Amyotrophic Lateral Sclerosis Frontotemporal Dementia Research Articles

Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes?

Within the cell nucleus the nucleolus is the site of rRNA transcription and ribosome biogenesis and its activity is clearly essential for a correct cell function, however its specific role in neuronal homeostasis remains mainly unknown. Here we review recent evidence that impaired nucleolar activity is a common mechanism in different neurodegenerative disorders. We focus on the specific causes and consequences of impaired nucleolar activity to better understand the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In particular, we discuss the genetic and epigenetic factors that might regulate nucleolar function in these diseases. In addition, we describe novel animal models enabling the dissection of the context-specific series of events triggered by nucleolar disruption, also known as nucleolar stress. Finally, we suggest how this novel mechanism could help to identify strategies to treat these still incurable disorders.

Semantic deficits in amyotrophic lateral sclerosis

Our objective was to investigate, and establish neuroanatomical correlates of, semantic deficits in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD), compared to semantic dementia (SD) and controls. Semantic deficits were evaluated using a naming and semantic knowledge composite score, comprising verbal and non-verbal neuropsychological measures of single-word processing (confrontational naming, comprehension, and semantic association) from the Sydney Language Battery (SYDBAT) and Addenbrooke's Cognitive Examination – Revised (ACE-R). Voxel based morphometry (VBM) analysis was conducted using the region of interest approach. In total, 84 participants were recruited from a multidisciplinary research clinic in Sydney. Participants included 17 patients with ALS, 19 with ALS-FTD, 22 with SD and 26 age- and education-matched healthy controls. Significant semantic deficits were observed in ALS and ALS-FTD compared to controls. The severity of semantic deficits varied across the clinical phenotypes: ALS patients were less impaired than ALS-FTD patients, who in turn were not as impaired as SD patients. Anterior temporal lobe atrophy significantly correlated with semantic deficits. In conclusion, semantic impairment is a feature of ALS and ALS-FTD, and reflects the severity of temporal lobe pathology.

Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.

A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2. The previous genetic linkage approach by microsatellite haplotyping was continued in new families. A whole genome sequencing was performed to find all possibly pathogenic mutations in the linked area. The detected variations were verified by Sanger sequencing. Six new SMAJ families were identified based on the unique founder haplotype. A critical recombination in 1 family restricted the linked area to 727kb between markers SHGC-106816 and D22S345. In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families. Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. During the preparation of this article other mutations were reported to cause frontotemporal dementia-amyotrophic lateral sclerosis syndrome, indicating that the CHCHD10 gene is largely important for the motor and cognitive neuronal systems.

A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.

