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Abstract INTRODUCTION Some people with dementia develop changes in behaviour and cognition that may lead to interactions with police or the legal system. However, large, prospective case–control studies examining these behaviours are lacking. METHODS One hundred and forty‐four people with dementia and 53 controls completed the Misdemeanours and Transgressions Screener. RESULTS Criminal risk behaviours were reported in: 65.6% of behavioural‐variant frontotemporal dementia, 46.2% of right‐lateralised semantic dementia, and 27.0% of Alzheimer's disease patients. In 19.1% of patients these behaviours led to contact with police or authority figures. Compared to controls, people with dementia showed higher rates of physical assault (p = 0.024), financial/professional recklessness (p = 0.009), and inappropriate behaviours (p = 0.052). DISCUSSION Criminal risk behaviours are common across dementia subtypes and may be one of the first clinical signs of frontotemporal dementia. Further research to understand how to balance risk minimisation with an individual's liberties as well as the inappropriate criminalisation of people with dementia is needed. Highlights The Misdemeanours and Transgressions Screener is a new tool to assess criminal risk behaviours. Forty‐seven percent of patients with dementia show criminal risk behaviour after dementia onset. Behaviours included verbal abuse, traffic violations, physical assault. New onset of criminal risk behaviours >50 years is a clinical sign for frontotemporal dementia.

Abstract Neuroinflammation is a hallmark of frontotemporal dementia (FTD), a heterogeneous group of proteinopathies characterized by the progressive degeneration of the frontal and temporal lobes. It is marked by microglial activation and subsequent cytokine release. Although cytokine levels in FTD brain and CSF have been examined, the number of cytokines measured in each study is limited and knowledge on cytokine concentrations in FTD serum is scarce. Here, we assessed 48 cytokines in FTD serum and brain. The aim was to determine common cytokine dysregulation pathways in serum and brain in FTD. Blood samples and brain tissue samples from the superior frontal cortex (SFC) were collected from individuals diagnosed with behavioral variant FTD (bvFTD) and healthy controls, and 48 cytokines were measured using a multiplex immunological assay. The data were evaluated by principal component factor analysis to determine the contribution from different components of the variance in the cohort. Levels of a number of cytokines were altered in serum and SFC in bvFTD compared to controls, with increases in GRO-α and IL-18 in both serum and SFC. These changes could be associated with NLRP3 inflammasome activation or the NFκB pathway, which activates NLRP3. The results suggest the possible importance of the NLRP3 inflammasome in FTD. An improved understanding of the role of inflammasomes in FTD could provide valuable insights into the pathogenesis, diagnosis and treatment of FTD.

Background: Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored. Methods: Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls). Results: Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p ≤ .001). Conclusions: These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets.

Phan et al. assess the presence of human endogenous retrovirus K (HERV-K) in the serum and brain samples of individuals with behavioral variant frontotemporal dementia (bvFTD) with TDP-43 pathology, as seen in amyotrophic lateral sclerosis. The authors show HERV-K is associated with manifestations of bvFTD with TDP-43 pathology.

Abstract Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothing is known about the impact of VLCFA-lipids in neurodegenerative diseases. Here, we investigated the possible role of VLCFA-lipids in frontotemporal dementia (FTD), which is a leading cause of younger-onset dementia. Using quantitative discovery lipidomics, we identified three VLCFA-lipid species that were significantly increased in FTD brain compared to controls, with strong correlations with ELOVL4. Increases in ELOVL4 expression correlated with significant decreases in the membrane-bound synaptophysin in FTD brain. Furthermore, increases in ABCD1 expression correlated with increases in VLCFA-lipids. We uncovered a new pathomechanism that is pertinent to understanding the pathogenesis of FTD.

Abstract Objective The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS‐FTD. Methods In a prospective case‐controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS‐Plus), ALS‐FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel‐based morphometry analyses determined atrophy patterns in patients experiencing psychosis‐like experiences and other perceptual abnormalities. Results The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS‐FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer‐based reports (18%) and self‐report measures of psychotic‐like experiences (21%). In an ENTER regression model, social anxiety and ACE‐III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis‐like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. Interpretation The model for psychosis proneness in ALS‐FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.

Abstract 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: rs = 0.462; p = 0.001), as well as overall functional decline (Frontotemporal Dementia Rating Scale: rs = −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.

