Frontotemporal Dementia Cohort Research Articles

Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations’ association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations’ association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.

Social-semantic knowledge in frontotemporal dementia and after anterior temporal lobe resection

Abstract Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural variant FTD. Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialized for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance with that of matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared with non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non–social-semantic tests. Our trans-diagnostic approach included behavioural variant FTD, semantic dementia and ‘mixed’ intermediate cases to capture the FTD clinical spectrum, as well as age-matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy were also recruited to assess how selective damage to the left or right ATL impacts social- and non–social-semantic knowledge. Social- and non–social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left versus right differences in social-semantic knowledge or general semantic processing and with only naming showing a greater deficit following left versus right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing (i) FTD severity, (ii) semantic memory and (iii) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non–social-semantic knowledge degrade in FTD (semantic dementia and behavioural variant FTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally implemented, functionally unitary semantic hub in the ATLs. Our results also highlight the value of a trans-diagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD.

Genetic spectrum features and diagnostic accuracy of four plasma biomarkers in 248 Chinese patients with frontotemporal dementia.

Frontotemporal dementia (FTD) is characterized by phenotypic and genetic heterogeneities. However, reports on the large Chinese FTD cohort are lacking. Two hundred forty-eight patients with FTD were enrolled. All patients and 2010 healthy controls underwent next generation sequencing. Plasma samples were analyzed for glial fibrillary acidic protein (GFAP), α-synuclein (α-syn), neurofilament light chain (NfL), and phosphorylated tau protein 181 (p-tau181). Gene sequencing identified 48 pathogenic or likely pathogenic mutations in a total of 19.4% of patients with FTD (48/248). The most common mutation was the C9orf72 dynamic mutation (5.2%, 13/248). Significantly increased levels of GFAP, α-syn, NfL, and p-tau181 were detected in patients compared to controls (all p<0.05). GFAP and α-syn presented better performance for diagnosing FTD. We investigated the characteristics of phenotypic and genetic spectrum in a large Chinese FTD cohort, and highlighted the utility of plasma biomarkers for diagnosing FTD. This study used a frontotemporal dementia (FTD) cohort with a large sample size in Asia to update and reveal the clinical and genetic spectrum, and explore the relationship between multiple plasma biomarkers and FTD phenotypes as well as genotypes. We found for the first time that the C9orf72 dynamic mutation frequency ranks first among all mutations, which broke the previous impression that it was rare in Asian patients. Notably, it was the first time the C9orf72 G4C2 repeat expansion had been identified via whole-genome sequencing data, and this was verified using triplet repeat primed polymerase chain reaction (TP-PCR). We analyzed the diagnostic accuracy of four plasma biomarkers (glial fibrillary acidic protein [GFAP], α-synuclein [α-syn], neurofilament light chain [NfL], and phosphorylated tau protein 181 [p-tau181]) at the same time, especially for α-syn being included in the FTD cohort for the first time, and found GFAP and α-syn had the highest diagnostic accuracy for FTD and its varied subtypes.

De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.

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.

Executive Summary of 2023 International Conference of the Korean Dementia Association (IC-KDA 2023): A Report From the Academic Committee of the Korean Dementia Association.

The Korean Dementia Association (KDA) has been organizing biennial international academic conferences since 2019, with the International Conference of the KDA (IC-KDA) 2023 held in Busan under the theme 'Beyond Boundaries: Advancing Global Dementia Solutions.' The conference comprised 6 scientific sessions, 3 plenary lectures, and 4 luncheon symposiums, drawing 804 participants from 35 countries. Notably, a Korea-Taiwan Joint Symposium addressed insights into Alzheimer's disease (AD). Plenary lectures by renowned scholars explored topics such as microbiome-related AD pathogenesis, social cognition in neurodegenerative diseases, and genetic frontotemporal dementia (FTD). On the first day, specific presentations covered subjects like the gut-brain axis and neuroinflammation in dementia, blood-based biomarkers in AD, and updates in AD therapeutics. The second day's presentations addressed recent issues in clinical neuropsychology, FTD cohort studies, and the pathogenesis of non-AD dementia. The Academic Committee of the KDA compiles lecture summaries to provide comprehensive understanding of the advanced dementia knowledge presented at IC-KDA 2023.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40 . GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Familial FTD in India

