Affect Neurosci 2020 07;15(6):681-694

School of Psychology, The University of Sydney, Sydney, Australia.

Negative and positive emotions are known to shape decision-making toward more or less impulsive responses, respectively. Decision-making and emotion processing are underpinned by shared brain regions including the ventromedial prefrontal cortex (vmPFC) and the amygdala. How these processes interact at the behavioral and brain levels is still unclear. We used a lesion model to address this question. Study participants included individuals diagnosed with behavioral-variant frontotemporal dementia (bvFTD, n = 18), who typically present deficits in decision-making/emotion processing and atrophy of the vmPFC, individuals with Alzheimer's disease (AD, n = 12) who present with atrophy in limbic structures and age-matched healthy controls (CTRL, n = 15). Prior to each choice on the delay discounting task participants were cued with a positive, negative or neutral picture and asked to vividly imagine witnessing the event. As hypothesized, our findings showed that bvFTD patients were more impulsive than AD patients and CTRL and did not show any emotion-related modulation of delay discounting rate. In contrast, AD patients showed increased impulsivity when primed by negative emotion. This increased impulsivity was associated with reduced integrity of bilateral amygdala in AD but not in bvFTD. Altogether, our results indicate that decision-making and emotion interact at the level of the amygdala supporting findings from animal studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/scan/nsaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393308PMC
July 2020

Constructing the social world: Impaired capacity for social simulation in dementia.

Cognition 2020 09 8;202:104321. Epub 2020 May 8.

The University of Sydney, Brain and Mind Centre, Sydney, Australia; The University of Sydney, School of Psychology, Sydney, Australia; Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia. Electronic address:

Scene construction refers to the capacity to imagine richly detailed scenes in one's mind's eye and has been demonstrated to be compromised across a range of clinical disorders in which episodic memory processes are also affected. It remains unclear however, how task demands modulate the content of the to-be-simulated scenes. Here, we sought to investigate the capacity for social forms of scene construction in the behavioural-variant of frontotemporal dementia (bvFTD), a progressive neurodegenerative disorder characterised by pronounced social cognitive and executive dysfunction, alongside episodic memory impairments. Twenty bvFTD patients, 14 Alzheimer's disease (AD) patients, and 20 healthy controls completed a scene construction task involving imagining social (e.g., busy restaurant, crowded train), and non-social (e.g., forest, abandoned warehouse) scenes, as well as a comprehensive neuropsychological battery. Relative to Controls, patient groups provided significantly fewer contextual details during scene construction, irrespective of condition, with no difference between the patient groups. A significant group by condition interaction reflected the fact that bvFTD patients were disproportionately impaired on social relative to non-social scenes, whereas performance was comparable across conditions within Control and AD groups. Social construction impairments correlated with response inhibition and verbal episodic memory in bvFTD, with no such associations emerging in the AD group. A multiple regression confirmed that response inhibition and verbal episodic memory were significant predictors of social construction capacity, accounting for ~54% of the overall variance on the task. Our findings suggest that the capacity to simulate social scenes represents a special class of mental construction that relies upon a number of interacting cognitive processes, including aspects of executive function and episodic memory. How the process of social construction relates to acts of prosocial behaviour or empathy will be important for future studies to address.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cognition.2020.104321DOI Listing
September 2020

Neither white nor black: embracing clinical variability in dementia diagnosis.

Authors:
Olivier Piguet

Brain 2020 05;143(5):1291-1293

The University of Sydney, School of Psychology and Brain & Mind Centre, Sydney NSW 2005, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa119DOI Listing
May 2020

Cerebellar structural connectivity and contributions to cognition in frontotemporal dementias.

Cortex 2020 08 28;129:57-67. Epub 2020 Apr 28.

