2012 Dementia and Geriatric Cognitive Disorders  
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The genetics of FTD has been one of the success stories in genetics over the past 15 years. Classic family based linkage studies have identified genes that explain a large part of the families with a Mendelian inheritance of the disease. This group of familial FTD patients has now been linked to mutations in several genes, including the microtubule-associated protein tau (MAPT), progranulin (GRN),
more » ... containing protein (VCP), charged multivescicular body protein 2B (CHMP2B), TAR DNA-binding protein 43 (TDP43) and Fused in Sarcoma (FUS) and most recently C9Orf72. Over the years the identified genes have triggered many studies that increased our understanding of the disease process. Neuropathologically the disease can be divided in two major groups that have a clear correlation with their genetic background; hose with tau-positive inclusions and those with ubiquitin-positive and TDP-43 positive inclusions. The field of genetics keeps changing rapidly thanks to technological developments, first with the development of Genome Wide Association Studies (GWAS) studies but now also with the use of next generation sequencing, as was already demonstrated with the identification of the expanded repeat in C9Orf72, and we can also expect many whole exome or whole genome sequencing studies. This review provides an overview of the genetics of FTD, with an update of recent discoveries. Reassessing and refining clinical associations within frontotemporal lobal degeneration Keith Josephs Mayo Clinic, USA The frontotemporal lobar degenerations (FTLDs) are a group of heterogeneous disorders. Biochemical abnormalities accounting for the FTLD spectrum of disorders, while still being refined, currently involve three major proteins: Tau, TDP-43, and FUS. These three proteins account for the pathologies associated with FTLD. Patients with FTLD however, can present with a barrage of signs and symptoms and different syndromes, resulting in complex and obscure relationships between clinical and pathological diagnoses. Common FTLD syndromes include behavioral variant frontotemporal dementia, semantic dementia, progressive apraxia of speech, agrammatic aphasia, progressive supranuclear palsy syndrome, corticobasal syndrome, ALS-dementia, frontotemporal dementia with motor neuron disease, as well as other less common syndromes. A further complicating feature of FTLD is the issue of "sporadic" versus familial disease that has led to recent important genetic discoveries including, but not limited to, mutations in the microtubule associated protein, tau (MAPT) and progranulin (GRN) genes, and repeat expansions in the C9ORF72 gene. Neuroanatomical associations within the FTLD spectrum of disorders are complex, but do reveal signature patterns of pathology and genetics which could have clinical utility. Understanding how clinical syndromes are associated with biochemistry, pathology, anatomy, and genetics in FTLD will be reappraised resulting in a novel proposal in the way we could think about the FTLDs. FUS loss of function pathomechanism in FTLD A subset of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases are characterized by abnormal accumulation of fused in sarcoma (FUS) protein as cellular inclusions. FUS is a multifunctional DNA/RNA binding protein that shuttles between the nuclear and cytoplasmic compartments, but is predominantly localized to neuronal nuclei. Although the specific mechanisms of FUS-associated neurodegeneration are not known, several lines of evidence support a role for loss of FUS physiological function. FUS mutations that cause ALS primarily affect the C-terminus that includes the nuclear localization signal. The degree to which these mutations interfere with transportin-mediated nuclear import correlates with the severity of clinical disease and neuropathology. Cases of FTLD-FUS, which are not associated with FUS mutations, also demonstrate reduced nuclear FUS staining of inclusion bearing neurons. This strongly suggests that neurodegeneration is directly related to cellular redistribution of FUS, with one logical explantation being a reduced ability of FUS to perform its normal nuclear functions. Although the results from animal models have been inconsistent, knockdown of FUS or its homologues has been shown to result in abnormal development, reduced viability, motor deficits and abnormal neuronal morphology, with some of these deficits rescued by expression of FUS transgenes. Evidence against a toxic-gain-of-function mechanism include the absence of abnormal molecular species in FTLD-FUS, the lack of neurodegeneration in some anatomical regions with abundant cytoplasmic FUS inclusions and the absence of FUS aggregates in some models of toxicity. The fact that all FET proteins co-accumulate in the cellular inclusions of FTLD-FUS and evidence that dysregulation of several other RNA