AbstractBackgroundThe burden of dementia in India is estimated to increase by 197% by 2050, and Frontotemporal dementia (FTD) is among the leading causes of young‐onset dementia. With recent advances in molecular pathology, genetic mechanisms and emerging therapies in FTD, it is important to understand familial FTD patterns in the heterogeneous sociocultural context of India. High genetic diversity is characteristic of India, and its population bears genetic imprints of European, Asian and even African genomes. The objective of this presentation is to provide an account of FTD in India, with a focus on familial FTD and genetic mechanisms recently being identified.MethodThe prevalence of FTD in clinical dementia cohorts across different geographic regions in India, frequency of familial FTD, clinical presentations in the context of sociolinguistic and ethnic diversity, and genetic mechanisms are reported.ResultThe reported prevalence of FTD in clinical and research groups across India varies from 7% to 26%. The proportion of familial FTD ranges from 9.5% in Kolkata in the east, 15% in Trivandrum in the south, 24.6% from Hyderabad and more recently, as high as 40% in a recent study from Bangalore. Few genetic mutations were reported in early studies. In a recent large effort from Bangalore, India, 200 patients with FTD syndromes underwent three generation pedigree analysis, clinical and neuropsychological evaluation and MRI according to ADNI protocol. Nearly half underwent genetic analysis by next generation sequencing and RT‐PCR was done to analyse C9orf 11 in a subset. Novel gene mutations including SQSTM1, GRN, MAPT, PSEN2, TBK1 and C9orf were detected. Of these mutations, 11 were pathogenic in 11 and 26 were variants of unknown significance (VUS). Apart from abnormal protein accumulation due to MAPT and GRN, we also identified CSF1R, TREM2 and TYROBP, that are recognised as primary microgliopathies. A few examples of VUS include PRNP, LRRK2, GBA and PANK2 mutations.ConclusionResearch from familial FTD cohorts in India is contributing to growing evidence of a wider spectrum of genetic mechanisms for FTD. Our findings provide compelling evidence to increase harmonised global efforts to reduce risk and develop novel treatment strategies for FTD.

A - 44 Social Cognition and its Neuroanatomic Correlates in Frontotemporal Dementia.

Frontotemporal dementia (FTD) often presents with impaired social cognition in both the behavioral and language variants. Establishing reliable measures and neural correlates of social cognition may aid in staging and monitoring FTD subtypes. Here, we examined group differences in social cognitive measures between FTD subtypes and cortical thickness correlates of social cognition across groups. Participants with behavioral variant FTD (n = 53; bvFTD), semantic variant primary progressive aphasia (n = 32; svPPA) and non-fluent variant PPA (n = 32; nfPPA) were enrolled in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD). In first-visit data, we examined group differences in social cognition measures [Interpersonal Reactivity Index (IRI), Revised Social-Monitoring Scale (RSMS), and Behavioral Inhibition/Activation (BIS/BAS) Scales]. We used multivariate regression adjusted for age, total intracranial volume, and CDR global score to explore associations between social cognition and cortical thickness in pre-specified regions. Reduced perspective-taking and sensitivity to socio-emotional expressiveness was observed in early-stage bvFTD and svPPA groups compared to the nfPPA group. Across FTD cohorts, increased perspective-taking was associated with reduced cortical thickness of regions within the salience and default mode networks. Increased empathic concern was associated with increased left inferior parietal cortical thickness. Increased behavioral inhibition was associated with reduced right posterior cingulate cortical thickness. Increased behavioral activation was associated with reduced right pars triangularis cortical thickness. Social cognition is affected in early-stage bvFTD and svPPA to a greater extent than nfPPA. Neural correlates of social cognition are varied and warrant additional study as our findings contrast with previous literature that has typically linked lower perspective-taking with atrophy.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. To evaluate psychopharmacological medication use at the time of FTD diagnosis. Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration.

Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.

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

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. 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. 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. 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.

Genetically Proxied Angiotensin‐Converting‐Enzyme Inhibition is Potentially Causal for Alzheimer Disease: A Mendelian Randomization Study

