Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level. OBJECTIVE: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis. METHODS: Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for C9orf72 were obtained from the published literature. RESULTS: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)). CONCLUSION: Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.

Prevalence of and Factors Associated with Hypersexuality in Patients with Dementia: A Retrospective Cross-Sectional Study.

INTRODUCTION: The psychological and behavioral symptoms of dementia are frequently observed in clinical practice, and those related to sexuality are particularly challenging. However, few studies have evaluated the prevalence or factors associated with hypersexuality in patients with dementia. OBJECTIVES: This study aims to determine the prevalence of hypersexuality in patients with dementia, describe associated factors, and qualitatively report the most common presentations and treatments. METHODS: This retrospective cross-sectional study collected data from semi-structured charts of dementia patients who were followed up at a secondary care reference center between 2015 and 2019. Results: Of 552 total patients, 52 (9.3%) were hypersexual, which was associated with male sex (P < .000; OR 2.95, 95% CI 1.73-5.01), frontotemporal dementia (P < .007), alcohol use (P < .015; OR 2.35, 95% CI 1.16-4.73) and tobacco use (P < .000; OR 2.88, 95% CI 1.61-5.13). CONCLUSIONS: Although our findings were similar to the literature, their significant variability reflects the limited and low quality of the available evidence and a lack of standardization regarding terminology, definitions, and diagnostic criteria for hypersexuality.

Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Criminal Behaviour After Diagnosis of a Neurocognitive Disorder: A Nationwide Finnish Register Study.

OBJECTIVE: To explore criminal behavior of individuals with Alzheimer's disease (AD), frontotemporal dementia (FTD), or Lewy body dementias (LBD) after the diagnosis. DESIGN: Nationwide register study. SETTING: Information on diagnoses and criminality was received from Finnish registers. Crime types and incidences were compared between disorders and the general population. PARTICIPANTS: All Finnish individuals diagnosed with AD, LBD, or FTD (n = 92 189) during 1998-2015. MEASUREMENTS: Types of crimes and incidences, the standardized criminality ratio (SCR, number of actual crimes per number of expected crimes), numbers of observed cases, and person-years at risk counted in 5-year age groups and for both sexes and yearly. RESULTS: Among men, at least one crime was committed by 2.8% of AD, 7.2% of FTD, and 4.8% of LBD patients. Among women, the corresponding figures were 0.4%, 2.0%, and 2.1%. The most frequent type of crime was traffic offence, followed by property crime. After age adjustment, the relative number of crimes between groups did not differ, except that men with FTD and LBD committed more crimes than those with AD. The SCR (95% CI) among men were 0.40 (0.38-0.42) in AD, 0.45 (0.33-0.60) in FTD, and 0.52 (0.48-0.56) in LBD. Among women, these were 0.34 (0.30-0.38), 0.68 (0.39-1.09), and 0.59 (0.51-0.68). CONCLUSIONS: The diagnosis of a neurocognitive disorder does not increase criminal behavior, but rather reduces it by up to 50%. Differences in crime activity are present between different neurocognitive disorders and between the sexes.

The Association Between Somatic Symptom Disorders and Neurocognitive Disorders: A Systematic Review.

OBJECTIVE: Onset of neuropsychiatric symptoms in older adults may represent prodromal manifestations of neurodegenerative disorders. The association between the onset of somatic symptom and related disorders (SSRD) and the subsequent development of neurodegenerative disorders remains unclear. A critical review of studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia was performed. OBJECTIVE: To critically review studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia. METHODS: A systematic review of Web of Science Core databases was carried out from inception of databases up to May 2021 to identify observational studies pertaining to both SSRD and neurodegenerative disorders. Data was extracted and compiled regarding subjects enrolled, age at onset of the SSRD and at onset of the neurodegenerative disorders, and specific SSRD manifestations and underlying neuropathologies reported. RESULTS: Thirteen articles were included. Of the 123 identified subjects with SSRD at baseline, 34.1% developed a neurodegenerative disorder, with 80.9% of these being a Lewy body spectrum disorder. The interval between onset of SSRD manifestations and subsequent development of a neurodegenerative disorder was less than 3 years for half of the cases. Of the 1,494 subjects with a neurodegenerative disorder at baseline retrieved, SSRD manifestations were reported in 33.4% of Lewy body spectrum disorders cases. Onset of SSRD manifestations antedated or was concomitant to the diagnosis of the Lewy body spectrum disorder in 65.6% of cases. CONCLUSION: While limited, current evidence suggests a possible association between late-onset SSRD and the subsequent development of neurodegenerative disorders, notably Lewy body spectrum disorders.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

"I felt like I had been put on the shelf and forgotten about" - lasting lessons about the impact of COVID-19 on people affected by rarer dementias.