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke’s cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p

Abstract Background The Centiloid scale was developed to standardise the results of beta-amyloid (Aβ) PET. We aimed to determine the Centiloid unit (CL) thresholds for CERAD sparse and moderate-density neuritic plaques, Alzheimer’s disease neuropathologic change (ADNC) score of intermediate or high probability of Alzheimer’s Disease (AD), final clinicopathological diagnosis of AD, and expert visual read of a positive Aβ PET scan. Methods Aβ PET results in CL for 49 subjects were compared with post-mortem findings, visual read, and final clinicopathological diagnosis. The Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results A threshold of 20.1 CL (21.3 CL when corrected for time to death, AUC 0.97) yielded highest accuracy in detecting moderate or frequent plaque density while 45 CL. Positive visual read agreed highly with results > 26 CL. Conclusions Centiloid values 20 CL indicated the presence of at least moderate plaque density, but approximately 50 CL or more best confirmed both neuropathological and clinicopathological diagnosis of Alzheimer’s disease.

Abstract Introduction Timely diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging because it depends on clinical expertise and potentially ambiguous diagnostic guidelines. Recent recommendations highlight the role of multimodal neuroimaging and machine learning methods as complementary tools to address this problem. Methods We developed an automatic, cross‐center, multimodal computational approach for robust classification of patients with bvFTD and healthy controls. We analyzed structural magnetic resonance imaging and resting‐state functional connectivity from 44 patients with bvFTD and 60 healthy controls (across three imaging centers with different acquisition protocols) using a fully automated processing pipeline, including site normalization, native space feature extraction, and a random forest classifier. Results Our method successfully combined multimodal imaging information with high accuracy (91%), sensitivity (83.7%), and specificity (96.6%). Discussion This multimodal approach enhanced the system's performance and provided a clinically informative method for neuroimaging analysis. This underscores the relevance of combining multimodal imaging and machine learning as a gold standard for dementia diagnosis.

Abstract Introduction Exploring the degree of heritability in a large cohort of frontotemporal lobar degeneration with tau‐immunopositive inclusions (FTLD‐tau) and determining if different FTLD‐tau subtypes are associated with stronger heritability will provide important insight into disease pathogenesis. Methods Using modified Goldman pedigree classifications, heritability was examined in pathologically proven FTLD‐tau cases with dementia at any time (n = 124) from the Sydney‐Cambridge collection. Results Thirteen percent of the FTLD‐tau cohort have a suggested autosomal dominant pattern of inheritance, 25% have some family history, and 62% apparently sporadic. MAPT mutations were found in 9% of cases. Globular glial tauopathy was associated with the strongest heritability with 40% having a suggested autosomal dominant pattern of inheritance followed by corticobasal degeneration (19%), Pick's disease (8%), and progressive supranuclear palsy (6%). Discussion Similar to clinical frontotemporal dementia syndromes, heritability varies between pathological subtypes. Further identification of a genetic link in cases with strong heritability await discovery.

Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients.Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity.Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments.Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.

Behavioral variant frontotemporal dementia (bvFTD) is a younger onset form of neurodegeneration initiated in the frontal and/or temporal lobes with a slow clinical onset but rapid progression. bvFTD is highly complex biologically with different pathological signatures and genetic variants that can exhibit a spectrum of overlapping clinical manifestations. Although the role of innate immunity has been extensively investigated in bvFTD, the involvement of adaptive immunity in bvFTD pathogenesis is poorly understood. We analyzed blood serum proteomics to identify proteins that are associated with autoimmune disease in bvFTD. Eleven proteins (increased: ATP5B, CALML5, COLEC11, FCGBP, PLEK, PLXND1; decreased: APOB, ATP8B1, FAM20C, LOXL3, TIMD4) were significantly altered in bvFTD with autoimmune disease compared to those without autoimmune disease. The majority of these proteins were enriched for glycoprotein-associated proteins and pathways, suggesting that the glycome is targeted in bvFTD with autoimmune disease.

Abstract Background Frontotemporal dementia (FTD) is associated with complex changes in eating behavior and metabolism, which potentially affect disease pathogenesis and survival. It is currently not known if body composition changes and changes in fat deposition also exist in FTD, the relationship of these changes in eating behavior and appetite, and whether these changes are centrally mediated. Methods Body composition was measured in 28 people with behavioral‐variant frontotemporal dementia (bvFTD), 16 with Alzheimer’s disease (AD), and 19 healthy controls, using dual energy x‐ray absorptiometry. Changes in body composition were correlated to brain grey matter atrophy using voxel‐based morphometry on high‐resolution magnetic resonance imaging. Results Behavioral‐variant FTD was characterized by changes in body composition, with increased total fat mass, visceral adipose tissue area (VAT area), and android: gynoid ratio compared to control and AD participants (all P values

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.

