Symptoms Of Frontotemporal Dementia Research Articles

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats.

Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but mechanisms linking mutant gene products to neuronal toxicity remain debatable. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs) but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved a MAPK signaling pathway that affects fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. In primary cultured neurons, GP but not other DPRs promote the "dying-back" axonopathy seen in ALS. Interestingly, GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclear membrane, promoting "dying-forward" neuropathy. All C9-DPR-mediated toxic effects observed in these studies are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. Finally, C9ORF72 human tissues confirmed a close association between GP and active P38 in degenerating motor neurons as well as GR-associated nuclear damage in the cortex. Collectively, our studies establish compartment-specific toxic effects of C9-DPRs associated with degeneration, suggesting that two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with ALS and/or FTD symptoms.

Neuropsychiatric Symptoms in Frontotemporal Dementia: More Than Just Noise?

Neuropsychiatric symptoms cause significant suffering and poor quality of life for patients and their caregivers. They are not considered specific to frontotemporal dementia (FTD); therefore, their clinical role and impact might be underestimated. The aims of the present study are to: 1) describe the prevalence of neuropsychiatric symptoms in FTD starting from the prodromal stage, 2) define their association with disease severity, 3) identify symptoms which are unrelated to FTD-specific symptoms, and 4) assess their association with clinical features and outcomes. In this retrospective study, we analyzed data of 461 FTD patients, including behavioral variant of FTD (bvFTD, n = 318) and primary progressive aphasia (PPA, n = 143). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory, and patients' staging and global disease severity were estimated using the Clinical Dementia Rating plus NACC FTLD. The most common neuropsychiatric symptoms in prodromal FTD were irritability (48%), depression (35%), and anxiety (34%); delusions were reported in 6%of prodromal bvFTD cases. The severity of most neuropsychiatric symptoms increased with global disease severity. Psychosis (delusions and hallucinations) and mood symptoms (depression and anxiety) were mostly independent from FTD-specific symptoms. Psychosis was associated with older age, higher disease severity, shorter survival rate, and was higher in bvFTD than in PPA. Neuropsychiatric symptoms are common in patients with FTD, also in the prodromal phase. Psychosis might be unrelated to FTD pathology, and be associated with worse clinical outcomes. The prompt detection and treatment of these symptoms might improve patient's management and quality of life.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal Dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioral variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls (HCs) at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA, and 30 non-fluent variant PPA (nfvPPA) cases, and 110 HCs from Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus HCs. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 HCs in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 HCs in Dataset 2) and symptom-specific networks [combined dataset 1 and 2, apathy without depression Vs non-apathy without depression (80:26), disinhibition Vs non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region, and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

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.

Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.

A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.

Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Cortical signature of depressive symptoms in frontotemporal dementia: A surface-based analysis.

Depressive symptoms are frequently reported in patients affected by frontotemporal dementia (FTD). At structural MRI, cortical features of depressed FTD patients have been poorly described. Our objective was to investigate correlations between cortical measures and depression severity in FTD patients. Data were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database. We included 98 controls and 92 FTD patients, n = 38 behavioral variant FTD (bvFTD), n = 26 non-fluent variant Primary Progressive Aphasia (nfvPPA), and n = 28 semantic variant Primary Progressive Aphasia (svPPA). Patients underwent clinical and cognitive evaluations, as well as a 3D T1-weighted MRI on a 3 Tesla scanner (Siemens, Trio Tim system). Depression was evaluated by means of Geriatric Depression Scale (GDS). Surface-based analysis was performed on T1-weighted images to evaluate cortical thickness, a measure of gray matter integrity, and local gyrification index (lGI), a quantitative metric of cortical folding. Patients affected by svPPA were more depressed than controls at NPI and depression severity at GDS was higher in svPPA and bvFTD. Severity of depression correlated with a decrease in lGI in left precentral and superior frontal gyrus, supramarginal and postcentral gyrus and right precentral, supramarginal, superior parietal and superior frontal gyri. Furthermore, depression severity correlated positively with cortical thickness in the left medial orbitofrontal cortex. We found that lGI was associated with depressive symptoms over brain regions involved in the pathophysiology of major depressive disorder. This finding provides novel insights into the mechanisms underlying psychiatric symptoms in FTD.