BACKGROUND: The public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer's disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping. METHODS: This was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes. RESULTS: 184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement. CONCLUSIONS: This study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of - and may inform the development of - tailored support for these underrepresented groups more generally.

Sleep apnea and the risk of dementia: A systematic review and meta-analysis.

Sleep apnea (SA) is potentially a modifiable risk factor for dementia. However, its associations to specific aetiologies of dementia remain uncertain. A systematic review and meta-analysis of cohort studies investigating the association between sleep apnea and specific aetiologies of dementia, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD), vascular dementia (VaD), and frontotemporal dementia (FTD) was performed. The use of biomarkers to support clinical diagnoses in eligible studies was collected. Eleven studies were included, comprising 1,333,424 patients. Patients with sleep apnea had an increased risk of developing any type of neurocognitive disorder (HR: 1.43 [95% CI 1.26-1.62]), Alzheimer's disease (HR: 1.28 [95% CI 1.16-1.41]), and Parkinson's disease (HR: 1.54 [95% CI 1.30-1.84]). No statistically significant association was found for vascular dementia. One study reported a two-fold increased risk for Lewy body dementia (HR: 2.06 [95% CI 1.45-2.91]). No studies investigated the risk for frontotemporal dementia and none of the studies reported results pertaining to biomarkers. Sleep apnea is associated with a significantly increased risk of dementia, particularly for Alzheimer's disease and Parkinson's disease, but not for vascular dementia. Future studies should look at the impact of sleep apnea on specific dementia biomarkers.

FRONTotemporal dementia Incidence European Research Study-FRONTIERS: Rationale and design.

INTRODUCTION: The incidence of Frontotemporal Lobar Degeneration (FTLD)-related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap. METHODS: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long-lasting experience in FTLD-related disorders and comprehensive regional referral networks, enabling incidence estimation over well-defined geographical areas. ENDPOINTS: The primary endpoints are (1) the incidence of FTLD-related disorders across Europe; (2) geographic trends of FTLD-related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD-related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. EXPECTED IMPACTS: FRONTIERS will improve the understanding of FTLD-related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.

Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.

ALS Genes in the Genomic Era and their Implications for FTD.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.

Criminal Behavior in the Four Years Preceding Diagnosis of Neurocognitive Disorder: A Nationwide Register Study in Finland.

OBJECTIVE: To explore the criminality of patients with subsequent diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), or Lewy body dementias (LBD) in the four years preceding diagnosis. DESIGN: Nationwide register study. SETTING: Data on Finnish patients were collected from the discharge register and data on criminal offending from the police register. Research findings were compared with the same-aged general population. PARTICIPANTS: A total of 92,191 patients who had received a diagnosis of AD (N = 80,540), FTD (N = 1,060), and LBD (N = 10,591) between 1998 and 2015. MEASUREMENTS: Incidences and types of crimes, the standardized criminality ratio (number of actual crimes per number of expected crimes), and the numbers of observed cases and person-years at risk counted in five-year age groups and separately for both genders and yearly. RESULTS: At least one crime was committed by 1.6% of AD women and 12.8% of AD men, with corresponding figures of 5.3% and 23.5% in FTD, and 3.0% and 11.8% in LBD. The first crime was committed on average 2.7 (standard deviation 1.1) years before the diagnosis. The standardized criminality ratio was 1.85 (95% confidence interval [CI] 1.43-2.37) in FTD women and 1.75 (95% CI 1.54-1.98) in FTD men, and in AD 1.11 (95% CI 1.04-1.17) and 1.23 (95% CI 1.20-1.27), respectively. Traffic offences and crimes against property constituted 94% of all offences. CONCLUSION: Criminal acts may occur several years prior to the diagnosis of dementia. If novel criminality occurs later in life, it may be associated with neurocognitive disorder.

Frontotemporal Dementia: A Cross-Cultural Perspective.

