Early-onset Frontotemporal Dementia Research Articles

Are We Missing Early-onset Frontotemporal Dementia as Late-onset Primary Psychiatric Disorder? A Case Series

Abstract Frontotemporal dementia (FTD) presents with a wide variability in clinical progressive syndromes, genetic etiologies, and underlying pathologies. Early diagnosis of combined features of behavioral and language variants of FTD poses a clinical challenge due to its complex heterogeneous clinical presentations, phenotypical overlap, and frequent normal neuroimaging during the initial phase. This masquerading nature has often led to unintended “misdiagnoses,” as typical dementia features evolve late. The enigmatic resemblance of early-onset (<65 years of age) FTD with a range of late-onset (>45 years of age) primary psychiatric disorders emphasizes the need for high index of clinical suspicion, thorough family history for neurocognitive disorders, and regular follow-up of such individuals. We describe the clinical profile and management of four cases of combined variant FTD (cvFTD) that clinically mimicked late-onset psychiatric disorders such as catatonia, depressive disorder, psychosis, and personality changes. Parkinsonian-like features and mid-brain atrophy in FTD may indicate phenotypical overlap and shared neuropathology with progressive supranuclear palsy.

Clinical and genetic characteristics of patients with very early onset frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) spectrum disorders may occur in patients who are under 45 years old, often posing a diagnostic challenge, yet little is known about the clinical presentation and underlying genetic causes in this age group.MethodAs part of a prospective study focused on FTD, 780 participants met the research criteria for an FTD spectrum disorder between 2002‐2021. Of these, 40 patients (5.1%, 18 females) presented with age at onset < 45 years and constituted the very early onset frontotemporal dementia (VEO‐FTD) group. Their research records were reviewed to delineate their clinical characteristics. A panel of 40 dementia and amyotrophic lateral sclerosis‐associated genes was screened for pathogenic genetic variation using standardized methods.ResultBehavioral variant of frontotemporal dementia was disproportionally represented in the VEO‐FTD group (n = 35, 87.5%) suggesting selective vulnerability of the social‐emotional brain networks to frontotemporal lobar degeneration underlying neuropathologies in this age range. The median age at first symptom was 39 (interquartile range (IQR) = 32‐42.2) years, and the median diagnostic delay from symptom onset was 4 (IQR 2‐8.25) years. Initial misdiagnosis with a primary psychiatric disorder was prevalent, occurring in 17 (42.3%) of patients, and was diverse including mood, psychotic, anxiety, and addictive disorders. In five patients (12.5%), positive psychotic symptoms were reported, mostly as a presenting symptom or arising within a year from the first symptom. Among the VEO‐FTD patients, 18 (45%) carried C9orf72, MAPT or UBQLN2 pathogenic variants.ConclusionFTD spectrum disorders may occur under the age of 45 and are often misdiagnosed. The high prevalence of monogenic causes in this age group warrants timely genetic testing, especially in the era of emerging gene‐specific therapies.

B - 103 Early Onset Frontotemporal Dementia: a Neuropsychological Case Study.

A neuropsychological case review of Early-Onset Frontotemporal Dementia (FTD) utilizing the Meyers Neuropsychological Battery (MNB). FTD is a degeneration of brain nerve cells resulting in behavioral deterioration and other effects upon personality and brain functions. Due to early onset of FTD, diagnostic ambiguity is often the case. The current case was a patient referred by neurology to rule-out adult ADHD/LD. The patient is a 51-year-old, Caucasian, right-handed male. Initially, his symptoms were sleep changes, anxiety, reduced attention concentration, and memory. The medical community indicated the possibility of an undiagnosed ADHD condition. MRI and EEG of the brain revealed an arachnoid cyst and focal slowing in the left temporal region. In addition, asymmetric enlargement of the left Sylvian fissure and brain parenchyma were noted. MNB neurocognitive findings were diffuse and revealed lateralized motor impairments in primary and psychomotor abilities. MNB Premorbid Estimate (T-48), OTBM (T-31), and DTBM (T-27) were comparatively significant. Psychological findings were consistent with an anxiety disorder. Contrary to the medical community diagnostic initial impression, ADHD was ruled out. MNB revealed a pattern of findings consistent with a neurodegenerative condition (FTD, Cor. = 0.74, Conf. = 0.80). This study highlights the importance of administering a full thorough neuropsychological examination rather than assessing the patient's complaints of "reduced attention concentration." FTD is statistically increasing, hence the importance to fully evaluate across the lifespan, especially in consideration to early onset FTD.