Treatment Efficacy of Pharmacotherapies for Frontotemporal Dementia: A Network Meta-Analysis of Randomized Controlled Trials

The neuropsychiatric symptoms of frontotemporal dementia (FTD) have a profound negative impact on disease outcomes and care burden. Available pharmacotherapies might be supported by small-scale randomized controlled trials (RCTs); however, clinical recommendations might not be conclusive. We systematically searched several databases from inception to April 30, 2022, for RCTs of drug therapy in patients with FTD and neuropsychiatric symptoms (primary outcome). Secondary outcomes included changes in caregiver stress, daily interactive activities, cognitive function, and acceptability (adverse event or dropout rates). The network meta-analysis (NMA) procedure was performed under the frequency model, showing effect sizes as standardized mean differences (SMD) or odds ratios (OR) with 95% confidence intervals (95% CIs). Seven RCTs with 243 participants were included. Compared with placebo, high-dose oxytocin (72 international units) was associated with the greatest improvement in patients' neuropsychiatric symptoms (SMD=-1.17, 95% CIs=-2.25 to -0.08, z=-2.10, p=0.035). Piracetam significantly worsened neuropsychiatric symptoms (SMD=3.48, 95% CIs=1.58 to 5.37, z=3.60, p < 0.001) and caregiver stress (SMD=2.40, 95% CIs=0.80-4.01, z=2.94, p=0.003). Trazodone had significantly higher rates of adverse events (OR=9.53, 95% CIs=1.85-49.20, z=2.69, p=0.007). No pharmacological intervention significantly benefited cognitive function. This study provides the first NMA for clinical recommendation to support the use of high-dose oxytocin and caution regarding the use of piracetam for neuropsychiatric symptoms in patients with FTD.

Bifrontal electroconvulsive therapy leads to improvement of cerebral glucose hypometabolism in frontotemporal dementia with comorbid psychotic depression – a case report

BackgroundDifferentiating depression and dementia in elderly patients represents a major clinical challenge for psychiatrists. Pharmacological and non-pharmacological treatment options for both conditions are often used cautiously due to fear of adverse effects. If a clinically indicated therapy is not initiated due to fear of adverse effects, the quality of life of affected patients may significantly be reduced.Case presentationHere, we describe the case of a 65-year-old woman who presented to the department of psychiatry of a university hospital with depressed mood, pronounced anxiety, and nihilistic thoughts. While several pharmacological treatments remained without clinical response, further behavioral observation in conjunction with 18F-fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed the diagnosis of frontotemporal dementia (FTD). To counter the pharmacological treatment resistance of psychotic depression, we decided to perform electroconvulsive therapy (ECT). Remarkably, ten sessions of ECT yielded an almost complete remission of depressive symptoms. In addition, the patient’s delusional ideas disappeared. A follow-up 18F-FDG PET/CT after the ECT series still showed a frontally and parieto-temporally accentuated hypometabolism, albeit with a clear regression compared to the previous image. The follow-up 18F-FDG PET/CT thus corroborated the diagnosis of FTD, while on the other hand it demonstrated the success of ECT.ConclusionsIn this case, ECT was a beneficial treatment option for depressive symptoms in FTD. Also, 18F-FDG PET/CT should be discussed as a valuable tool in differentiating depression and dementia and as an indicator of treatment response.

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia.

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPTcarriers.

Biological basis and psychiatric symptoms in frontotemporal dementia.