binding proteins is also associated with FTLD best supports a common loss of function mechanism related to misregulated RNA processing or transcription. FUS is a ubiquitously expressed multifunctional DNA/RNA binding protein and under physiological conditions it is mainly localized to the nucleus. In about 10 % of FTLD patients (subsumed as FTLD-FUS), and in familial forms of ALS associated with mutations in the FUS gene, abnormal accumulation of FUS into cytoplasmic inclusions are the defining hallmark lesion. The mechanisms leading to cytoplasmic FUS accumulation in FTLD-FUS in the absence of FUS mutations and the processes of FUS-associated neurodegeneration are not known yet. Model systems addressing the fundamental questions on the underlying mechanisms are just emerging with some inconsistent findings. However, there is some evidence supporting the idea that neurodegeneration might be triggered through a neurotoxic/ gain of function effect of cytoplasmic FUS rather than by a loss of function. In human pathology, inclusion bearing cells often retain their physiological nuclear FUS staining, arguing against a loss of nuclear function mechanism. In yeast, FUS toxicity is closely related to its cytoplasmic localization. In transgenic worms and rat models expression of cytoplasmic FUS was sufficient to induce motor defects and premature death while no depletion of nuclear FUS was observed. Moreover, the severity of phenotype nicely correlates with the level of cytoplasmic FUS, thereby supporting the idea of a neurotoxic effect of cytoplasmic FUS. This might be either mediated by abnormal interaction with TDP-43 is the major protein component of the abnormal inclusions in FTLD-TDP and most non-SOD1 ALS. TDP-43 is a multifunctional hnRNP protein involved in regulation of RNA splicing, translation, miRNA processing, and mRNA transport and stability. There is evidence for TDP-43 autoregulation, participation in stress granule formation, and a proteaseresistant prion-like domain in the C-terminal region. TDP-43 has more than 6,000 RNA targets. Mutations in TARDBP occur predominantly in the C-terminal region, most causing ALS and some causing FTLD. Various cell, fly, and rodent models have shown evidence for either loss or gain of function, or both, in the pathogenesis of TDP-43 proteinopathy, but none have completely modeled human disease. Evidence for a toxic gain of function in model systems has included the following: in rodent models, overexpression of both wild type (WT) and mutant TDP-43 are neurotoxic in a dose-dependent manner, and in some rodent models C-terminal fragments (CTFs) correlate with disease progression; in cultured rodent neurons, one study showed that CTFs impair neurite outgrowth that is rescued by full-length TDP-43, while in another, neurotoxicity correlated with the amount of cytoplasmic TDP-43 expression; and Drosophila studies have shown neurotoxicity with both expression of full-length WT and mutant TDP-43. TARDBP mutations also increase stress granule formation in response to cellular stress, increase cleavage of TDP-43 and formation of CTFs, and increase the production of low molecular weight prion-like protease-resistant fragments. The evidence for toxic gain of function due to overexpressed or mutant TDP-43 or cytoplasmic TDP-43/CTFs is compelling, but given the numerous crucial functions carried out by normal TDP-43, there is also compelling evidence for loss of function in the pathogenesis of TDP-43 proteinopathy, and it is likely that both have a role in these diseases. TDP-43 protein is tightly controlled within narrow limits by an auto-regulatory mechanism and both over-and under-expression of TDP-43 result in impaired neuronal viability but the precise mechanisms leading to cell death are not known. It has been proposed that the TDP-43 loss-of-function mechanisms may contribute to neurodegeneration and these are the subject of active investigation. Except for cases with mutations in the TARDBP gene which likely result in loss-of-function degeneration, alternative etiologies may contribute to pathogenesis in sporadic cases. Cellular stress is an attractive precipitating factor because it is a feature of most TDP-43 proteinopathies, including both primary diseases (that is those where the primary molecular pathology is frontotemporal lobar degeneration with TDP-43 proteinopathy (sporadic and familial forms of FTLD-TDP with GRN, C9ORF72, TARDBP, or VCP mutation) and those where it is a secondary disease process or co-morbidity (Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease). Cellular stress likely causes redistribution of TDP-43 to the cytoplasm where its intrinsic self-aggregating property leads to inclusion body formation or trafficking to stress granules. Cytoplasmic, and less commonly nuclear, aggregation is accompanied by several posttranslational of the TDP-43 knockout. We have recently generated zebrafish TDP-43 loss of function