Frontotemporal Dementia

Back to table of contents Previous article Next article Communications and UpdatesFull AccessFrontotemporal DementiaEdward D. Huey, M.D.Edward D. HueySearch for more papers by this author, M.D.Published Online:1 Jun 2014https://doi.org/10.1176/appi.ajp.2014.14020215AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail by MillerBruce L.. New York, Oxford University Press, 2013, 200 pp., $145.00.I highly recommend Bruce Miller’s extraordinary book, Frontotemporal Dementia, to all psychiatrists for two reasons: because it is a fun, interesting, and informative read and because it is important. Unlike most medical books, which are a compilation of chapters contributed by different authors, this book is written entirely by Dr. Miller, a behavioral neurologist who has done more than anyone to treat, study, and bring this fascinating disorder to international attention. Having a single author, the book has a cohesiveness and continuity that many multiauthor medical books lack. With his extensive expertise on the topic, the book is authoritative and current. One of my favorite things about this book is how Dr. Miller’s clinical wisdom and expertise complement the discussions of research findings. There are many important issues in the field with a dearth of data, for example, the topic of slowly progressive frontotemporal dementia, and Dr. Miller supplements his discussion of the limited research on these topics with his own extensive clinical experience.The book is an engaging and well-written overview of frontotemporal dementia and related disorders. It has something to offer for clinicians and researchers at any level, from beginner to experts on this topic. Readers will come away with a broad base of knowledge about the disorders that make up the frontotemporal dementia spectrum. Dr. Miller skillfully integrates important recent research findings with the background knowledge about these disorders to give a sense of where the field is going and why those with these disorders are such an interesting group of patients to care for and study. He covers frontotemporal dementia and related disorders, including language variants and the variants that present with prominent motor symptoms such as corticobasal syndrome, progressive supranuclear palsy, and frontotemporal dementia-amyotrophic lateral sclerosis, from the genetics and neuropathological findings to the imaging findings and clinical presentation.Sections of particular interest to psychiatrists describe the insights to be gained from these patients on how emotion, empathy, the self, and social cognition are represented in the brain and what happens when these functions are disrupted. The frontal and anterior temporal lobes, more than any other part of the brain, make us “human,” and the dysfunction of these systems can lead to fascinating symptoms. Dr. Miller describes a series of his patients with frontotemporal dementia with right frontal degeneration who had dramatic alterations of self, including changes in political views and religion, and patients with right anterior temporal damage who become rigid, unbending, and lost their empathy for others. He describes creative experiments, such as one in which frontotemporal dementia patients watched a videotape of themselves singing the song “My Girl” but did not show the signs of embarrassment that healthy people show when doing this. He also reviews genetic findings with important implications for psychiatric disorders, including the recent evidence that mutations in the C9ORF72 gene frequently initially present with psychiatric syndromes including psychosis and personality disorders.I have made the case that Frontotemporal Dementia is an entertaining and informative book to read. But why is it particularly important for psychiatrists to read? Psychiatry should be especially concerned with disorders such as frontotemporal dementia that affect frontal and limbic functions, including emotion, social cognition, and behavior regulation. To date, the field of psychiatry has shown little interest in frontotemporal dementia and other neurodegenerative disorders that affect these brain regions. This creates a fundamental contradiction: We wish psychiatry to be taken seriously as a brain-based medical specialty, but we exclude patients with brain disorders that manifest with psychiatric symptoms such as frontotemporal dementia. Patients with frontotemporal dementia usually present to mental health settings and are commonly misdiagnosed with psychiatric disorders. The study of patients with frontotemporal dementia can provide unique insights into the neuroanatomy and genetics of psychiatric disorders. Having more psychiatrists read Dr. Miller’s excellent book will not fix the problem of integrating the study of frontal lobe disorders into psychiatry, but it would be a good start.Dr. Huey is the Herbert Irving Assistant Professor of Psychiatry and Neurology, Columbia University Medical Center, New York.The author reports no financial relationships with commercial interests. FiguresReferencesCited byDetailsCited ByNone Volume 171Issue 6 June 2014Pages 695-696 Metrics PDF download History Accepted 1 March 2014 Published online 1 June 2014 Published in print 1 June 2014

Frontotemporal Dementia Associated With theC9ORF72Mutation

While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort. A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia

The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF72 ALS/FTD. Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.

Repeat-associated non-ATG (RAN) translation in neurological disease

Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to frame fundamental questions on what proteins a cell synthesizes, how proteins work and to predict the consequences of mutations. For a group of neurological diseases caused by the abnormal expansion of short segments of DNA (e.g. CAG•CTG repeats), mutations within or outside of predicted coding and non-coding regions are thought to cause disease by protein gain- or loss-of-function or RNA gain-of-function mechanisms. In contrast to these predictions, the recent discovery of repeat-associated non-ATG (RAN) translation showed expansion mutations can express homopolymeric expansion proteins in all three reading frames without an AUG start codon. This unanticipated, non-canonical type of protein translation is length-and hairpin-dependent, takes place without frameshifting or RNA editing and occurs across a variety of repeat motifs. To date, RAN proteins have been reported in spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), fragile X tremor ataxia syndrome (FXTAS) and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In this article, we review what is currently known about RAN translation and recent progress toward understanding its contribution to disease.

The Disease-associated r(GGGGCC)n Repeat from the C9orf72 Gene Forms Tract Length-dependent Uni- and Multimolecular RNA G-quadruplex Structures

Certain DNA and RNA sequences can form G-quadruplexes, which can affect promoter activity, genetic instability, RNA splicing, translation, and neurite mRNA localization. Amyotrophic lateral sclerosis and frontotemporal dementia were recently shown to be caused by expansion of a (GGGGCC)n·(GGCCCC)n repeat in the C9orf72 gene. Mutant r(GGGGCC)n-containing transcripts aggregate in nuclear foci possibly sequestering repeat-binding proteins, suggesting a toxic RNA pathogenesis. We demonstrate that the r(GGGGCC)n RNA but not the C-rich r(GGCCCC)n RNA forms extremely stable uni- and multimolecular parallel G-quadruplex structures (up to 95 °C). Multimolecular G-quadruplex formation is influenced by repeat number and RNA concentration. MBNL1, a splicing factor that is sequestered in myotonic dystrophy patients by binding to expanded r(CUG)n repeat hairpins, does not bind the C9orf72 repeats, but the splicing factor ASF/SF2 can bind the r(GGGGCC)n repeat. Because multimolecular G-quadruplexes are enhanced by repeat length, RNA-RNA interactions facilitated by G-quadruplex formation at expanded repeats might influence transcript aggregation and foci formation in amyotrophic lateral sclerosis-frontotemporal dementia cells. Tract length-dependent G-quadruplex formation by the C9orf72 RNA should be considered when assessing the role of this repeat in C9orf72 gene activity, protein binding, transcript foci formation, and translation of the C9orf72 product, including the noncanonical repeat-associated non-ATG translation (RAN translation) into pathologic dipeptide repeats, as well as any oligonucleotide repeat-based therapy.