It is predictable that syndromes of frontotemporal dementia (FTD) may have a worldwide distribution; however, data available on their incidence and prevalence are variable. This variability most likely reflects disparities across regions in the distribution of the expertise, technology, and resources available for FTD research and care. Important discoveries have been made regarding FTD's phenotypes, genetics, and cultural influences on the expression of symptoms; however, in many countries, there are barriers posed by a dearth of resources. There are pressing needs to further develop research on FTD: including first, population studies designed to fill the gaps in our knowledge about FTD's frequency and risk factors in developing regions and among minority groups in developed countries. It is also necessary to facilitate the psychometric characterization of contemporary diagnostic criteria and their translation to different languages and cultural contexts. Furthermore, much needed is the analysis of differences in the genetic risk factors for FTD, particularly non-Mendelian susceptibility factors. It is hoped that reflections on FTD from an international perspective will spur an extension of the vibrant multicenter collaborations, that exist in North America and Europe, toward new centers to be established and supported in the developing regions of the world.

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.

Epidemiology of early onset dementia and its clinical presentations in the province of Modena, Italy.

INTRODUCTION: Patients with early onset dementia (EOD), defined as dementia with symptom onset at age <65, frequently present with atypical syndromes. However, the epidemiology of different EOD presentations, including variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD), has never been investigated all together in a population-based study. Epidemiologic data of all-cause EOD are also scarce. METHODS: We investigated EOD epidemiology by identifying patients with EOD seen in the extended network of dementia services of the Modena province, Northern Italy (≈700,000 inhabitants) from 2006 to 2019. RESULTS: In the population age 30 to 64, incidence was 13.2 per 100,000/year, based on 160 new cases from January 2016 to June 2019, and prevalence 74.3 per 100,000 on June 30, 2019. The most frequent phenotypes were the amnestic variant of AD and behavioral variant of FTD. DISCUSSION: EOD affects a significant number of people. Amnestic AD is the most frequent clinical presentation in this understudied segment of the dementia population.

Amyotrophic lateral sclerosis: a clinical review.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.

Bipolar Disorder Among Patients Diagnosed With Frontotemporal Dementia.

OBJECTIVE: Previous studies have documented manic and hypomanic symptoms in behavioral variant frontotemporal dementia (bvFTD), suggesting a relationship between bipolar disorder and bvFTD. METHODS: The investigators conducted a literature review as well as a review of the psychiatric histories of 137 patients with bvFTD, and patients with a prior diagnosis of bipolar disorder were identified. The clinical characteristics of patients' bipolar disorder diagnosis, family history, features of bvFTD, and results from fluorodeoxyglucose positron emission tomography (FDG-PET), as well as autopsy findings, were evaluated. RESULTS: Among the 137 patients, 14 (10.2%) had a psychiatric diagnosis of bipolar disorder, eight of whom met criteria for bipolar disorder (type I, N=6; type II, N=2) 6-12 years preceding onset of classic symptoms of progressive bvFTD. Seven of the eight patients with bipolar disorder had a family history of mood disorders, four had bitemporal predominant hypometabolism on FDG-PET, and two had a tauopathy involving temporal lobes on autopsy. Three additional patients with late-onset bipolar I disorder proved to have a nonprogressive disorder mimicking bvFTD. The remaining three patients with bvFTD had prior psychiatric symptoms that did not meet criteria for a diagnosis of bipolar disorder. The literature review and the findings for one patient further suggested a shared genetic mutation in some patients. CONCLUSIONS: Manic or hypomanic episodes years before other symptoms of bvFTD may be a prodrome of this dementia, possibly indicating anterior temporal involvement in bvFTD. Other patients with late-onset bipolar disorder exhibit the nonprogressive frontotemporal dementia phenocopy syndrome. Finally, a few patients with bvFTD have a genetic predisposition for both disorders.

Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials.

Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

Incidence of frontotemporal disorders in Olmsted County: A population-based study.

INTRODUCTION: Frontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. METHODS: Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995-2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. RESULTS: We identified 35 FTDs cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI: 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI: 1.3, 4.5); we observed an increased trend over time (B = 0.83, 95% CI: 0.54, 1.11, P < .001). At autopsy, clinical diagnosis was confirmed in eight (72.7%) cases. DISCUSSION: We observed an increased incidence and trends of FTDs over time. This may reflect a better recognition by clinicians and improvement of clinical criteria and diagnostic tools.