Early onset frontotemporal dementia following cannabis abuse: a case report

BackgroundFrontotemporal disorders (FTD) are the consequence of impairment to neurons in the frontal and temporal lobes of the brain. Also, no definitive treatment has been found for FTD. Cannabinoid products can be used to manage treatment-resistant behavioral variants of Frontotemporal dementia (bvFTD).Case presentationWe describe the case of 34 years old male with two years of marijuana abuse. At first, he presented with symptoms of apathy and bizarre behavior, which became more severe, and led to disinhibition. The clinical symptoms and imaging findings made FTD probable for him, which was very interesting to report.ConclusionsWhile cannabis has demonstrated potential in managing behavioral and mental symptoms of dementia, the presented case highlights the profound impact of cannabis consumption on brain structure and chemistry, including the potential for neurodegenerative disorders like FTD.

Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation.

Tauopathies are a group of neurodegenerative diseases, which include frontotemporal dementia (FTD) and Alzheimer's disease (AD), broadly defined by the development of tau brain aggregates. Both missense and splicing tau mutations can directly cause early onset FTD. Tau protein is a microtubule-associated protein that stabilizes and regulates microtubules, but this function can be disrupted in disease states. One contributing factor is the balance of different tau isoforms, which can be categorized into either three repeat (3R) or four repeat (4R) isoforms based on the number of microtubule-binding repeats that are expressed. Imbalance of 3R and 4R isoforms in either direction can cause FTD and neurodegeneration. There is also increasing evidence that 3R tauopathies such as Pick's disease form tau aggregates predominantly comprised of 3R isoforms and these can present differently from 4R and mixed 3R/4R tauopathies. In this study, multiple mutations in 3R tau were assessed for MT binding properties and prion-like aggregation propensity. Different missense tau mutations showed varying effects on MT binding depending on molecular location and properties. Of the mutations that were surveyed, S356T tau is uniquely capable of prion-like seeded aggregation and forms extensive Thioflavin positive aggregates. This unique prion-like tau strain will be useful to model 3R tau aggregation and will contribute to the understanding of diverse presentations of different tauopathies.

Clinical and genetic characteristics of patients with very early onset frontotemporal dementia (S39.007)

Clinical and genetic characteristics of patients with very early onset frontotemporal dementia (S39.007)

Initial symptoms of early-onset dementia in Japan: nationwide survey.

The aim of this study was to investigate initial symptoms of early-onset dementia (EOD) for each dementia subtype. We conducted a nationwide, population-based EOD prevalence study in Japan. Data were collected through service providers for people with EOD. Initial symptoms were assessed in six domains: loss of memory, difficulty in word generation, irritability, loss of motivation, increased mistakes in the workplace or domestically, and unusual behaviours or attitudes other than those listed. Participants were 770 people with EOD. Characteristic initial symptoms were observed for each EOD subtype. Loss of memory was more common in early-onset Alzheimer's disease (75.7%, P < 0.001), difficulty in word generation was more common in early-onset vascular dementia (41.3%, P < 0.001), and loss of motivation, increased mistakes in the workplace or domestically, and unusual behaviours or attitudes other than those listed were more common in early-onset frontotemporal dementia (34.9%, P < 0.001; 49.4%, P < 0.001; 34.9%, P < 0.001, respectively). In addition, we observed gender differences whereby loss of memory was more common among women and irritability was more common among men. More than half of the participants were employed at symptom onset, and 57.2% of those who were employed at the onset had initial symptoms of increased mistakes in the workplace or domestically. This report reveals differences in the frequency of initial symptoms by EOD subtype. The results contribute to increasing public awareness of the initial symptoms of EOD, which will facilitate early diagnosis and social support.