Frontotemporal dementia is a neurodegenerative disease characterized by focal degeneration of the frontal and temporal lobes, clinically presenting with disinhibited behavior, personality changes, progressive non-fluent aphasia and/or impaired semantic memory. Research progress has been made in re-organizing the clinical concept of frontotemporal dementia and neuropathological classification based on multiple accumulating proteins. Alongside this progress a list of genetic mutations or variants that are causative or increase the risk of frontotemporal dementia have been identified and some of these gene products are extensively studied. However, there are still a lot of points that need to be overcome, including lack of specific diagnostic biomarker which enable antemortem diagnosis of underlying neurodegenerative process, and lack of disease modifying therapy which could prevent disease progression. Early and precise diagnosis of frontotemporal dementia is urgently required. In this context, how to define prodromal frontotemporal dementia and early differential diagnosis from primary psychiatric disorders are also important issues. In this review we will summarize and discuss current understanding of biological basis and psychiatric symptoms in frontotemporal dementia.

Developing RNA Therapeutics for TDP‐43 Proteinopathy in ALS/FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both fatal neurodegenerative disorders characterized by neuronal loss. ALS is primarily characterized by motor impairments stemming from degeneration of motor neurons, whereas the main symptoms of FTD include changes in personality, behavior, and language stemming from degeneration of cortical neurons in the frontal and temporal lobes. ALS and FTD exist on a clinical continuum, where some patients present with features of both diseases. A molecular hallmark shared by almost all ALS patients and approximately half of FTD patients is the pathological aggregation of the RNA‐binding protein TDP‐43. It has recently been established that the solubility of TDP‐43 is increased by its binding to RNA. I hypothesize that aberrant aggregation of TDP‐43 in ALS/FTD models is due to alterations in TDP‐43:RNA interactions. I have utilized in vitroaggregation assays with purified TDP‐43 and short 34 nucleotide bait RNAs designed to bind TDP‐43. I find that bait RNAs can prevent aggregation of all tested disease‐linked TDP‐43 variants. I also find that disease‐causing missense mutations in TDP‐43 can alter the potency of bait RNAs against aggregation of TDP‐43. These results suggest that there are differences in the RNA interactions of TDP‐43 in disease. These findings also support the development of bait RNAs as a therapeutic strategy for ALS/FTD.

Experiences of families of people living with frontotemporal dementia: a qualitative systematic review.

Frontotemporal dementia (FTD) is characterised by atrophy of the frontal and/or temporal lobes. People with FTD show language and emotional disturbances from onset, and communication problems usually affect people with FTD and their families even before diagnosis. These unique characteristics of FTD are not well understood and create substantial problems for people living with FTD and their families. This review explores the experiences of families of people living with FTD. Studies were selected and screened according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched four bibliographic databases for articles up to February 2021 to identify qualitative data on the experiences of families. The Critical Appraisal Skills Programme checklist for qualitative studies was used to assess all included studies. Of 235 identified articles, we included six studies in the qualitative synthesis. Meta-ethnography was conducted to interpret families' experiences of people living with FTD. The emergent concepts were synthesised into five themes: Something is wrong with my loved one; No one fully understands; Existential pain of caring for a loved one with FTD; Increased burden owing to specific FTD symptoms; and Forced to adapt to new and unique ways of living with a loved one with FTD. This review highlighted families' confusion and suffering (which began in the early stages of the disease, and sometimes before diagnosis) and the difficulty of communicating with people with FTD. These findings have implications for future practice, as they demonstrate the positive effect on family life of appropriate support that is provided early, rather than after the disease has progressed.

Brainstem atrophy is linked to extrapyramidal symptoms in frontotemporal dementia