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1–q12.2: genetic, clinical and neuropathological analysis

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1078-9) contains supplementary material, which is available to authorized users.

Frontotemporal Dementia in a Brazilian Kindred With the C9orf72 Mutation

To describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations. Report of a kindred. Dementia center at a university hospital. One kindred encompassing 3 generations. The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen. Behavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.

Grey and White Matter Changes across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Continuum

There is increasing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10), ALS-FTD (n = 10) and behavioural variant FTD (bvFTD; n = 15) as well as controls (n = 18), underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum.

Rapidly progressive frontotemporal dementia and bulbar amyotrophic lateral sclerosis in Portuguese patients with C9orf72 mutation

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) form a spectrum of clinically, pathologically, and genetically overlapping disorders, as confirmed by the recent report that it can be caused by a hexanucleotide repeat expansion in C9orf72. One hundred and fourteen Portuguese cases diagnosed as probable or possible familial FTLD, as part of the EOD consortium study, and nine further Portuguese cases with familial ALS were tested for the presence of this mutation. Results showed that six Portuguese patients from unrelated families had the mutation, five (4.4%) patients from the FTLD group and one (11.1%) from the ALS sample. Of these, three patients had FTLD and rapidly progressive bulbar ALS. Electromyography confirmed diffuse loss of motor units with marked bulbar involvement. In conclusion, the cases now reported showed a very rapid progression, suggesting bulbar ALS could be particularly common and aggressive in patients with the C9orf72 hexanucleotide repeat expansion, in the Portuguese population.

Neuropsychiatric Features of C9ORF72 Mutation-Associated bvFTD and FTD-ALS (IN9-2.003)

Objective: To characterize neuropsychiatric features associated with C9ORF72 mutations in behavioral variant frontotemporal dementia (bvFTD) and FTD-amyotrophic lateral sclerosis (FTD-ALS). Background Hexanucleotide repeat expansions in the C9ORF72 gene may be the most common genetic cause of bvFTD and FTD-ALS, but the neuropsychiatric features associated with C9ORF72 mutations remain largely uncharacterized. Design/Methods: Four hundred and sixteen patients with FTD or related disorders and asymptomatic family members evaluated at UCSF were tested for C9ORF72 expansion (C9+: N=37). Eighty-six cases (C9+/bvFTD=12; C9-/bvFTD=47; C9+/FTD-ALS=11; C9-/FTD-ALS=16) underwent blinded chart review to identify first reported neuropsychiatric symptoms. Neuropsychiatric Inventory (NPI) scores at first evaluation were analyzed for all C9+ cases and a subset of C9-/bvFTD controls matched for disease severity according by MMSE and CDR-SB. Results:First neuropsychiatric symptoms: In C9+/bvFTD, delusions and aggression were more frequently reported as presenting symptoms (p=0.04). In C9+/FTD-ALS, more rash/careless actions (p=0.04) and greater disinhibition were seen (p=0.13), whereas apathy, anxiety and depression were less frequently reported (p=0.09, 0.12 and 0.12) compared to C9-/FTD-ALS patients. By first evaluation: On the NPI, C9+/bvFTD cases had less disinhibition (p=0.04), aberrant motor (p=0.03) and eating behaviors (p=0.08), but higher anxiety (p=0.12) than C9- bvFTDs. In FTD-ALS, C9+ and C9- NPI scores did not differ. Total NPI scores did not differ by genotype in either group. Conclusions: In bvFTD, C9ORF72 mutation carriers9 first neuropsychiatric symptoms are more frequently delusions and aggression. Later they develop greater anxiety than non-carriers with bvFTD but show less disinhibition or aberrant eating/motor behaviors. In FTD-ALS, C9ORF72 mutation carriers display greater disinhibition as their first symptom, but later become neuropsychiatrically indistinct from non-carriers with FTD-ALS. Further investigation in larger samples will improve differentiation of the neuropsychiatric features caused by C9ORF72 mutations. Supported by: In part by M01-RR0079 General Clinical Research Center; the National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; the State of California, Alzheimer9s Disease Research Center of California (ARCC) grant 03-7527. NIH grants R01AG038791, R01AG031278. Disclosure: Dr. Takada has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Rankin has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Fong has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis. Dr. Boxer has received personal compensation for activities with BMS, Plexxikon and Phloronol as a consultant. Dr. Boxer has received research support from Elan, Forest, Genentech, Medivation, BMS, Janssen and Pfizer Pharmaceuticals. Dr. Miller has received personal compensation for activities with Allon Therapeutics, Inc. and TauRx Therapeutics, Ltd. Dr. Miller has received research support from Novartis.