Abstract- Poster

INTRODUCTION.§ Frontotemporal dementia (FTD) refers to a group of dementias characterized by degeneration in the frontal and temporal lobes of the brain. Rates of early-onset FTD are high with 13% of individuals with FTD being under the age of 50.§ Younger cases of FTD tend to exhibit frequent abrupt mood changes, increased aggression, behavioral disinhibition, lack of empathy, and deficits in working memory.There are three clinical presentations of FTD: behavioral variant (bvFTD) and two forms of primary progressive aphasia.Here we report a a 37 yr Old married man was brought with complaints of a progressive history of changes in behaviour and personality.The patient was in good baseline health until age 35 years, when his family noticed an increase in change in behavior with history of cannabis smoking for 2 yrs, H/O multiple extra marital affairs for 2 yrs,with H/O restlessness,dull and withdrawn, sleep disturbance,poor self care, refusing to eat properly, slowly not speaking to anyone, poor work performance for the past 6 months. He was diagnosed as a case of substance induced psychosis with catatonic features and treated. Again after three months pt presented to psychiatric opd with complaints of restlessness, speech difficulty forgetting things, inappropriate laugh,disinterest in daily activities, walking in the house all the time, disinhibited behaviour,weight loss,excessive craving for tobacco,putting inedible things at mouth all these symptoms for one month.On Mse O/E he was alert,ambulant,kempt,yawning frequently during interview, not cooperative, sits in chair and gets up frequently, no Spontaneous speech. He did not attempt to initiate conversation, answering questions with short, terse responses. relevant replies. He often gazed with a prolonged, fixed stare and exhibited motor stereotypies such as clapping his thighs or tapping his feet vigorously.— There were no upper or lower motor neurone signs, frontal release signs positive, and no parkinsonism or limb apraxia. His gait was normal. He scored only 55 out of 100 on the Addenbrooke’s Cognitive Examination-III, with impairments across domains but with particularly poor executive function (naming only two words beginning with P in a minute, and only 10 animals over a minute, leading to a very low verbal fluency score of 4 out of 14). Attention (score 12 out of 18), language (19 out of 26), memory (9 out of 26) and visuospatial (11 out of 16) abilities were also affected.— Further neuropsychological testing identified a global reduction in general intellectual function, with severe executive function deficits as well as poor verbal working— Neurology opinion obtained as a case of young onset FTD— MRI scan of the brain showed substantial bilateral, symmetrical frontal atrophy, with no evidence of white matter changes that would be typical of a vascular, vasculitic or inflammatory cause (figure 1). In addition, autoimmune encephalitis was negative; and HIV and syphilis serology were all normal or negative. Cerebrospinal fluid (CSF) contained no white cells or abnormal cells and therefore no evidence of an active inflammatory, infective or malignant process; the CSF protein concentration was also normal. PET scan suggestive of FTDReference 1. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456?77.2. Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004;17:355?9.3. Warren JD, Rohrer JD, Rossor MN. Clinical review. Frontotemporal dementia. BMJ 2013;347:f4827.4. Neumann M, Mackenzie IRA. Review: Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol Appl Neurobiol 2019;45:19?40.5. Mann DMA, Snowden JS. Frontotemporal lobar degeneration: pathogenesis, pathology and pathways to phenotype. Brain Pathol 2017;27:723?36. Ct brain showed bilateral frontoparietotemporal Subdural HYGROMA.Neurologist opinion obtained. There was no focal neurological defecit and conservative management suggested. Patient was treated with tab risperidone 2mg 1-0-1 tab sodium valproate 200 mg 1-1-1, tab diazepam 5mg 0-0-1, her symptom improved with treatment (ymrs-12.)

A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family

Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain’s morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

Pathogenic MAPT mutations Q336H and Q336R have isoform-dependent differences in aggregation propensity and microtubule dysfunction.

Tauopathies are a group of heterogeneous neurodegenerative disorders characterized by brain deposition of tau inclusions. These insidious disorders include Alzheimer's disease and frontotemporal dementia, the two leading causes of dementia. Mutations in the microtubule-associated protein tau (MAPT) gene lead to familial forms of frontotemporal dementia. Previously, we used cell-based assays to screen over 20 missense tau mutations and found that decreased microtubule (MT) binding affinity was the most shared property. As a break from this trend, the MAPT mutations Q336H and Q336R are thought to promote MT assembly rather than inhibit it based on in vitro studies. Q336H and Q336R MAPT mutations also cause early onset frontotemporal dementia with Pick bodies, which are mostly composed of 3R tau isoforms. To provide further insights on the pathobiology of these mutations, we assessed Q336H and Q336R tau mutants for aggregation propensity and MT binding in cell-based assays in the context of both 0N3R and 0N4R tau isoforms. Q336R tau was prone to prion-like seeded aggregation but both Q336H and Q336R tau led to increased MT binding. Additionally, we found that different tau isoforms with these mutations heterogeneously regulate different MT subpopulations of tyrosinated and acetylated MTs, markers of newly formed MTs and stable MTs. The Q336H and Q336R tau mutations may exemplify an alternative mechanism where pathogenic tau can bind MTs with higher affinity and hyperstabilize MTs, which prevent proper MT regulation and homeostasis.