Abstract Introduction Overlapping and evolving symptoms lead to ambiguity in the diagnosis of dementia. Visuospatial function relies on parietal lobe function, which may be affected in the early stages of Alzheimer's disease (AD). This review evaluates visuospatial dysfunction in patients with AD, frontotemporal dementia, dementia with Lewy bodies, and vascular dementia to determine the diagnostic and prognostic potential of visuospatial tasks in AD. Methods A systematic search of studies (1960–2016) investigating visuospatial dysfunction in dementia was conducted. Results Tests measuring construction, specifically Block Design and Clock Drawing Test, and visual memory, specifically Rey‐Osterrieth Complex Figure recall and topographical tasks, show the greatest diagnostic potential in dementia. The Benton visual retention, Doors and People, and topographical memory tests show potential as prognostic markers. Discussion Tests of visuospatial function demonstrate significant diagnostic and prognostic potential in dementia. Further studies with larger samples of pathologically confirmed cases are required to verify clinical utility.

Posterior cortical atrophy is a neurodegenerative syndrome characterised by progressive disruption of visual and perceptual processing, associated with atrophy in the parieto-occipital cortex. Current diagnostic criteria describe relative sparing of episodic memory function, but recent findings suggest that anterograde memory is often impaired. Whether these deficits extend to remote memory has not been addressed. A large body of evidence suggests that the recollection of an autobiographical event from the remote past coincides with the successful retrieval of visual images. We hypothesised that the profound visual processing deficits in posterior cortical atrophy would result in impaired autobiographical memory retrieval. Fourteen posterior cortical atrophy patients, eighteen typical Alzheimer's disease patients and twenty-eight healthy controls completed the Autobiographical Interview. Autobiographical memory in posterior cortical atrophy was characterised by a striking loss of internal, episodic detail relative to controls and to same extent as typical Alzheimer's disease patients, in conjunction with an increase in external details tangential to the memory described. The memory narratives of posterior cortical atrophy patients showed a specific reduction in spatiotemporal and perceptual detail. Voxel-based morphometry analysis revealed atrophy of the parieto-occipital cortices in posterior cortical atrophy but relatively spared hippocampi bilaterally, compared with characteristic atrophy of the medial temporal lobes in typical Alzheimer's disease. Analysis of brain regions showing posterior cortical atrophy-specific atrophy revealed a correlation between perceptual details in autobiographical memory and grey matter density in the right precuneus. This study demonstrates remote memory impairment in posterior cortical atrophy despite relatively preserved medial temporal lobe structures. The results demonstrate, for the first time, profound autobiographical memory impairment in PCA and suggest that this is driven by the well-recognised deficits in higher-order visual processing. The findings are discussed in the context of posterior parietal contributions to imagery and memory, and the clinical implications of autobiographical memory impairment for diagnostic and management protocols in posterior cortical atrophy. Keywords: Posterior cortical atrophy, Autobiographical memory, Visual imagery, Alzheimer's disease

Abstract Introduction Ensuring reliable administration and reporting of cognitive screening tests are fundamental in establishing good clinical practice and research. This study captured the rate and type of errors in clinical practice, using the Addenbrooke's Cognitive Examination‐III (ACE‐III), and then the reduction in error rate using a computerized alternative, the ACEmobile app. Methods In study 1, we evaluated ACE‐III assessments completed in National Health Service (NHS) clinics (n = 87) for administrator error. In study 2, ACEmobile and ACE‐III were then evaluated for their ability to capture accurate measurement. Results In study 1, 78% of clinically administered ACE‐IIIs were either scored incorrectly or had arithmetical errors. In study 2, error rates seen in the ACE‐III were reduced by 85%–93% using ACEmobile. Discussion Error rates are ubiquitous in routine clinical use of cognitive screening tests and the ACE‐III. ACEmobile provides a framework for supporting reduced administration, scoring, and arithmetical error during cognitive screening.