AbstractBackgroundAngiotensin‐converting enzyme (ACE) has been implicated in the pathogenesis of Alzheimer disease (AD), in which ACE plays a role in metabolizing Amyloid Beta (AB). Genetic variants in the ACE locus have also been associated with AD. The effect of ACE inhibitors on AD risk remains unclear. We sought to investigate the potential causal relationship between ACE inhibition and AD and other neurodegenerative disorders using a mendelian randomization (MR) approach.MethodA genetic proxy for ACE inhibition (MR exposure) was generated using 17 single nucleotide polymorphisms (SNPs) in the ACE gene that were previously associated with lower ACE blood levels in a candidate gene study (n = 4,147; adjusted‐P &lt; 0.05). Summary genome‐wide association study (GWAS) statistics for AD (111,326 cases, 677,663 controls), Frontotemporal dementia (FTD) (3526 cases, 9402 controls) and Lewy body dementia (LBD) (cases 2591, controls 4027) were used as proxies for the MR outcomes. Inverse weighted variance MR was performed to test the potentially causal relationship between the exposure and outcomes. Sensitivity analyses were completed to test the robustness of the results.ResultACE inhibition was significantly associated with increased risk of AD (OR = 1.07, P = 0.0000005); with robust and consistent effects in all sensitivity analyses. Using leave one out method; rs4343 (A allele) showed the strongest effect. rs4343 is in mild linkage disequilibrium with the SNP associated at genome wide significant level with AD rs4277405 (R2 0.35). Rerunning the MR analysis on the AD cohort after removing rs4343 continued to show significant results (OR = 1.04, P = 0.02). ACE inhibition was also associated with increased risk for FTD (OR = 1.16, P = 0.009), but the findings were not robust in some sensitivity analyses, possibly due to lower sample size of FTD cohort. ACE inhibition was not associated with LBD.ConclusionThis is the first study to provide robust genetic evidence for the potentially causal relationship between ACE inhibition in the blood and the diagnosis of AD. These results should encourage further investigation of the potential neurodegenerative side effects of ACE inhibition; and further suggest ACE related pathways as pharmacological targets for treatment and/or prevention of AD.

Shorter disease duration in females with sporadic frontotemporal dementia

AbstractBackgroundPrevious reported sex differences on disease duration (DD) of frontotemporal dementia (FTD) have been inconsistent and lack the comparison between genetic and sporadic FTD. Our aim was to study the difference in disease duration between males and females in genetic and sporadic FTD.MethodMortality data was obtained from 61 deceased patients with genetic FTD (52% male) and 117 deceased patients with sporadic FTD (64% male) from the international FTD cohort previously reported by de Boer et al., 2021. The age at symptom onset (AAO), age at death (AAD) and the DD (defined as the time between age at symptom onset and age at death) were compared between males and females in the genetic and sporadic FTD group using Mann Whitney U tests.ResultGenetic FTD did not show significant sex differences in AAO, AAD and DD (p = 0.3, p = 0.3, p = 0.8 respectively, Figure 1). In sporadic FTD, the AAO and AAD did not significantly differ between males and females (p = 0.8 and p = 0.2 respectively). The DD in the sporadic FTD group was significantly shorter in females (median DD 7.0 years) in comparison to males (median DD 8.0 years, p = 0.01, Figure 2).ConclusionIn this study we show that females with sporadic FTD have a shorter disease duration than males whereas in genetic FTD the disease duration does not differ between sex. These findings suggest the existence of sex‐related differences in the disease course of sporadic FTD. We urge the need for international epidemiological FTD studies to further explore the role of sex in both genetic and sporadic FTD.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

Study protocol: computerised cognitive testing in a cohort of people with frontotemporal dementia

IntroductionThe term frontotemporal dementia (FTD) refers to a heterogeneous group of neurodegenerative disorders affecting the frontal and temporal lobes. Cognitively, impairment of executive function and social cognition predominates across the...

The New Zealand Genetic Frontotemporal Dementia Study (FTDGeNZ): a longitudinal study of pre-symptomatic biomarkers

ABSTRACT The New Zealand Genetic Frontotemporal Dementia Study (FTDGeNZ) is an emerging longitudinal study of a large New Zealand pedigree with genetic frontotemporal dementia (FTD). Natural history studies of genetic FTD cohorts provide a unique opportunity to identify biomarkers of pre-symptomatic dementia, as carriers can be identified and studied decades before expected symptom onset. FTDGeNZ was established in 2016 with the aim of identifying the earliest pre-symptomatic biomarkers of FTD, in collaboration with international multi-centre cohorts. We enrolled 25 participants from a single family between April 2016 and August 2018. Participants were genotyped to determine whether they were pre-symptomatic carriers of the mutation (MAPT IVS 10 + 16 C > T), or non-carrier controls. Participants have undergone clinical assessments including neuropsychological and mood assessment; olfactory testing; assessment of social cognition; and blood collection for analyses of microRNA and protein fluid biomarkers annually. We have also performed structural and functional MRI of the brain and assessment of autobiographical memory biennially, and retinal imaging at baseline. Here, we describe the full study protocol and the baseline demographic and clinical characteristics of the FTDGeNZ cohort, and we highlight the latest findings in the field.