Extrapyramidal (EP) symptoms are a known feature in a subpopulation of patients with behavioral variant frontotemporal dementia (bvFTD). Concomitant EP symptoms with FTD-like neuropsychiatric symptoms are also core features in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). This complicates the early diagnosis of these disorders. Our retrospective register study aimed to discover imaging (MRI and FDG-PET) biomarkers to differentiate PSP, CBD, and bvFTD patients with extrapyramidal symptoms (EP +) from bvFTD patients without EP symptoms (EP-). The records of 2751 patients were screened for the diagnoses and presence of EP symptoms. A total of 222 patients were submitted to imaging analysis and applicable imaging data were recovered from 139 patients. Neuroimaging data were analyzed using Freesurfer software. In the whole cohort, EP + patients showed lower volumes of gray matter compared to EP- patients in the putamen (p = 0.002), bilateral globus pallidum (p = 0.002, p = 0.042), ventral diencephalon (p = 0.002) and brain stem (p < 0.001). In the bvFTD subgroup, there was volumetric difference between EP + and EP− patients in the brain stem. FDG-PET scans in the bvFTD patient subgroup showed that EP + patients had comparative hypometabolism of the superior cerebellar peduncle (SCP) and the frontal lobes. We discovered that EP symptoms are linked to brainstem atrophy in bvFTD patients and the whole cohort. Also, evident hypometabolism in the SCP of bvFTD EP + patients was detected as compared to bvFTD EP− patients. This could indicate that the EP symptoms in these diseases have a more caudal origin in the brainstem than in Parkinson’s disease.

The severity of behavioural symptoms in FTD is linked to the loss of GABRQ-expressing VENs and pyramidal neurons.

AimsThe loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social–emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ‐expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms.MethodsWe quantified VENs and GABRQ‐immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD‐TDP) (n = 34), tau (FTLD‐tau) (n = 24) or FUS (FTLD‐FUS) (n = 8) pathology, neurologically healthy controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we quantified VENs and the GABRQ‐expressing population in relation to presence of behavioural symptoms in the first years of disease onset.ResultsThe number of VENs and GABRQ‐expressing neurons and the ratio of VENs and GABRQ‐expressing neurons over total Layer 5 neuronal population decreased in FTLD‐TDP and FTLD‐FUS, but not in FTLD‐tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count.ConclusionWe show that in FTD, a loss of VENs together with GABRQ‐expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD‐tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD‐tau sample size. Overall, we show the GABRQ‐expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD.

Neuroanatomy of FTD: Whole‐brain correlations between symptoms and pathologies

Distinct pathologies accumulate in multiple brain regions (BR) and shape the heterogeneous clinical presentation of frontotemporal dementia (FTD). It is unknown how regional pathological burden links to symptoms, what the role of co-occurring pathologies is, and whether the localization of pathology might be a bigger contributor to symptoms than the type of pathology. Our aim is to investigate how early FTD symptoms correlate to the burden of multiple pathologies throughout the brain.Post-mortem brain tissue of frontotemporal lobar degeneration (FTLD) donors from the Netherlands brain bank was dissected into twenty standard BR and stained for TAR DNA-binding protein 43 (TDP-43), tau, fused-in-sarcoma (FUS), amyloid-beta (Aβ), and alpha-synuclein. The burden of each pathological protein in each BR was quantified. All clinical records were reviewed to assess psychiatric, behavioral, language, and motor symptoms in the first three years from disease onset. Whole-brain clinico-pathological partial correlations were assessed using the heterogeneous correlation function (R 3.6.1). The local false discovery rate threshold was set at 0.01.Eighty-eight FTLD brain donors were studied, including 46 TDP-43, 35 tau, and 7 FUS. Significant positive partial correlations (p < 0.01) were found between hippocampal TDP-43 pathology and hallucinations (R = 0.23), perseverative-compulsive behavior (R = 0.25), depression (R = 0.28), and mania (R = 0.32). Tau pathology in the substantia nigra and locus coeruleus was linked to depression (R = 0.25, R = 0.24). Both TDP-43 and Aβ in the subthalamus were associated with severe disinhibition (R = 0.23, R = 0.25), while apathy correlated with both TDP-43 and tau burden in the parietal lobe (R = 0.27, R = 0.24). Parkinsonism was linked to TDP-43 burden in the substantia nigra (R = 0.33).Neuropsychiatric symptoms of FTD are linked to pathology burden in BR beyond the frontal lobes, including subcortical structures such as the hippocampus, the substantia nigra and locus coeruleus. Co-occurring pathologies are not simple bystanders, but could play a role in configuring FTD clinical phenotype. Different pathologies in the same BR correlate with the same symptoms.

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. ClinicalTrials.gov Identifier: NCT02149160.