mutants. Homozygous loss of function mutations in zebrafish tardbp show no morphological phenotype due to compensation by a splice variant of tardbpl (Tar DNA binding protein of 43 kDa like), a second zebrafish orthologue of human TARDBP. tardbp and tardbpl double homozygous mutants show muscle degeneration, strongly reduced blood circulation and a dramatic mispatterning of intersomitic vessels, impaired spinal motor axon outgrowth, and early death. A quantitative proteomic approach identified a muscle specific protein to be upregulated in tardbp and tardbpl double homozygous mutants. Strikingly, the same protein is similarly increased in the frontal cortex of FTLD-TDP patients suggesting aberrant expression in vascular smooth muscle cells. Thus, these findings reveal an unexpected role of TDP-43 in vascular patterning and muscle maintenance. The improved nosology of FTLD provides an opportunity for precise genetic diagnosis or increasing confidence in predicting the underlying molecular pathology from detailed phenotyping in sporadic cases. This has opened up new opportunities for future pharmacological interventions. The tau based FTLD cases offer an ideal group for assessing tau directed interventions which may be applicable to Alzheimer's disease. The progranulin haplo-insufficiency associated with GRN mutations may offer a more immediately tractable problem than neurodegeneration arising from protein misfolding. The improved understanding of clinical features can also more effectively direct general management options. For example, monitoring for bulbar weakness and directing the early intervention of speech aids. It can also direct the increasingly sophisticated complex health interventions for the management of behavioural and emotional deficits. As genes emerge that are linked with human Frontotemporal Dementias (FTDs), we are challenged to modify these genes in animals to yield models that faithfully replicate the pathological, biochemical and behavioral features of the human diseases. These efforts are often undertaken before even the basic biology of these genes and their respective proteins is understood. This talk will discuss our attempts to model frontotemporal dementias using tau, TDP-43 and progranulin mouse models. I will detail which features of human FTDs have been recreated in ours and other rodent models. This talk will also discuss which key features of human FTD are missing from currently available models and detail the challenges that exist in replicating these salient features. Finally, I will discuss how unexpected data from a progranulin knock-out model provided an unexpected link between 8 Objective: Common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), supporting the idea of a disease continuum. A recent study showed mutations in the sequestosome 1 (SQSTM1) gene in patients with ALS. The SQSTM1 gene is located on 5q35 and encodes p62, a multifunctional protein implicated in several cellular activities like autophagy and oxidative stress response. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in Italian FTLD and ALS patients. Methods: We sequenced the promoter region and all exons of the SQSTM1 in a large group of unrelated subjects, consisting of 170 FTLD patients, 124 ALS patients and 145 healthy controls. The clinical characteristics of FTLD/ALS patients with gene mutations were examined. Results: We identified six missense mutations in the coding region of the SQSTM1 gene in patients belonging to the FTLD/ALS clinical spectrum, none of which were found in healthy controls. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, seven novel non-coding SQSTM1 variants were found in FTLD and ALS patients, including four variations in the promoter region. Discussion: Our study confirms the presence of SQSTM1 gene mutations in patients with ALS. In addition, we detected SQSTM1 mutations in patients with FTLD. Whether SQSTM1 is a major gene or a modifier gene in ALS and FTLD is, at present, not well defined. Additional clinical and experimental studies are needed in order to better elucidate the role of this gene in FTD and ALS pathogenesis. The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy and spastic paraplegia. Recently, mutations in the CSF1R gene were identified as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS) offering the possibility for an in-life diagnosis and further demonstrating the difficulties in the clinical diagnosis of HDLS patients. In order to better understand the genetic role of mutations in this gene we sequenced a large cohort of adult onset leukodystrophy cases. In a collaborative study we have performed whole exome sequencing of families and Sanger sequencing of CSF1R in a large cohort of mostly European patients with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a broad picture of leukodystrophy. Cases and probands had previously been investigated to rule out the acquired and suspected inherited causes of