TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.

Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction.

Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer's disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.

FUS Interacts with HSP60 to Promote Mitochondrial Damage.

FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.

WITHDRAWN: Revisiting the cholinergic hypothesis in Alzheimer's disease: Emerging evidence from translational and clinical research.

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An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel ß-structure and induces TDP-43 redistribution.

TDP-43 proteinopathies are clinically and genetically heterogeneous diseases that had been considered distinct from classical amyloid diseases. Here, we provide evidence for the structural similarity between TDP-43 peptides and other amyloid proteins. Atomic force microscopy and electron microscopy examination of peptides spanning a previously defined amyloidogenic fragment revealed a minimal core region that forms amyloid fibrils similar to the TDP-43 fibrils detected in FTLD-TDP brain tissues. An ALS-mutant A315E amyloidogenic TDP-43 peptide is capable of cross-seeding other TDP-43 peptides and an amyloid-ß peptide. Sequential Nuclear Overhauser Effects and double-quantum-filtered correlation spectroscopy in nuclear magnetic resonance (NMR) analyses of the A315E-mutant TDP-43 peptide indicate that it adopts an anti-parallel ß conformation. When added to cell cultures, the amyloidogenic TDP-43 peptides induce TDP-43 redistribution from the nucleus to the cytoplasm. Neuronal cultures in compartmentalized microfluidic-chambers demonstrate that the TDP-43 peptides can be taken up by axons and induce axonotoxicity and neuronal death, thus recapitulating key neuropathological features of TDP-43 proteinopathies. Importantly, a single amino acid change in the amyloidogenic TDP-43 peptide that disrupts fibril formation also eliminates neurotoxicity, supporting that amyloidogenesis is critical for TDP-43 neurotoxicity.

TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.

Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

A novel frontal pathway underlies verbal fluency in primary progressive aphasia.

The frontal aslant tract is a direct pathway connecting Broca's region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

The evolving landscape of human cortical connectivity: facts and inferences.

Human cognitive brain mapping is at a crossroads. On the one hand, it can access a rich data set of synaptic connectivity in the cerebral cortex of the monkey, an animal that lacks many of the complicated behaviors of interest. On the other hand, it is rapidly amassing an even richer data set on the functional map of the human cerebral cortex, but with relatively little hard data on underlying structural connectivity. This second point tends to be blurred in the current literature because of the multiple ways in which the term 'connection' is used in the context of the human brain. In some instances the term is used at a conceptual level, to designate a pathway that should be there if the behavior is to be performed. In other instances, it refers to the computational demonstration of a functional relationship, the structural basis of which is not necessarily known. A third usage is based on connections that are known to exist in the monkey and that are inferred to also exist in the human. The fourth and most direct usage involves connections structurally proven to exist in the human. These four usages have been invoked interchangeably to propose connectivistic mechanisms of human cognitive function. To enlarge the currently limited data set on structural connectivity is of considerable importance for conducting biologically more valid explorations of large-scale neurocognitive networks. This challenging goal will require histological laboratory investigations of the human brain to resume their former prominence and to play an increasingly more substantial role in brain mapping research.

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

Communication Bridge™-2 (CB2): an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. METHOD: Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. DISCUSSION: The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. TRIAL REGISTRATION: ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease.

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain-behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinico-anatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.

Neurology of anomia in the semantic variant of primary progressive aphasia.

The semantic variant of primary progressive aphasia (PPA) is characterized by the combination of word comprehension deficits, fluent aphasia and a particularly severe anomia. In this study, two novel tasks were used to explore the factors contributing to the anomia. The single most common factor was a blurring of distinctions among members of a semantic category, leading to errors of overgeneralization in word-object matching tasks as well as in word definitions and object descriptions. This factor was more pronounced for natural kinds than artifacts. In patients with the more severe anomias, conceptual maps were more extensively disrupted so that inter-category distinctions were as impaired as intra-category distinctions. Many objects that could not be named aloud could be matched to the correct word in patients with mild but not severe anomia, reflecting a gradual intensification of the semantic factor as the naming disorder becomes more severe. Accurate object descriptions were more frequent than accurate word definitions and all patients experienced prominent word comprehension deficits that interfered with everyday activities but no consequential impairment of object usage or face recognition. Magnetic resonance imaging revealed three characteristics: greater atrophy of the left hemisphere; atrophy of anterior components of the perisylvian language network in the superior and middle temporal gyri; and atrophy of anterior components of the face and object recognition network in the inferior and medial temporal lobes. The left sided asymmetry and perisylvian extension of the atrophy explains the more profound impairment of word than object usage and provides the anatomical basis for distinguishing the semantic variant of primary progressive aphasia from the partially overlapping group of patients that fulfil the widely accepted diagnostic criteria for semantic dementia.

Representation, inference, and transcendent encoding in neurocognitive networks of the human brain.

The anatomical basis of conscious experience has traditionally been linked to sensory-fugal (inward) pathways that convey sensory information to progressively "higher" association cortices. Current thinking is emphasizing the importance of sensory-petal pathways that run in the opposite (outward) direction. According to emerging views, many aspects of cognition may represent an iterative neural dialogue between sensory-fugal connections, which reflect the physical nature of ambient events, and sensory-petal connections, which infer the nature of the stimulus based on empirical accounts of past experience. These reciprocal pathways, embedded within the internally generated oscillations of the brain, are further modulated by top-down projections from high-order association cortices, most prominently located in prefrontal cortex. This set of top-down projections has the capacity to transcend experience-based representations and to insert internally generated priorities into the interpretation of ongoing events. The characteristically human capacity for resisting stimulus-bound responses and favoring novel interpretations may be linked to the influence of these top-down projections. The reciprocal sensory-processing pathways and their top-down modulations collectively define the conscious interpretation of experience.

Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia.

OBJECTIVE: To identify predictors of Alzheimer's disease (AD) versus frontotemporal lobar degeneration pathology in primary progressive aphasia (PPA), and determine whether the AD pathology is atypically distributed to fit the aphasic phenotype. METHODS: Neuropsychological and neuropathological analyses of 23 consecutive PPA autopsies. All had qualitative determination of neurofibrillary tangle (NFT) density. Additional quantitation was done in four of the PPA/AD cases and four AD cases with the typical amnestic dementia of the Alzheimer type. RESULTS: The sample contained mostly logopenic, agrammatic, and mixed forms of PPA. All six agrammatics had frontotemporal lobar degeneration (five of six with tauopathy). Seven of the 11 logopenics had AD. In logopenics, lower memory scores increased the probability of AD, but there were exceptions. The PPA/AD group showed predominance of entorhinal NFT typical of the amnestic dementia of the Alzheimer type. In the small subgroup examined quantitatively, neocortical NFTs were more numerous in the left hemisphere of PPA/AD. However, the asymmetry was low and inconsistent. Neuritic plaques did not display consistent asymmetry. Apolipoprotein E4, a major risk factor for typical AD, did not predict AD pathology in PPA. INTERPRETATION: Subtyping PPA helps to predict AD versus frontotemporal lobar degeneration pathology at the group level. However, our results and the literature also indicate that no clinical predictor is completely reliable in individual patients. The inconsistent concordance of NFT distribution with the asymmetric atrophy and the nonamnestic phenotype also raises the possibility that the AD markers encountered at autopsy in PPA may not always reflect the nature of the initiating neurodegenerative process.

TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.

Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3'-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.