The University of Sydney, School of Psychology, Sydney, NSW, Australia; The University of Sydney, Brain & Mind Centre, Sydney, NSW, Australia; Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, NSW, Australia. Electronic address:

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative brain disorders, primarily affecting the frontal and/or temporal lobes. Three main subtypes are recognised, each with distinct clinical and cognitive profiles: behavioural-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). Subtype-specific cerebellar grey matter atrophy has been associated with cognitive dysfunction in FTD; however, the extent and severity of structural abnormalities in the cerebro-cerebellar circuits in these disorders has not been investigated. This study aimed to identify patterns of cerebellar white matter changes and their relations to cognitive deficits in the main FTD subtypes. Results revealed bilateral cerebellar white matter changes in all FTD subtypes compared with controls, with greater cerebellar white matter changes in bvFTD than SD and PNFA. Both afferent and efferent cerebellar pathways were associated with cognition. The profiles of the involvement of cerebellar pathways in cognition varied across FTD syndromes. In bvFTD, the output pathway of the cerebellum was only associated with measures of episodic memory. The input pathway was associated with measures of attention, working memory, visuospatial, episodic memory, executive function, and emotion. In SD, both the output and input pathways were associated with measures of working memory, language, and emotion. Finally, in PNFA, both the output and input pathway of the cerebellum were associated with attention, language, and executive function. Additionally, the input pathway was associated with working memory, visuospatial, and emotion. This study is the first to identify patterns of cerebellar white matter changes across FTD syndromes, which in turn relate to cognitive deficits. These findings extend our understanding of the cerebro-cerebellar networks and provide new insight into the role of cerebellar white matter in cognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2020.04.013DOI Listing
August 2020

What to make of equivocal amyloid imaging results.

Neurocase 2020 06 15;26(3):137-146. Epub 2020 May 15.

Brain and Mind Centre, The University of Sydney , Sydney, Australia.

Introduction: Six patients with equivocal amyloid-PET results are discussed.

Methods: Patients underwent clinical/neuropsychological assessment, MRI, and amyloid-PET. Equivocal amyloid-PET was defined as cortical ligand binding with SUVR < 1.40. Follow-up for up to 5 years is presented.

Results: 6 patients (4 males, 2 females, mean age 71.8 +/- 2.5 years) with equivocal amyloid-PET were included from 136 patients who underwent amyloid-PET (4.4% of cases). Patients had variable language, behavioral, and cognitive deficits. Progression varied from no deterioration to residential care within 3 years.

Discussion: Equivocal amyloid-PET should be interpreted cautiously. Improved biomarkers of AD and other neurodegenerative diseases are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13554794.2020.1764056DOI Listing
June 2020

Phenotypic variability in ALS-FTD and effect on survival.

Neurology 2020 05 10;94(19):e2005-e2013. Epub 2020 Apr 10.

From the Memory and Cognition Clinic, Department of Clinical Neurosciences (R.M.A., M.C.K.), Royal Prince Alfred Hospital; Central Sydney Medical School and Brain & Mind Centre (R.M.A., E.M.D., J.R.H., M.C.K.) and School of Psychology and Brain & Mind Centre (C.S.-B., O.P.), The University of Sydney; and ARC Centre of Excellence of Cognition and its Disorders (C.S.-B., O.P.), Sydney, Australia.

Objective: To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD).

Methods: Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale.

Results: In the ALS-FTD group, 41 (69%) patients were categorized as having an initial cognitive presentation and 18 (31%) a motor presentation. Patients with motor presentation experienced a significantly shorter median survival of 2.7 years compared to 4.4 years ( < 0.001) in those with a cognitive presentation. No differences between motor vs cognitive onset ALS-FTD were found on cognitive testing. When compared to bvFTD, ALS-FTD-cognitive presentation was characterized by reduced language function ( < 0.001), verbal fluency ( = 0.001), and naming ( = 0.007). Both motor and cognitive onset ALS-FTD showed reduced emotion processing ( = 0.01) and exhibited greater motor cortex and dorsal lateral prefrontal cortex atrophy than bvFTD. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.

Conclusions: Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009398DOI Listing
May 2020

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Brain 2020 03;143(3):783-799

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 9RX, UK.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089666PMC
March 2020

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

Brain 2020 06;143(6):1632-1650

Department of Neurology, UCLA Medical Centre, University of California Los Angeles, Los Angeles, USA.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849953PMC
June 2020