Objective: This present study aims to address the gap in the literature regarding the severity and underlying neural correlates of psychotic symptoms in frontotemporal dementia with and without the C9orf72 gene expansion. Methods: Fifty-six patients with behavioural variant frontotemporal dementia (20 with concomitant amyotrophic lateral sclerosis) and 23 healthy controls underwent neuropsychological assessments, detailed clinical interview for assessment of psychosis symptoms, brain MRI and genetic testing. Carers underwent a clinical interview based upon the neuropsychiatric inventory. Patients were assessed at ForeFront, the Frontotemporal Dementia Research Group at Neuroscience Research Australia or at the Brain and Mind Centre, between January 2008 and December 2013. An index of psychosis was calculated, taking into account the degree and severity of psychosis in each case. Voxel-based morphometry analyses were used to explore relationships between the psychosis index and grey matter changes. Results: Thirty-four percent of frontotemporal dementia patients showed psychotic features. C9orf72 expansion cases were more likely to exhibit psychotic symptoms than non-carriers (64% vs. 26%; p = 0.006), which were also more severe (psychotic index 23.1 vs. 8.1; p = 0.002). Delusions comprised persecutory, somatic, jealous and grandiose types and were present in 57% of C9orf72 carriers and 19% of non-carriers (p = 0.006). Auditory, visual or tactile hallucinations were present in 36% of C9orf72 carriers and 17% of non-carriers (p = 0.13). Increased psychotic symptoms in C9orf72 expansion carriers correlated with atrophy in a distributed cortical and subcortical network that included discrete regions of the frontal, temporal and occipital cortices, as well as the thalamus, striatum and cerebellum. Conclusions: This study underlines the need to consider and assess for psychotic symptoms in the frontotemporal dementia-amyotrophic lateral sclerosis continuum particularly in those with C9orf72 gene expansions. The network of brain regions identified in this study is strikingly similar to that identified in other psychotic disorders such as schizophrenia, which suggests that treatment strategies in psychiatry may be beneficial for the management of psychotic symptoms in frontotemporal dementia.

Abstract Introduction Clinicopathologic correlation in non‐Alzheimer's tauopathies is variable, despite refinement of pathologic diagnostic criteria. In the present study, the clinical and neuroimaging characteristics of globular glial tauopathy (GGT) were examined to determine whether subtyping according to consensus guidelines improves clinicopathologic correlation. Methods Confirmed GGT cases (n = 11) were identified from 181 frontotemporal tauopathy cases. Clinical and neuroimaging details were collected, and cases sub‐typed according to the consensus criteria for GGT diagnosis. Relationships between clinical syndrome and GGT subtype were investigated. Results In total, 11 patients (seven males, four females, mean age = 67.3 +/− 10.6 years) with GGT were included. Most, but not all, presented with behavioral variant frontotemporal dementia, but none had amyotrophic lateral sclerosis. Subtyping of GGT proved to be difficult and did not improve clinicopathologic correlation. Discussion Sub‐classification of GGT pathology may be difficult and did not improve clinicopathologic correlation. Better biomarkers of tau pathology are needed.

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.

The C9orf72 genetic mutation is the most common cause of familial frontotemporal dementia (FTD) and motor neuron disease (MND). Previous family studies suggest that while some common clinical features may distinguish gene carriers from sporadic patients, the clinical features, age of onset and disease progression vary considerably in affected patients. Whilst disease presentations may vary across families, age at disease onset appears to be relatively uniform within each family. Here, we report two individuals with a C9orf72 repeat expansion from two generations of the same family with markedly different age at disease onset, clinical presentation and disease progression: one who developed motor neuron and behavioural symptoms in their mid 40s and died 3 years later with confirmed TDP-43 pathology and MND; and a second who developed cognitive and mild behavioural symptoms in their mid 70s and 8 years later remains alive with only slow deterioration. This report highlights the phenotypic variability, including age of onset, within a family with the C9orf72 repeat expansion.

Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick's disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression.Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after ~12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression.Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle—bvFTD pattern I; corticostriatal pathway—bvFTD pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III) did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV) reached significance. The findings in the corticospinal tract were due to a “dichotomous” behavior of FA changes there.Conclusion: Longitudinal TOI analysis demonstrated a pattern of white matter pathways alterations consistent with patterns of pTDP-43 pathology.