leukodystrophy. We identified twelve probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically-proven HDLS. These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene. symmetric, relatively localised (predominantly temporal lobe) atrophy (tau mutations); strongly asymmetrical, distributed atrophy (Pick's disease); and relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, FUS pathology). TDP-43 type A pathology was associated with substantial individual variation, however within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We present a novel synthesis of the findings motivated by recent evidence for diffusive network disintegration in FTLD: according to the model we propose, the neuroanatomical specificity of FTLD pathologies depends on an interaction of diseasespecific and network-specific factors, suggesting a new paradigm of pathologically determined, specific network degenerations or 'molecular nexopathies'. Introduction: Updated consensus criteria for frontotemporal dementia (FTDC), have been shown to have good sensitivity. Specificity, essential for determining diagnostic utility, has yet to be assessed. The study addressed both sensitivity and specificity of the FTDC in an independent patient cohort. Methods: Anonymised clinical data from a pathologically confirmed cohort of 224 patients from the Manchester Brain Bank were examined by two 'naïve' raters, who had no knowledge of the patients and were blind to their clinical diagnosis. The presence or absence of features listed in the FTDC was recorded on the basis of clinical historical information obtained at the time of patients' initial referral and their neuropsychological test results. To allow comparison with previous studies patients presenting with progressive aphasia were excluded from the analysis. Results: The pathological cohort comprised 72 with FTD pathologies (TDP-43, FUS and tau) and 152 with non-FTD pathologies, the majority of the latter having Alzheimer's disease. 69 of 150 patients for whom full documentation was available met clinical criteria for possible FTD, yielding an overall sensitivity of 88.5% and specificity of 76.5%. Loss of sympathy and empathy had the highest specificity (84.8%) although its sensitivity was considerably lower (61.5%). 42 patients met criteria for probable FTD, yielding a sensitivity of 76.60% and specificity of 94.06%. Background: Patients meeting clinical criteria for behavioral variant frontotemporal dementia (bvFTD) may have different pathologies. When these patients are sub-typed by autopsy findings, clinical and pathological differences may emerge. Objective: To characterize the clinicopathological differences among patients diagnosed clinically as having bvFTD. Methods: This study reviewed all patients entered as clinical bvFTD with autopsy data in the National Alzheimer's Coordinating Center's database from 1984 to 2011. Among the 100 patients identified, 5 who evolved to corticobasal degeneration or progressive supranuclear palsy were excluded. Of the remaining, 74 had frontotemporal lobar degeneration or related pathologies (FTD-FTLD) and 21 had Alzheimer's disease on pathology (FTD-AlzP). The FTD-FTLD patients were further divided them into those with tau-positive (n=23) or taunegative pathology (n=51). Results: The FTD-FTLD patients were significantly more likely to present with socioemotional personality changes and poor judgment/decision-making compared to the FTD-Alz patients, who had memory difficulty, agitation, delusions/hallucinations, and disinhibition. The tau-positive FTD-FTLD patients presented with socioemotional personality changes and had more hippocampal sclerosis compared to the tau-negative patients who had poor judgment/decision-making, apathy, disinhibition, and speech impairment. Conclusion: AD patients may be misdiagnosed with bvFTD if they have early disinhibition and other neuropsychiatric features despite greater memory difficulty and more intact personality and executive functions. Among those with FTLD pathology, taupositive bvFTD patients tend to socioemotional personality changes and hippocampal sclerosis, and tau-negative patients tend to decreased executive function and apathy. These findings offer important clues to recognition of pathological subtypes of bvFTD during life. OBJECTIVE: To evaluate the large-scale neural network that supports communicating with a conversational partner in behavioral variant frontotemporal dementia (bvFTD). BACKGROUND: bvFTD is characterized by executive and social/behavioral limitations with relative sparing of language. Successful communication requires a speaker and a conversational partner to "coordinate", or adapt their language, to optimize communicative clarity. DESIGN/METHODS: 11 bvFTD patients and 11 healthy seniors (HS) were presented with two story scenes in which a target animal character (e.g, "pig") moved from one position to another. We manipulated two factors in a counterbalanced