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.

Early-onset of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in an Albanian Patient with a c.1319C&gt;T Variant in the UBQLN2 Gene

Background: Frontotemporal Dementia (FTD) is the second most common cause of dementia under 65 years of age; it has a prevalence of 4-15 per 100,000 persons. The overt disease usually manifests in the sixth decade, and it is extremely rare to find affected patients in their twenties. Objective: Here, we present the clinical and molecular genetic findings of an Albanian family with a patient with early-onset FTD and Amyotrophic Lateral Sclerosis (ALS). Methods: Given the great variability of clinical presentation of FTD and the number of genes involved, targeted Next Generation Sequencing (NGS) was used to screen the DNA of the 27-year-old male patient. Segregation analysis was performed in available family members. Results and Discussion: A variant, consisting of a proline-leucine amino acid substitution in position 440, was identified in the UBQLN2 gene on the X-chromosome. This variant was previously reported as a variant of unknown significance in a 30-year-old female patient with amyotrophic lateral sclerosis. With the description of our case, we add evidence on its involvement, also in ALS-FTD. The variant is in a functional domain important for interaction with HSP70 and this, in turn, may impair the shuttling of proteins to the proteasome leading to an accumulation of protein aggregates. The variant was inherited from the unaffected mother, in line with the fact that incomplete penetrance has been widely described for this gene. Conclusion:The present report adds information regarding one of 34 variants in the UBQLN2 gene reported so far in association with neurodegeneration and proposes a molecular pathogenesis of ALS-FTD in this patient.

Frontotemporal brain sagging syndrome: Craniospinal hypovolemia secondary to a T6-T7 cerebrospinal fluid-venous fistula

Background: The frontotemporal brain sagging syndrome (FTBSS) is defined as an insidious/progressive decline in behavior and executive functions, hypersomnolence, and orthostatic headaches attributed to cerebrospinal fluid (CSF) hypovolemia. Here, a T6 CSF-venous fistula (e.g., between the subarachnoid CSF and a paraspinal vein) resulted in a CSF leak responsible for craniospinal hypovolemia.Case Description: A 56-year-old male started with orthostatic headaches and fatigue after scuba diving. His symptoms included progressive, vertigo, tinnitus, nausea, lack of judgment, inappropriate behavior, memory dysfunction, apathy, tremor, orofacial dyskinesia, dysarthria, dysphagia, and hypersomnolence. The lumbar puncture revealed an opening pressure of 0 cm H2O. Magnetic resonance imaging (MRI) findings included brain sagging, bilateral temporal lobe herniation, and pachymeningeal enhancement. The computed tomography (CT) myelogram showed a thoracic diverticulum and a CSF-venous leak at the T6-T7 level. Surgery, which comprised a T6-T7 laminotomy, allowed for dissecting, clipping, and ligating the diverticulum/fistula. The patient improved postoperatively (e.g., cognitive, behavioral, and brainstem symptoms). The follow-up MRI’s showed the reversion of the sagging index/uncal herniation.Conclusion: The FTBSS should be considered in the differential diagnosis of an early onset frontotemporal dementia. Establishing the diagnosis and localizing the site of a spinal CSF/venous leak warrant both MRI and myelogram CT studies, to pinpoint the CSF leak site for proper surgical clipping/ligation of these thoracic diverticulum/CSF-venous leaks.

Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment

Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFINTYROBP deletion that covers 4 of the gene's 5 exons. We genotyped 3220 older Finns (mean age 79, range 58–104) and found 11 deletion carriers (mean age 78, range 60–94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing Mini-Mental State Examination (MMSE) scores and diagnoses of dementia, we did not find any significant differences between TYROBP deletion carriers and noncarriers (all p-values >0.5). Neuropathological analysis of 2 deletion carriers (aged 89 and 94 years) demonstrated only minimal beta amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment.

