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ObjectiveTo determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.MethodsWe recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.ResultsAsymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.ConclusionFrontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

Corticobasal degeneration (CBD) may be expressed as an atypical parkinsonism with a mean disease survival of about 7 years,(1) the shortest reported survival being 24 months.(2) We report a patient with corticobasal syndrome (CBS) and pathology-confirmed CBD whose 10-month course was manifested as a frontal alien hand evolving into agrypnia excitata.

Objective:To specify the presenting symptoms and clinical course of patients with frontotemporal dementia (FTD) and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion.Background:The 2011 discovery of the C9ORF72 repeat expansion causing familial FTD and amyotrophic lateral sclerosis has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish carriers of the C9ORF72 mutation from other patients with FTD. Prior reports identified a subset of patients with FTD who had an unusually high prevalence of psychosis, although their specific symptoms had not yet been fully described.Methods:From a cohort of 62 patients with FTD, we conducted a retrospective chart review of 7 patients who had C9ORF72 mutations on genetic testing, and 1 untested sibling of a C9ORF72 carrier.Results:Detailed histories revealed a higher prevalence of psychosis, including visual and auditory hallucinations and delusions, in the 8 C9ORF72 carriers than in our patients with sporadic FTD.Conclusions:This cohort confirms and adds clinical details to the reports of a high prevalence of psychotic phenomena in patients who have C9ORF72 mutations as well as FTD or amyotrophic lateral sclerosis.

Objective: Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD. Methods: We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed. Results: We identified CSF1R mutations in both POLD families: in family 5901, we found c. 2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wildtype CSF1R. Conclusions: We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity. Neurology (R) 2013; 80: 1033-1040

Objective: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion. Methods: A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS). Results: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. Conclusions: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature. Neurology (R) 2012;79:1002-1011

Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion. Neurology (R) 2012;79:566-574

Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubule-associated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN = 6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p = 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure. Neurology (R) 2011; 77: 393-398

Objective: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). Methods: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. Results: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. Conclusions: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions. Neurology (R) 2011;76:475-483

Objective: To determine the proton magnetic resonance spectroscopy (H-1 MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study. Methods: Patients with MAPT mutations (N279K, V337M, R406W, IVS9-10G>T, P301L) from 5 different families (n = 24) underwent MRI and single voxel H-1 MRS from the posterior cingulate gyrus inferior precuneus at 3 T. Ten of the patients were symptomatic with median Clinical Dementia Rating sum of boxes score (CDR-SOB) of 6.5 and 14 patients were presymptomatic with CDR-SOB of 0. Age-and sex-matched controls (n = 24) were recruited. Results: Symptomatic MAPT mutation carriers were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a possible marker for glial activity, decreased NAA/mI, and hippocampal atrophy (p < 0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p < 0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/Cr (R-2 = 0.22; p = 0.021) and hippocampal volumes (R-2 = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers. Conclusion: H-1 MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the H-1 MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. H-1 MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies. Neurology (R) 2010;75:771-778

Background: Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau ( MAPT ) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin ( PGRN ) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs). Methods: PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations. Results: PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations. Conclusion: PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.

Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.1,2 At autopsy, α-synuclein–positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease–related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.2 The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein ( SNCA ) and APOE loci as influencing the individual risk to DLB.3 These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD. Acknowledgment: The authors thank all those who have contributed to their research, particularly the patients and families who donated DNA samples and brain tissue for this work.

Yu et al.1 investigated the association of TMEM106B variants with TAR-DNA binding protein 43 (TDP-43) pathology in elderly individuals without frontotemporal lobar degeneration (FTLD-TDP). They also examined whether these associations were independent of comorbid pathologic processes, such as Alzheimer disease (AD) and hippocampal sclerosis (HS). The results confirmed earlier findings that TMEM106B variants are an important TDP-43 pathology risk factor in FTLD-TDP, sporadic amyotrophic lateral sclerosis, AD, tangle predominant dementia, and Lewy body disease.2,–,4 The …

Amyotrophic lateral sclerosis (ALS) is a neurologic disorder, characterized by progressive degeneration of both upper and lower motor neurons in the brain and spinal cord. Previous genetic studies have identified mutations in Cu/Zn superoxide dismutase ( SOD1 ), transactive response binding protein