FTD-PSP is an Unusual Clinical Phenotype in A Frontotemporal Dementia Patient with A Novel Progranulin Mutation.

Progranulin (GRN) mutations are a major cause of frontotemporal dementia (FTD); the spectrum of clinical phenotypes of FTD is much more extensive than previously reported. The frequency and locations of GRN mutations in Chinese patients with FTD remain uncertain. We performed cDNA sequencing in one sporadic male patient who initially presented FTD symptoms. Brain magnetic resonance imaging (MRI) and positron emission computed tomography/computed tomography (PET/CT) were applied to further confirm the diagnosis of FTD from this patient. Cellular apoptosis and survival test were performed to identify the function of GRN. We identified one novel missense GRN mutation (c.1498G>A, p.V500I) in this patient, who initially presented typical behavioral-variant frontotemporal dementia (bvFTD) features but then presented progressive supranuclear palsy (PSP) clinical characteristics 5 years after onset. Besides, WT GRN protein showed an adequate trophic stimulus to preserve the survival of SH-SY5Y cells in the medium free of serum, while GRN mutation (c.1498G>A, p.V500I) may impair the ability of supporting cell survival. This study owns significant implications for genetic counseling and clinical heterogeneity. We illustrate the fact that FTD presenting features of bvFTD and PSP in one patient could be considered as a specific phenotype in patients with GRN mutations. GRN p.V500I led to the neuronal degeneration in vitro; this finding provides a significant evidence that this mutation may be a new causative mutation in patients with FTD.

Reward motivation and cognitive flexibility in tau null-mutation mice

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau−/−) and wild-type mice using progressive ratio and reversal learning tasks. Tau−/− mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau−/− mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.

Trajectory of apathy, cognition and neural correlates in the decades before symptoms in frontotemporal dementia

AbstractBackgroundIn frontotemporal dementia (FTD), apathy is reported to negatively impact the prognosis and survival of patients. The study of genetic FTD in its pre‐symptomatic period permits the investigation of markers in the early stages of disease progression. Therefore, in pre‐symptomatic gene carriers in the multicentre Genetic FTD Initiative (GENFI), we examined longitudinal apathy changes in association with cognitive decline over time, and baseline measures of atrophy.MethodSix hundred participants from Data Freeze 4 (2019) were included: 304 pre‐symptomatic mutation carriers, and 296 family members without mutations. Clinical assessment and a structural MRI scan were undertaken at baseline, and annually for at least 2‐years. Latent Growth Curve modelling (LGCM) was used to assess: 1) longitudinal changes in apathy, as measured by the apathy subscale of the Revised Cambridge Behavioural Inventory; 2) the relationship with longitudinal changes in executive function; 3) the association with baseline regional grey matter volumes. The time to the expected year of symptom onset was included as a covariate.ResultUnivariate LGCM identified a significant linear increase in apathy scores for pre‐symptomatic carriers (estimate= 0.51, se=0.18, z scores= 2.88, p=0.004), but not in non‐carriers (estimate= 0.08, se=0.08, z scores=1.04, p=0.30). An equality constrained comparison suggested a significant group difference in the progression of apathy (i.e. the slope) ((∆ χ2=10.14; p=0.0015). Pre‐symptomatic carriers also had a significant decline in executive functions (est=‐0.07, se=0.03, z scores=‐2.49, p=0.017), which was predicted by baseline apathy (standard estimate=‐0.40, p=0.008). In pre‐symptomatic carriers only, the annual rate of change in apathy was significantly associated with brain volume in frontal lobe (standard estimate=‐0.47, p=0.008) and cingulate cortex (standard estimate=‐0.29, p=0.05) at the baseline.ConclusionApathy progresses significantly in pre‐symptomatic FTD and predicts a sub‐clinical deterioration of executive performance in gene carriers. Apathy changes over 2 years are associated with volume in the frontal lobe and cingulate gyrus measured at the baseline. We suggest that apathy may be a modifiable factor to protect function and cognition in those with, or at risk of, frontotemporal dementia.