Differential Effect of the C9ORF72 Hexanucleotide Repeat on Brain Morphology in bvFTD and FTD-ALS (IN9-2.005)

Objective: To identify effects of the C9ORF72 repeat variant on brain atrophy patterns in behavioral variant frontotemporal dementia (bvFTD) and FTD-amyotrophic lateral sclerosis (ALS). Background The GGGGCC repeat in the noncoding region of C9ORF72 was recently found to be a major contributor to genetic risk for FTD and ALS in both familial and sporadic cases. Whether the C9 variant confers specific morphological characteristics to degeneration associated with bvFTD/FTD-ALS is unknown. Design/Methods: Four-hundred-sixteen patients with FTD or related disorders and asymptomatic family members evaluated at UCSF were tested for C9ORF72 expansion (C9+:n=37). DARTEL-based voxel-based morphometry (VBM) analyses of combined gray-white maps were performed on structural MRIs from 25 bvFTD cases (C9+:n=6, C9-:n=19), 9 FTD-ALS cases (C9+:n=5, C9-:n=4), and 164 cognitively normal older adults. Comparisons were analyzed for: bvFTD(C9+) versus controls; bvFTD(C9-) versus controls; interaction of (C9+)x(bvFTD) versus bvFTD(C9-) and controls; FTD-ALS(C9+) versus controls; FTD-ALS(C9-) versus controls; interaction of (C9+)x(FTD-ALS) versus FTD-ALS(C9-) and controls. Results: BvFTD(C9+) cases demonstrated greater lateral parietal (right>left) and bilateral thalamic, and less medial frontal atrophy than bvFTD(C9-) cases. A significant interaction was found where bvFTD(C9+) patients showed greater thalamic (left>right; T=5.00, p FWE =0.05; T=4.05 p uncorr uncorr uncorr left), particularly in the medial occipital lobes and cerebellum, and less medial frontal and brainstem atrophy than FTD-ALS(C9-) cases. A significant interaction was found where FTD-ALS(C9+) cases demonstrated more atrophy in the right superior frontal gyrus (T=4.73, p FWE =0.03), bilateral central sulcus (T=3.67-3.70, p FWE =0.07) and inferior frontal pars triangularis (T=3.58, p FWE =0.07). Conclusions: We found greater posterior and thalamic atrophy in C9+ than in sporadic bvFTDs, and greater posterior and less brainstem atrophy in FTD/ALS(C9+) cases. If confirmed in larger samples, these findings suggest C9ORF72 confers specific atrophy patterns to bvFTD and FTD/ALS with potential clinical ramifications. Supported by: In part by M01-RR0079 General Clinical Research Center; the National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; the State of California, Alzheimer9s Disease Research Center of California (ARCC) grant 03-7527; NIH grants R01AG038791, R01AG031278. Disclosure: Dr. Yokoyama has nothing to disclose. Dr. Takada has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Fong has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis. Dr. Boxer has received personal compensation for activities with BMS, Plexxikon and Phloronol as a consultant. Dr. Boxer has received research support from Elan, Forest, Genentech, Medivation, BMS, Janssen and Pfizer Pharmaceuticals. Dr. Miller has received personal compensation for activities with Allon Therapeutics, Inc. and TauRx Therapeutics, Ltd. Dr. Miller has received research support from Novartis. Dr. Rankin has nothing to disclose.

Screening for C9ORF72 repeat expansion in FTLD

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Frontotemporal Dementia-amyotrophic Lateral Sclerosis Complex is Simulated by Neurodegeneration With Brain Iron Accumulation

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.