Objective: To compare and contrast the features of parkinsonism in cases with different genetic mutations associated with frontotemporal lobar degeneration (FTLD). Background FTLD has been associated with mutations in the microtubule associated protein tau ( MAPT) , progranulin (PGRN) and the GGGGCC hexanucleotide repeat expansion in the open reading frame 72 on chromosome 9 ( C9ORF72 ). Several of affected individuals with an FTLD syndrome exhibited parkinsonism. The specific features of parkinsonism associated with these mutations have not been well-characterized. Design/Methods: Using data collected prospectively on the UPDRS during the course of yearly visits, we analyzed all the parkinsonian features of the patients affected by one of the three mutations. Results: We compared 14 cases with C90RF72 , 12 with PGRN and 12 with MAPT that had parkinsonism. A symmetric akinetic-rigid parkinsonism phenotype was present in the majority of the cases. Hypomimia and bradykinesia were the most common features. Tremor was present in 5% of the cases with C90RF72 , 18% with MAPT , and absent in all cases with PGRN . None in whom levodopa therapy was administered benefited from treatment. Conclusions: Although some variability exists, among those with familial FTLD associated with mutations in C90RF72, PGRN and MAPT mutations, the parkinsonian features are typically akinetic rigid and symmetric without a significant presence of tremor. Supported by: Grants AG016574, AG006786, the ALS Association, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer s Disease Research Program of the Mayo Foundation. Disclosure: Dr. Savica has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Adeli has nothing to disclose. Dr. Boot has nothing to disclose. Dr. Kuntz has received research support from Cephalon, Inc. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Boeve has nothing to disclose.

Objective: To recognize the variable presentation of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) due to C9ORF72 mutation. Background FTD and ALS are closely related syndromes with common pathological substrates. Recent identification of mutations in the C9ORF72 gene as a cause of both familial FTD and ALS further highlights their relationships. In this study we analyzed the clinical presentation from 16 unrelated families with proven mutation in the C9ORF72 gene. Design/Methods: Subjects were recruited from families with proven FTLD-TDP pathology for longitudinal assessment. Clinical charts were also retrospectively reviewed in deceased subjects. The GGGGCC hexanucleotide repeats were detected by repeat-primed PCR reaction and RNA-FISH confirmation. Clinical diagnosis of FTD was based on Neary criteria and ALS diagnosis was based on El Escorial criteria. The presence of clinical features was scored using a semiquantitative grading system (0, absent; 1, mild; 2, moderate; 3, severe). Results: Thirty subjects (70% male) from 16 unrelated families with proven C9ORF72 mutation were identified. Age of onset ranged from 34 to 74. Initial diagnoses included 15 bvFTD, 9 ALS, 1 FTD-ALS, 2 alcoholic dementia, 1 mild cognitive impairment, 1 psychosis/schizophrenia, and 1 atypical Alzheimer disease. The common presenting symptoms are behavioural (47%) and language (47%), followed by executive dysfunction (40%), affective changes (40%), motor weakness (33%), memory problems (30%), and extrapyramidal symptoms (10%). ALS increased to 50% of the subjects in longitudinal follow up, and had a negative impact on survival (2.8 yrs +/- 1.5 with ALS vs. 8.4 +/- 3.8 without ALS). Conclusions: While patients with FTD and ALS associated with C9ORF72 hexanucleotide expansion have a common molecular mechanism and typical pathology, their initial clinical presentations can be quite variable and may overlap with other clinical syndromes. Early recognition requires a high clinical acumen. Other genetic or environmental factors may influence the presentation of clinical phenotype. Supported by: Canadian Institutes of Health Research [operating grants #179009, #74580] and the Pacific Alzheimer Research Foundation [center grant C06-01]. Disclosure: Dr. Hsiung has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Feldman has received personal compensation for activities with Bristol-Myers Squibb Company as an employee. Dr. Feldman holds stock and/or stock options in Bristol-Myers Squibb Company. Dr. Sengdy has nothing to disclose. Dr. Bouchard-Kerr has nothing to disclose. Dr. Dwosh has nothing to disclose. Dr. Leung has nothing to disclose. Dr. Fok has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Mackenzie has nothing to disclose.