Quantification of neocortical sulcal widening as a rapidly‐computable brain atrophy metric: Application to frontotemporal dementia

AbstractBackgroundRegional patterns of brain atrophy are characteristic features of neurodegenerative disorders. Radiological assessments of cortical brain atrophy tend to reflect sulcal widening and brain shrinkage, whereas quantitative assessments based on grey matter volume or cortical thickness can be hampered by poor SNR and inaccurate estimation of grey/white matter boundaries. Our aim was to define a simple and rapidly‐computable marker of localized sulcal widening based on standard brain tissue segmentation tools and assess it in a cohort of individuals with frontotemporal dementia (FTD) and SV2A PET scans.Method3DT1 MRI and [11C]UCB‐J PET scans were analyzed from individuals with FTD (N=8, MMSE range 10‐28) and age‐matched healthy volunteers (HV, N=17) within the MIND‐MAPS consortium. 3DT1 images were segmented into gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF) using SPM12. The lobar CSF occupancy fraction (CSFOF) was calculated as CSF/(GM+WM+CSF) in the frontal, parietal, temporal and occipital lobes. The tissue type masks were created by a threshold of total tissue occupancy &gt; 50% then assigning each voxel to the tissue for which it has the maximum probability. 3DT1 scans were also assessed using cortical thickness (Freesurfer v6.0). SV2A binding was quantified as distribution volume ratio (DVR‐1) from [11C]UCB‐J using centrum semiovale as reference region.ResultThe CSFOF computation time was approximately 6 minutes per scan on a 2019 MacBook pro. CSFOF was significantly higher in FTD than in HV (ANOVA F=19.6, p&lt;0.0001, Figure 1). Corrected, non‐parametric linear relationships between CSFOF and MMSE, cortical thickness and [11C]UCB‐J DVR‐1 are summarized in Table 1 and Figure 2 for the frontal lobe. The relationships were weaker in the FTD cohort alone, compared with the full sample. Cortical thickness was the only nominally significant association remained after correction for age and MMSE, suggesting that CSFOF and SV2A density may reflect different aspects of the disease.ConclusionThe CSFOF provides a simple, rapid and robust quantification of lobar brain atrophy, reflecting sulcal widening and both grey and white matter atrophy. It complements other imaging markers of neurodegeneration and extends the concepts of ventricular volume and hippocampal occupancy fraction to the wider neocortex.

Addressing dementia challenges through international networks: Evidence from the Latin American and Caribbean Consortium on Dementia (LAC-CD).

LAC-CD has recently reported that challenges faced by LAC countries are very similar to those experienced by HIC, and that regional networks will be needed to bridge gaps. ReDLat is a US-LAC multi-partner consortium aimed at expanding dementia research in LAC. The UK-Latin America Brain Connectivity Research Network (UL-BCRN) focuses on developing new affordable EEG-based biomarkers for dementia. The Language and Brain Health Network (LBHN) integrate international multidisciplinary efforts to reveal linguistic markers of neurodegenerative diseases. ReDLat is collecting genomic, neuroimaging, clinical, cognitive, and socioeconomic data from a first-in-class cohort anchored in six LAC (Argentina, Chile, Colombia, Brazil, Mexico, and Peru) and will compare these to US data (> 4200 participants, including 2100 controls, 1050 AD patients, and 1050 FTD patients). The 5-year project will develop innovative, harmonized, and cross-nation approaches on two of the most prevalent neurodegenerative diseases, Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). The UL-BCRN currently links seven EEG labs from Colombia, Argentina, Chile, Brazil and the UK. The network's vision is to forge strong relationships between labs through which new methodologies, EEG plus multidimensional datasets, and experience will be developed and shared. The LBHN will analyze speech samples from massive AD, FTD, and control cohorts across LAC, Spain, and the US. This effort aims to identify low-cost disease-specific markers in diverse Latino and English-speaking patients. ReDLat will aims to reveal unique risk factors for AD and FTD in LAC compared to US populations. Data collection strategies have been adapted to face the challenges brought by the COVID-19 pandemic. The UL-BCRN has now standardised recording protocols across LAC and UK labs and is collecting data from longitudinal cohorts of patients at risk of dementia relying on novel culture-free cognitive paradigms. Preliminary LBHN data shows that, automated speech analyses can identify Latinos with AD and FTD, with good generalization across socio-biological profiles, dialects, and languages. By broadening our understanding of dementia phenotypes, risk factors, and affordable diagnostic approaches in LAC, adding new evidence on variability across HIC and LMIC, the above networks will contribute unique knowledge that will help enhance future global dementia strategies.

Contribution of rare variant associations to neurodegenerative disease presentation

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.