Behavioral variant frontotemporal dementia (bvFTD) is the most prevalent form of FTD syndromes. bvFTD is characterized clinically by changes in behavior and cognition and pathologically by focal brain atrophy and concomitant loss of lipids. bvFTD is further characterized by eating abnormalities that result in dyslipidemia. Although dyslipidemia is apparent in bvFTD, very little is known about global lipid changes in bvFTD and lipid dysregulation underlying bvFTD. Here, we undertook a comprehensive lipidomics analysis of blood plasma from patients with bvFTD, patients with Alzheimer’s disease (AD) and controls, using liquid chromatography-tandem mass spectrometry, with the aim of understanding lipid dysregulation in bvFTD. In our analysis, we detected all four major classes of lipids (glycerolipids, phospholipids, sphingolipids, sterols), 17 subclasses of lipids, and 3,225 putative individual lipid species in total, as well as a group of dietary lipids. We found that the levels of numerous lipid species were significantly altered in bvFTD compared to AD and control. We found that the total abundance of triglyceride (TG) increased significantly in bvFTD, whereas phosphatidylserine and phosphatidylglycerol decreased significantly in bvFTD. These results suggest manifestation of hypertriglyceridemia and hypoalphalipoproteinemia in bvFTD. We also identified five lipid molecules—TG (16:0/16:0/16:0), diglyceride (18:1/22:0), phosphatidylcholine (32:0), phosphatidylserine (41:5), and sphingomyelin (36:4)—that could potentially be used for developing biomarkers for bvFTD. Furthermore, an analysis of plant lipids revealed significant decreases in monogalactosyldiacylglycerol and sitosteryl ester in bvFTD, indicating altered eating behavior in bvFTD. This study represents the first lipidomics analysis of bvFTD and has provided new insights into an unrecognized perturbed pathology in bvFTD, providing evidence in support of considerable lipid dysregulation in bvFTD.

Background: The Addenbrooke's Cognitive Examination (ACE) is used to measure cognition across a range of domains in dementia. Identifying the order in which cognitive decline occurs across items, and whether this varies between dementia aetiologies could add more information to subdomain scores. Method: ACE-Revised data from 350 patients were split into three groups: Alzheimer's type (n = 131), predominantly frontal (n = 119) and other frontotemporal lobe degenerative disorders (n = 100). Results of factor analysis and Mokken scaling analysis were compared. Results: Principal component analysis revealed one factor for each group. Confirmatory factor analysis found that the one-factor model fit two samples poorly. Mokken analyses revealed different item ordering in terms of difficulty for each group. Conclusion: The different patterns for each diagnostic group could aid in the separation of these different types of dementia.

Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been hampered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed.

SUMMARY Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300–93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ∼1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.

Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and Emotion Selection) and found that all three patient groups were similarly impaired. Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia.

Emotional events gain special priority in how they are remembered, with emotionally arousing events typically recalled more vividly and with greater confidence than non-emotional events. In dementia, memory and emotion processing are affected to varying degrees, however, whether emotional enhancement of memory for complex ecologically valid events is differentially affected across dementia syndromes remains unclear, with previous studies examining effects of emotion on simple visual recognition only. Here, we examined memory for an emotionally arousing short story and a closely matched, emotionally neutral story in behavioural-variant frontotemporal dementia (bvFTD) (n = 13) and Alzheimer’s disease (AD) (n = 14), and contrasted their performance with healthy controls (n = 12). Multiple-choice recognition memory for specific details of the story was assessed after a 1-hour delay. While AD and control groups showed enhanced memory for the emotional story, the bvFTD group recalled a similar number of details from the emotional and neutral stories. Voxel-based morphometry analyses revealed emotional enhancement of memory correlated with distinct brain regions in each patient group. In AD, emotional enhancement was associated with integrity of the bilateral hippocampus, parahippocampal gyri, temporal fusiform gyrus and frontal pole, regions implicated in memory processes. In contrast in bvFTD, integrity of emotion processing regions, including the orbitofrontal cortex, right amygdala and right insula, correlated with the extent emotion enhanced memory. Our results reveal that integrity of frontal and temporal regions determine the quality and nature of emotional memories. While emotional enhancement of memory is present in mild AD, in bvFTD emotion does not facilitate memory retrieval for complex realistic events. This attenuation of emotional enhancement is due to degradation of emotion processing regions, which may be important for modulating levels of arousal.