design. In half of the scenes the target animal was embedded in a set of unique animals ("no-competitors") or in a set containing a "competitor", the same animal type (e.g., "pig") differing by a single visual features (e.g., color or size). In half of the trials participants described the scene to a "colorblind" partner or a "normal" partner. Participants were instructed to describe the scene with sufficient adjectives (e.g., "the pig" or "the large pig") so a partner could understand which animal was moving. Responses were coded for accuracy of adjective production. We used regression analyses to relate coordination limitations to gray matter (GM) in bvFTD. RESULTS: We observed a Group X Competitors interaction [F(1,20)=11.73; p < 0.005], with bvFTD patients being less accurate than HS in the context of a competitor. A regression analysis related this impairment to dorsal inferior frontal cortex (dIFC), often associated with executive limitations. We also observed a Group X Partner interaction [F(1,20)=6.70; p < 0.05]: bvFTD patients were least accurate when coordinating with a colorblind partner. A regression analysis related this limitation to ventromedial prefrontal cortex (VMPFC), often associated with ToM. CONCLUSIONS: bvFTD have limitations coordinating with a conversational partner and this may be due to a degraded large-scale network involving an executive mechanism in dIFC and a ToM mechanism in VMPFC. Background: Behavioural studies in frontotemporal dementia (FTD) have reported broad deficits in emotion recognition, regardless of clinical phenotype. Importantly, the neural correlates underlying these deficits remain unclear. The multimodal system model of emotion proposes that recognition of basic emotions (anger, disgust, fear, sadness, surprise, happiness) relies on partly dissociable neural substrates in the frontal and temporal lobes. This study aimed to establish the neural correlates of facial emotion recognition in FTD for each specific basic emotion. Methods: Performance on two facial emotion recognition tasks (Ekman 60, Ekman Caricatures) was investigated in 40 FTD patients (18 behavioural-variant FTD, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls. Task performance was correlated with changes in grey matter signal intensity using voxel-based morphometry. Results: Consistent with prior findings, recognition of all negative emotions was reduced in FTD, across both emotion recognition tasks. Voxel-based morphometry analyses identified discrete neural correlates for recognition of four basic emotions. Recognition of fear was associated with right amygdala intensity, disgust with left insula intensity, anger with left superior temporal gyrus intensity, and surprise with left inferior temporal gyrus intensity. Conclusions: This study is the first to identify discrete neural correlates for the recognition of fear and disgust in FTD. The regions identified here are consistent with prior animal, lesion, and imaging studies, lending further support to the multimodal system of emotion. Our data suggest that the emotion recognition deficits in FTD are driven by pathology in multiple, but partly dissociable, neural regions in the frontal and temporal lobes. Background: Studies of patients with semantic dementia (SD) have highlighted the importance of the anterior temporal lobes (ATL) bilaterally in supporting semantic memory. While a right hemisphere bias is present for the recognition of famous people and the processing of 16 emotions in SD, the role of the ATL in the recognition of famous tunes and musical emotions in SD is unclear. Methods: Patients with SD (n = 13), Alzheimer's disease (AD; n = 14) and a control group (n = 20) completed recognition tests for famous faces, famous tunes, facial and musical emotions as well as a structural MRI. Results: Group analyses revealed that recognition of famous tunes and emotions in music was most impaired in SD, with only mild deficits observed in AD, although some individuals with SD showed sparing of knowledge for famous tunes. MRI voxel-based morphometry analyses revealed that famous tunes recognition deficits correlated with right ATL atrophy, a region which overlapped with that involved in the recognition of famous faces. In contrast, facial and musical emotion recognition correlated with right-sided medial temporal lobe structures, such as the amygdala. Identification of musical (but not facial) emotions was also associated with left-sided structures previously attributed principally to language and verbal semantics. Conclusions: Our results show that music cognition is impaired in SD and relies on the integrity of regions within both the right and the left ATL. These findings highlight the common neural substrates which support the processing of differing semantic categories and contribute to the understanding of the neural basis of conceptual knowledge.
doi:10.1159/000342903 pmid:23007027 fatcat:io2rfqz7hndlddkrquqhkjhm7m