Predictors of Care Home Admission and Survival Rate in Patients With Syndromes Associated With Frontotemporal Lobar Degeneration in Europe.

BACKGROUND AND OBJECTIVES: Data on care home admission and survival rates of patients with syndromes associated with frontotemporal lobar degeneration (FTLD) are limited. However, their estimation is essential to plan trials and assess the efficacy of intervention. Population-based registers provide unique samples for this estimate. The aim of this study was to assess care home admission rate, survival rate, and their predictors in incident patients with FTLD-associated syndromes from the European FRONTIERS register-based study. METHODS: We conducted a prospective longitudinal multinational observational registry study, considering incident patients with FTLD-associated syndromes diagnosed between June 1, 2018, and May 31, 2019, and followed for up to 5 years till May 31, 2023. We enrolled patients fulfilling diagnosis of the behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS), and FTD with motor neuron disease (FTD-MND). Kaplan-Meier analysis and Cox multivariable regression models were used to assess care home admission and survival rates. The survival probability score (SPS) was computed based on independent predictors of survivorship. RESULTS: A total of 266 incident patients with FTLD were included (mean age ± SD = 66.7 ± 9.0; female = 41.4%). The median care home admission rate was 97 months (95% CIs 86-98) from disease onset and 57 months (95% CIs 56-58) from diagnosis. The median survival was 90 months (95% CIs 77-97) from disease onset and 49 months (95% CIs 44-58) from diagnosis. Survival from diagnosis was shorter in FTD-MND (hazard ratio [HR] 4.59, 95% CIs 2.49-8.76, p < 0.001) and PSP/CBS (HR 1.56, 95% CIs 1.01-2.42, p = 0.044) compared with bvFTD; no differences between PPA and bvFTD were found. The SPS proved high accuracy in predicting 1-year survival probability (area under the receiver operating characteristic curve = 0.789, 95% CIs 0.69-0.87), when defined by age, European area of residency, extrapyramidal symptoms, and MND at diagnosis. DISCUSSION: In FTLD-associated syndromes, survival rates differ according to clinical features and geography. The SPS was able to predict prognosis at individual patient level with an accuracy of ∼80% and may help to improve patient stratification in clinical trials. Future confirmatory studies considering different populations are needed.

Clinical implications of head trauma in frontotemporal dementia and primary progressive aphasia.

BACKGROUND: Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. METHODS: We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). RESULTS: Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1). CONCLUSIONS: Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

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.

The Etiology of Rapidly Progressive Dementia: A 3-Year Retrospective Study in a Tertiary Hospital in China.

Background: Rapidly progressive dementia (RPD), characterized by a rapid cognitive decline leading to dementia, comprises a diverse range of disorders. Despite advancements in diagnosis and treatment, research on RPD primarily focuses on Western populations. Objective: This study aims to explore the etiology and demographics of RPD in Chinese patients. Methods: We retrospectively analyzed 323 RPD inpatients at Huashan Hospital from May 2019 to March 2023. Data on sociodemographic factors, epidemiology, clinical presentation, and etiology were collected and analyzed. Results: The median onset age of RPD patients was 60.7 years. Two-thirds received a diagnosis within 6 months of symptom onset. Memory impairment was the most common initial symptom, followed by behavioral changes. Neurodegenerative diseases accounted for 47.4% of cases, with central nervous system inflammatory diseases at 30.96%. Autoimmune encephalitis was the leading cause (16.7%), followed by Alzheimer's disease (16.1%), neurosyphilis (11.8%), and Creutzfeldt-Jakob disease (9.0%). Alzheimer's disease, Creutzfeldt-Jakob disease, and frontotemporal dementia were the primary neurodegenerative causes, while autoimmune encephalitis, neurosyphilis, and vascular cognitive impairment were the main non-neurodegenerative causes. Conclusions: The etiology of RPD in Chinese patients is complex, with neurodegenerative and non-neurodegenerative diseases equally prevalent. Recognizing treatable conditions like autoimmune encephalitis and neurosyphilis requires careful consideration and differentiation.

Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review.

Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Age-specific prevalence of the different clinical presentations of AD and FTD in young-onset dementia.

BACKGROUND: Studies have shown that the prevalence of all-variants Alzheimer's disease (AD) and frontotemporal dementia (FTD) both increase with age, even before the age of 65. However, it is not known whether their different clinical presentations all increase in prevalence with age in the same way. METHODS: We studied the prevalence of the different clinical presentations of young-onset AD and FTD by 5-year age groups in a population-based study identifying all dementia patients with a diagnosis of AD and FTD and symptoms onset before age 65 in the Modena province, Italy. By using regression models of cumulative occurrences, we also estimated age-specific prevalence and compared the growth curves of the clinical presentations. RESULTS: The prevalence of all-variants AD increased with age, from 18/1,000,000 in the 40-44 age group to 1411/1,000,000 in the 60-64 age group. The prevalence of all-variants FTD also increased with age, from 18/1,000,000 to 866/1,000,000. An estimation of age-specific prevalence functions of each clinical presentation showed that atypical non-amnestic AD and aphasic FTD grew the most in early ages, followed by the behavioural variant of FTD (bvFTD). Then, around the age of 60, amnestic AD took over and its age-specific prevalence continued to increase disproportionally compared to all the other clinical variants of AD and FTD, which, instead, started to decrease in prevalence. CONCLUSIONS: Amnestic AD is the clinical presentation that increases the most with advancing age, followed by bvFTD, suggesting that there is a differential vulnerability to the effect of ageing within the same neurodegenerative disease.

The relationship between major depressive disorder and dementia: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Major depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population. METHOD: We collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out. RESULTS: In the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249-3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999-1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471-4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204-1.718, P = 0.335; MR-Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021-15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD. LIMITATIONS: The results of this study may not be generalizable to non-European populations. CONCLUSION: MDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.

Real world data analysis of frontotemporal dementia: Implications for future clinical research.

Frontotemporal dementia (FTD) is a progressive decline of cognitive abilities associated with other neuropsychiatric comorbidities. A real-world data (RWD) analysis of a large electronic healthcare records (EHR) database identified the comorbidities of FTD. Deidentified EHRs in the TriNetX Network database from >155,000,000 individuals in the United States established an FTD Cohort (ICD-10 Code G31.0) of adult patients who visited a healthcare provider in 2022. The non-FTD cohort were age-matched individuals who had not received a diagnosis of ICD-10 Code G31.0, and who had visited a healthcare provider in 2022. The median age of both cohorts was 73 years. A comparative analysis was performed between the FTD and non-FTD cohorts. There were 6660 individuals (aged ≥18) with FTD and 11,810,060 individuals (aged ≥63) without a diagnosis of FTD, with healthcare visits in 2022. There were 25 ICD-10 Codes for disorders that were present in >10% of FTD patients, with a Relative Risk (RR) of ≥2.0 compared the non-FTD cohort. Multiple neuropsychiatric disorders had RRs ≥ 2.0, with minimal evidence for significant involvement of other organ systems. These data document that FTD, as known previously, is associated with multiple neuropsychiatric comorbidities. There was minimal evidence of comorbid involvement of other organ systems. These data provide a baseline of general FTD symptoms for the rapidly evolving analysis of genetic subvariants of FTD. These data also provide insights into the clinical management of FTD, as well as recommendations for specific endpoints in clinical trials.

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.

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.

Risk factors of frontotemporal dementia compared with Alzheimer disease: Single psychiatric hospital-based research in Japan.