Fronto-temporal Dementia with Early Onset

IntroductionEven though it is not the most common type of dementia, frontotemporal dementia (FTD) is a major health problem. It affects people younger than 65 with similar frequency as Alzheimer's dementia (AD) and has a progressive course that leads to inevitable deterioration in functioning. Still, FTD is not a unique entity in ICD- 10 classification.ObjectivesTo investigate the diagnostic and treatment difficulties in FTD.AimsTo show very rapid and progressive deterioration in people with early onset FTD.MethodsWe will present a series of cases showing progressive cognitive deterioration and prominent personality changes in patients with FTD hospitalised at University Psychiatric Hospital Vrapce since 2013 to 2015. Collected data included anamnestic and heteroanamnestic information, blood tests and neroimaging.ResultsOur findings showed a significance of early onset FTD, with subtle, untypical symptoms at the beginning, and galloping deterioration during the course of illness.ConclusionsPresented patients with FTD showed rapid and progressive nature of disease with infaust prognosis. Even though early onset patients make 20% of overall number of patients with FTD, we consider that it is necessary to separate them from late onset patients in future classification systems.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Multiparametric computer-aided differential diagnosis of Alzheimer\u2019s disease and frontotemporal dementia using structural and advanced MRI

ObjectivesTo investigate the added diagnostic value of arterial spin labelling (ASL) and diffusion tensor imaging (DTI) to structural MRI for computer-aided classification of Alzheimer's disease (AD), frontotemporal dementia (FTD), and controls.MethodsThis retrospective study used MRI data from 24 early-onset AD and 33 early-onset FTD patients and 34 controls (CN). Classification was based on voxel-wise feature maps derived from structural MRI, ASL, and DTI. Support vector machines (SVMs) were trained to classify AD versus CN (AD-CN), FTD-CN, AD-FTD, and AD-FTD-CN (multi-class). Classification performance was assessed by the area under the receiver-operating-characteristic curve (AUC) and accuracy. Using SVM significance maps, we analysed contributions of brain regions.ResultsCombining ASL and DTI with structural MRI resulted in higher classification performance for differential diagnosis of AD and FTD (AUC = 84%; p = 0.05) than using structural MRI by itself (AUC = 72%). The performance of ASL and DTI themselves did not improve over structural MRI. The classifications were driven by different brain regions for ASL and DTI than for structural MRI, suggesting complementary information.ConclusionsASL and DTI are promising additions to structural MRI for classification of early-onset AD, early-onset FTD, and controls, and may improve the computer-aided differential diagnosis on a single-subject level.Key points• Multiparametric MRI is promising for computer-aided diagnosis of early-onset AD and FTD.• Diagnosis is driven by different brain regions when using different MRI methods.• Combining structural MRI, ASL, and DTI may improve differential diagnosis of dementia.

Clinical heterogeneity of LRRK2 p.I2012T mutation

IntroductionLeucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). However, only few cases carrying LRRK2 mutations have been reported in Taiwanese PD patients. MethodsWe used targeted next generation sequencing (NGS), covering 24 candidate genes involved in neurodegenerative disorders, to analyze 40 probands with familial PD, and 10 patients with mixed neurodegenerative disorders. Sanger sequencing of the identified mutation in the first set of the study was performed in additional 270 PD patients, including 139 familial PD and 131 early-onset PD (onset age less than 50 years old), and 300 age/gender matched control subjects. ResultsWe found a missense variant, p.I2012T, in the LRRK2 gene in one sporadic patient having early-onset frontotemporal dementia with parkinsonism and dystonia. Sanger sequencing this substitution in additional 270 PD patients in the second set of the study revealed two additional variant carriers: one having autosomal-dominant familial PD, and one with sporadic PD. The p.I2012T substitution was absent in 300 normal control subjects. Analyzing family members of the proband with p.I2012T revealed co-segregation of the variant and parkinsonism. Clinical presentations, levodopa responses, and Tc99mTRODAT-SPECT imaging findings of this index family were similar to idiopathic PD. ConclusionsOur results revealed clinical heterogeneity of the LRRK2 p.I2012T substitution, and demonstrated the use of targeted NGS for genetic diagnosis in multiplex families with PD or mixed neurodegenerative disorders.

The patterns of inheritance in early-onset dementia: Alzheimer's disease and frontotemporal dementia.

To investigate the patterns of inheritance and gene mutation status in early-onset dementia (EOD). Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer's disease (EOAD, n = 120) and early-onset frontotemporal dementia (EOFTD, n = 82) were studied. The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden.

Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease

Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with “pure” neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.

Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia.

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.