Objective: To review the phenotype of patients with ALS and FTD/ALS in c9FTD/ALS. Background A hexanucleotide repeat expansion in C9ORF72 recently reported as a major cause of familial ALS, FTD/ALS and FTD, designated c9FTD/ALS, also was found in sporadic ALS and FTD patients (doi:10.1016/j.neuron.2011.09.010; doi:10.1016/j.neuron.2011.09.011). Few data regarding the c9FTD/ALS phenotype in ALS and FTD/ALS are available. Design/Methods: 231 patients with ALS or FTD/ALS identified at the Mayo Clinic Florida ALS Center were screened for the c9FTD/ALS mutation. Patients completed a standard ALS diagnostic evaluation including EMG, and neuropsychological testing where indicated. Autopsy was performed in 5 mutation carriers. Results: Eighteen patients (15 ALS (9 male); 3 FTD/ALS (1 male; cognitive dysfunction preceded ALS in 2) representing 17 independent pedigrees had a c9FTD/ALS mutation. FTD suspected in 2/15 ALS patients was not confirmed owing to motor impairment. Nine probands reported first/second degree relatives with ALS or FTD/ALS; 5 probands reported relatives with FTD/dementia only and 2 probands reported no family history of ALS or FTD/dementia. One proband was adopted. All patients had El Escorial possible/probable/definite ALS except for a male with suspected ALS. Onset was bulbar in 2 patients (1 ALS; 1 FTD/ALS) and spinal in 16. Median onset age was 56 years (41-72yr). Median survival was 2.3 years (1-6.3yr) in 11 deceased; brain/spinal cord in 5 demonstrated TDP-43 pathology typical of ALS, with extramotor brain pathology in 2 FTD/ALS. Conclusions: The c9FTD/ALS phenotype of our patients was predominantly classical ALS with spinal onset. Frontotemporal cognitive impairment antedated motor signs in 2/3 FTD/ALS. Survival ranged from 1 to >6 years. c9FTD/ALS in 2 sporadic ALS patients may represent incomplete penetrance, incomplete ascertainment or new mutations and requires further study. Occurrence of FTD alone in family members supports consideration of FTD in first or second degree relatives of ALS patients as a potential marker of c9FTD/ALS. Supported by: ALS Association, Mayo Foundation and MCF ALS Center donor funds, NIH R01 NS065782 and R01 AG026251, NIH/NINDS 1RC2NS070276, NS057567, P50NS072187-01S2, Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Disclosure: Dr. Boylan has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Desaro has nothing to disclose. Dr. Johnston has nothing to disclose. Dr. Kryston has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Dickson has nothing to disclose. Dr. Rademakers has nothing to disclose.

Objective: To describe the MRI characteristics of HDLS patients with a known gene mutation on chromosome 5. Background Adult-onset leukoencephalopathies are a heterogeneous group of rare disorders, with natural histories ranging from being asymptomatic to inexorably progressive and fatal. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first described in 1984, and is an autosomal dominant disorder. Currently, 23 HDLS reports have been published. The pathological hallmark of HDLS is cerebral white matter lesions (WML) with axonal spheroids.Recently, a chromosome 5 mutation, CSF1R , was identified. Design/Methods: Twenty brain MRIs of 15 patients with autopsy/biopsy verified HDLS and chromosome 5 mutations were reviewed. Sagittal T1-, axial T1-, T2- weighted, and FLAIR images were assessed for distribution of WML, grey matter involvement, and atrophy. Results: In this study, the mean age of onset was 44 years (range, 19-71); mean disease duration was 5 years (range, 3-11); and the mean age at death was 50 years (30-75). 80 % (12/15) demonstrated focal WML, whereas in two the lesions were patchy. One patient had generalized WMLs. All patients had bilateral, though slightly asymmetric lesions. WMLs with frontal predominance, involving deep and subcortical regions, were found in all cases. 93 % (14/15) had periventricular involvement, while 73% (11/15) had involvement of the corpus callosum. Of the latter, seven had more than one callosal segment affected and five had involvement of the entire corpus callosum. Typically, brain atrophy was present in the same region as the WMLs; however, in three cases isolated atrophy of the parietal, occipital and temporal cortices were found, respectively. Central atrophy was invariably present. Corticospinal tract involvement occurred late in the disease course. The grey matter, brain stem and cerebellum were spared, and enhancement was absent. Conclusions: MRI is valuable in helping to define the natural history of HDLS and will be useful in assessing future treatment responses. The MRI patterns of HDLS are sufficiently typical to aid in diagnosis. Supported by: ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). SF is partially supported by MCF Research Committee CR program ( MCF #90052030). CS was partially supported by Anna-Lisa och Bror Bjornssons-, Sven and Dagmar Salens-, Signe och Olof Wallenius- and Gamla Tjanarinnor Foundations, Sweden. The Swedish Society of Medicine Gothenburg (GLS), Sweden, The Swedish Society of Medicine Sweden, The Swedish and Gothenburg Societies for the Neurologically Disabled and The Gothenburg Foundation for Neurological Research. Disclosure: Dr. Sundal has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Van Gerpen has nothing to disclose. Dr. Wider has nothing to disclose. Dr. Aasly has nothing to disclose. Dr. Shuster has nothing to disclose. Dr. Ghetti has received personal compensation for activities with Bayer Pharmaceuticals Corporation. Dr. Ghetti has received research support from the National Institute of Health. Dr. Garbern has received personal compensation for activities with Genzyme Corporation, Lundbeck Research USA, Inc., StemCells, Inc, and Serono, Inc. as a consultant and/or speaker. Dr. Garbern has received personal compensation in an editorial capacity for Medlink Neurology. Dr. Garbern has received research support from Genzyme Corporation. Dr. Tselis has received research support from Teva Neuroscience and Biogen Idec. Dr. Swerdlow has received personal compensation for activities with Eisai, Inc. as a consultant. Dr. Miller has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Broderick has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Roeber has nothing to disclose.