In this paper, we describe the detailed neuropsychological investigation of two cases of progressive supranuclear palsy (PSP) and demonstrate word-finding difficulties associated with pervasive problems in word-retrieval. The pattern of deficits resembles that seen in Parkinson’s Disease (PD) but is more severe, even in very mild PSP, and appears less amenable to cue facilitation. Performance on a variety of word-production tasks is compared, and experimental controls for motor effects on performance are included. The role of stimulus cues in speeded word-finding is addressed experimentally, as are central executive influences on task performance. This combines with functional brain-scan data from single photon emission computed tomography (SPECT) which shows reduced frontal perfusion in one of the two cases.

ABSTRACT Behavioural disturbances in frontotemporal dementia (FTD) are thought to reflect mainly atrophy of cortical regions. Recent studies suggest that subcortical brain regions, in particular the striatum, are also significantly affected and this pathology might play a role in the generation of behavioural symptoms. Objective: To investigate prefrontal cortical and striatal atrophy contributions to behavioural symptoms in FTD. Methods: One hundred and eighty-two participants (87 FTD patients, 39 AD patients and 56 controls) were included. Behavioural profiles were established using the Cambridge Behavioural Inventory Revised (CBI-R) and Frontal System Behaviour Scale (FrSBe). Atrophy in prefrontal (VMPFC, DLPFC) and striatal (caudate, putamen) regions was established via a 5-point visual rating scale of the MRI scans. Behavioural scores were correlated with atrophy rating scores. Results: Behavioural and atrophy ratings demonstrated that patients were significantly impaired compared to controls, with bvFTD being most severely affected. Behavioural-anatomical correlations revealed that VMPFC atrophy was closely related to abnormal behaviour and motivation disturbances. Stereotypical behaviours were associated with both VMPFC and striatal atrophy. By contrast, disturbance of eating was found to be related to striatal atrophy only. Conclusion: Frontal and striatal atrophy contributed to the behavioural disturbances seen in FTD, with some behaviours related to frontal, striatal or combined fronto-striatal pathology. Consideration of striatal contributions to the generation of behavioural disturbances should be taken into account when assessing patients with potential FTD.

ABSTRACT Behavioural-variant frontotemporal dementia (bvFTD) is characterised by insidious changes in personality and interpersonal conduct that reflect progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation and decision making. The underlying pathology is heterogeneous and classified according to the presence of intraneuronal inclusions of tau, TDP-43 or occasionally FUS. Biomarkers to detect these histopathological changes in life are increasingly important with the development of disease-modifying drugs. Gene mutations have been found which collectively account for around 10-20% of cases including a novel hexanucleotide repeat on chromosome 9 (C9orf72). The recently reviewed International Consensus Criteria for bvFTD propose three levels of diagnostic certainly: possible, probable and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process with support from neuropsychological testing designed to detect impairment in decision-making, emotion processing and social cognition. Brain imaging is important for increasing the level of diagnosis certainty. Carer education and support remain of paramount importance.

Abstract Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders with distinct profiles which are helpful in the diagnosis and monitoring of these disorders. The Cambridge Behavioural Inventory (CBI) has been shown to distinguish frontotemporal dementia (FTD), Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD), but it is lengthy. Objective: To develop a shorter version of the 81 item CBI. Methods: CBI data from 450 participants with behavioural variant frontotemporal dementia (bv-FTD) (64), AD (96), PD (215) and HD (75) were analysed using Principal Components Analysis and measures of internal consistency (Cronbach alpha). Results: A reduced 45-item questionnaire was developed. The instrument identified distinct behavioural profiles and performed as well as the original version. Conclusions: A shorter (45 item) version of the CBI is capable of differentiating bv-FTD and AD from PD and HD. It may be useful in delineating the type and extent of problems in these disorders as well as monitoring therapeutic interventions.

ABSTRACT FTD is a unique condition which manifests with a range of behavioural symptoms, marked dysfunction in activities of daily living (ADL) and increased levels of carer burden as compared to carers of other dementias. No efficacious pharmacological interventions to treat FTD currently exist, and research on pharmacological symptom management is variable. The few studies on non-pharmacological interventions in FTD focus on either the carer or the patients' symptoms, and lack methodological rigour. This paper reviews and discusses current studies utilising non-pharmacological approaches, exposing the clear need for more rigorous methodologies to be applied in this field. Finally, a successful randomised controlled trial helped reduce behaviours of concern in dementia, and through implementing participation in tailored activities, the FTD-specific Tailored Activities Program (TAP) is presented. Crucially, this protocol has scope to target both the person with FTD and their carer. This paper highlights that studies in this area would help to elucidate the potential for using activities to reduce characteristic behaviours in FTD, improving quality of life and the caregiving experience in FTD.