AIM: The objective of this study was to reveal risk factors for incident of frontotemporal dementia (FTD) compared with Alzheimer disease (AD) in Japan. METHOD: Fifty consecutive subjects diagnosed with FTD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) under 75 years old were included retrospectively. As a control group, 48 subjects who were diagnosed with AD according to the DSM-5 and matched by age, sex, educational history, and Mini-Mental State Examination were also included. In order to examine the distinctive risk factors of FTD, we compared the relationship between symptomatologic features, Clinical Dementia Rating, clinical factors, and sociopsychological factors in the two groups. RESULT: Patients with FTD were more likely than patients with AD to have meticulous premorbid personality and less likely to have a history of diabetes than patients with AD. Although the regression analysis was not significant, a history of psychiatric disorders tends to affect the incidence of FTD. CONCLUSIONS: These findings regarding the risk of FTD are expected to lead to early diagnosis and care of FTD. Geriatr Gerontol Int 2023; 23: 932-937.

"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.

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.

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries.

Importance: Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. Objective: To assess the incidence of FTLD across Europe. Design, Setting, and Participants: The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. Main Outcomes and Measures: Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. Results: Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. Conclusions and Relevance: The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

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.

Traumatic Brain Injury Associates with an Earlier Onset in Sporadic Frontotemporal Dementia.

BACKGROUND: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). OBJECTIVE: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. METHODS: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. RESULTS: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p = 0.050) or HC group (12%, p = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p = 0.010). CONCLUSION: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies.

Crime, mortality and neurocognitive disorders: A nationwide register study in Finland.

OBJECTIVES: To explore mortality of patients with Alzheimer's disease (AD), frontotemporal dementia (FTD), or Lewy body dementias (LBD) who had criminal behavior in the year preceding diagnosis. METHODS: Data were obtained from the nationwide registers. Mortality was compared between disorder groups with and without criminal acts and with the general population. The cohort included patients who had received a discharge register diagnosis of AD (N = 80,540), FTD (N = 1060), or LBD (N = 10,591) between 1998 and 2015. The incidences of crimes were calculated in the year preceding diagnosis. We further calculated age- and sex-adjusted survivals of different dementia groups with and without criminal acts, and in relation to the general population (SMR, Standardized Mortality Ratio). RESULTS: Criminal behavior was more common in men than in women. It was associated with decreased mortality in the AD group. SMRs due to unnatural causes, and in the LBD and FTD female groups, were higher in patients with criminal behavior than in those without. CONCLUSION: LBD and female FTD patients, who had criminal behavior before diagnosis, were at higher risk of death than patients without such behavior. Novel criminality in older adults may be associated with neurocognitive disorder, in which case medical attention is justified.

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.

Mutation spectrum of chinese amyotrophic lateral sclerosis patients with frontotemporal dementia.

BACKGROUND: Studies have reported that a noncoding hexanucleotide repeat in C9ORF72, is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasian population, nevertheless it is rare in Chinese population. Therefore, we aimed to investigate the mutation spectrum of Chinese ALS patients with FTD (ALS-FTD). METHODS: ALS patients with and without cognitive impairments were enrolled. Clinical features were collected including age, sex, disease duration, ALSFRS-r, family history and cognitive evaluation. Thirty-six ALS genes were screened by whole exome sequencing (WES) and repeat-primed polymerase chain reaction (PCR) were used for detection of and abnormal repeat expansions of C9ORF72. RESULTS: A total of 1208 patients, including 66 familial ALS (FALS) and 1142 sporadic ALS (SALS) patients were included. Twenty-three patients with sporadic ALS and one familial ALS index had concomitant FTD, which accounts for 1.99% (24/1208) of patients with ALS. In sporadic ALS-FTD, one case harboring C9ORF72 expansion variant, two cases harboring ANXA11 variants and one individual carrying CCNF variant were identified. A recurrent UBQLN2 variant was detected in a familial ALS-FTD patient. All of the ALS-FTD patients carrying variants in known causative genes manifested motor symptom onset (two bulbar onset and three limb onset) and developed cognitive impairment thereafter. It is not easy to draw a conclusion of the genotype-phenotype association in ALS-FTD with certain variants, limited by the small number of patients. CONCLUSION: Our findings provide an overview of spectrum of genetic variants in Chinese ALS-FTD patients. Variants of uncertain significance in UBQLN2, ANXA11 and CCNF were identified and further studies are required for causal relations of these variants with ALS-FTD.