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.

Objective: To describe two patients with slowly progressive behavioral variant frontotemporal dementia (bvFTD-SP) who harbor the C9ORF72 hexanucleotide repeat expansion. Background Some patients meeting bvFTD diagnostic criteria progress slowly and plateau at a mild symptom severity. Previously, such patients who feature stable longitudinal brain imaging showing mild atrophy not suggestive of typical bvFTD, have been referred to as bvFTD "phenocopies." The few post-mortem studies available on bvFTD-SP patients did not find FTLD neuropathology, suggesting that bvFTD-SP is a clinical syndrome that mimics true FTD. Here we describe two bvFTD-SP cases with FTD/ALS-associated C9ORF72 mutations. Design/Methods: We reviewed clinical data from 82 patients meeting FTDC consensus criteria for possible bvFTD, without motor neuron disease at initial evaluation, who had been screened for the C9ORF72 expansion. Patients were categorized as bvFTD-SP if they subsequently showed minimal progression on neurological, neuropsychological and imaging evaluations, with stable symptoms for at least five years without atrophy characteristic of bvFTD. Results: Four of 82 patients screened were categorized as bvFTD-SP, including 2/15 (13.3%) of C9ORF72 mutation carriers and 2/67 (3.0%) non-carriers. Over a follow-up period ranging from 2-6 years, all four bvFTD-SPs had milder cognitive deficits compared to typical bvFTDs, and all lacked characteristic bvFTD imaging abnormalities. As measured by voxel based morphometry, one C9ORF72-positive patient had predominantly thalamic atrophy and the other displayed a non-specific pattern of cortical atrophy without medial or orbito-insular frontal atrophy characteristic of bvFTD. Both C9ORF72 mutation carriers had a family history of late-life behavioral disorders, whereas neither of the non-carriers had a family history suggestive of neurodegenerative disease. Conclusions: Slowly progressive bvFTD can result from the C9ORF72 hexanucleotide expansion. Clinicians should consider genetic causes when evaluating a patient with slowly progressive bvFTD, especially when faced with a family history of neurodegenerative disease. 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 and R01AG031278. Disclosure: Dr. Khan has nothing to disclose. Dr. Rankin has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Takada has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Fong has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Rosen 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.

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.

Objective: To investigate the cognitive endophenotype associated with the GGGGCC repeat in C9ORF72 in subjects with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) compared to FTD subjects with no known mutations in C9ORF72, MAPT, or PGRN . Background We have previously shown that the cognitive profile in subjects with the GGGGCC expansion in C9ORF72 is characterized by slowed processing speed, executive dysfunction, and impairment in phonemic word fluency. However, this phenotype is not unique to C9ORF72 and resembles the well-known phenotypic characteristics of FTD. Thus, it remains unclear how the cognitive deficits associated with C9ORF72 may differ from the FTD phenotype in subjects without any known mutation. Design/Methods: Subjects were enrolled in Mayo Clinic Alzheimer9s Disease Research Center (ADRC) or Alzheimer9s Disease Patient Registry (ADPR). FTD/ALS subjects with the C9ORF72 mutation (“ C9ORF72 subjects,” n=25) and FTD subjects without any known mutations in C9ORF72, MAPT , and PGRN (n=65) who had neuropsychological data were identified. The neuropsychological battery included tests of attention/executive functions (Digit Span, Trailmaking-B, Stroop), processing speed (Trailmaking-A), language (phonemic and semantic word fluency, Boston Naming), and memory (Logical Memory and Auditory Verbal Learning Test, AVLT). All test scores were converted into age-corrected z-scores. Results: C9ORF72 subjects were younger (57.2 ± 9.1) than FTD subjects without any mutation (66.9 ± 9.8) (p C9ORF72 subjects showed marked deficits in executive functions, speed, and phonemic fluency, but not delayed recall. Compared to those without any known mutations, C9ORF72 subjects performed worse on Trailmaking-B (p = .002), Stroop (p = .04), and phonemic fluency (p = .05), yet significantly better on Logical Memory (p Conclusions: Although a common phenotype exists characterized by impairment in speed, executive functions, and phonemic fluency, subjects with the C9ORF72 mutation demonstrate significantly worse cognitive impairment compared to FTD subjects without any known mutations. Disclosure: Dr. Pedraza has nothing to disclose. Dr. Boeve has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Fields has received personal compensation for activities with Medtronic, Inc., as a consultant. Dr. Machulda has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Josephs has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Ferman has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Ivnik has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Boylan has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rademakers has nothing to disclose.