ABSTRACT There is great need to understand variables behind carer burden, especially in FTD. Carer burden is a complex construct, and its factors are likely to vary depending on the type of dementia, carer characteristics and cultural background. Objective: The present study aimed to compare profiles and severity of carer burden, depression, anxiety and stress in carers of FTD patients in India in comparison to Australia; to investigate which carer variables are associated with carer burden in each country. Methods: Data of 138 participants (69 dyads of carers-patients) from India and Australia (India, n=31; Australia, n=38). Carer burden was assessed with the short Zarit Burden Inventory; carer depression, anxiety and stress were measured with the Depression, Anxiety and Stress-21. Dementia severity was determined with the Frontotemporal Dementia Rating Scale (FTD-FRS), and a range of demographic variables regarding the carer and patient were also obtained. Results: Overall, levels of carer burden were not significantly different across India and Australia, despite more hours delivering care and higher dementia severity in India. Variables associated with burden, however, differed between countries, with carer depression, anxiety and stress strongly associated with burden in India. By contrast, depression, stress, and dementia severity were associated with burden in Australia. Conclusion: This study demonstrated that variables associated with carer burden in FTD differ between cultures. Consequently, cultural considerations should be taken into account when planning for interventions to reduce burden. This study suggests that addressing carers' skills and coping mechanisms are likely to result in more efficacious outcomes than targeting patient symptoms alone.

ABSTRACT Frontotemporal dementia (FTD) patients often present with severe behavioural disturbances and concomitant lack of insight. The underlying neural correlates of these disturbances are mostly attributed to prefrontal cortex dysfunction, but are still poorly understood. Objectives: The current study explores whether a simple visual magnetic resonance imaging (MRI) rating scale in combination with the Frontal System Behaviour Scale (FrSBe) can be used to identify the prefrontal correlates of behavioural symptoms in behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Methods: Forty-eight patients with a clinical diagnosis of bvFTD and AD participated in the study. Their behavioural profiles were assessed using the Frontal System Behaviour Scale (FrSBe) and cross-correlated to the atrophy of the sub-regions in the prefrontal cortex using a 5-point visual rating scale of MRI scans. Results: Patients with bvFTD showed higher incidence of behavioural disturbances than AD with apathy being the most significant. BvFTD patients also showed the highest incidence of atrophy in the orbital frontal cortex and this atrophy was correlated with the apathetic features. Conclusions: Employment of a simple visual MRI rating scale can be used in combination with a behavioural screening test to identify reliably the behavioural symptoms in bvFTD and AD. These findings will inform the diagnostic accuracy of the neural correlates of behavioural dysfunction in bvFTD in the future.

ABSTRACT Objective: Semantic dementia, a subtype of frontotemporal lobar degeneration, is characterised by cross-modal loss of conceptual knowledge attributable to progressive degeneration of the left anterior temporal lobe. Much less is known regarding the clinical presentation of SD patients with predominantly right-lateralised atrophy. Recent reports emphasise marked socioemotional and behavioural disturbances in such cases. Given the importance of the right anterior temporal lobes in social cognition, we hypothesised that socioemotional functioning would be disproportionately affected in right versus left-lateralised SD cases. Methods: We assessed well-characterised cases of predominantly right (n=10) and left (n=12) SD and 20 matched healthy controls on tests of emotion processing and interpersonal functioning. Results: Right SD cases showed disproportionate difficulties in the recognition of positive and negative facial emotions, specifically happiness and anger, compared with left SD cases. Deficits in anger recognition persisted in right SD despite covarying for facial and semantic processing. On a contextually rich task of emotion recognition using multimodal videos, no subgroup differences were evident. Finally, empathic concern was rated as significantly lower by caregivers of right versus left SD cases. Overall, the extent of socioemotional disturbance was associated with the degree of behavioural changes in SD. Conclusion: Our results reveal considerable overlap in the extent to which socioemotional processes are disrupted in left and right-lateralised cases of SD. Notably, however, right SD cases show disproportionate deficits for recognition of facial emotions and the capacity for empathic concern, supporting a specialised role for the right anterior temporal lobes in mediating these cognitive functions.