Autosomal Dominant Frontotemporal Dementia Research Articles

Life’s Simple 7 Relates to Better Cognitive and Brain Health in Individuals with Autosomal Dominant Frontotemporal Dementia

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.

Pathogenic tau decreases nuclear tension in cultured neurons.

Neurodegenerative tauopathies, including Alzheimer's disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer's disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex.

Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood-brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Background: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. Case Presentation: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. Conclusion: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion.

To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion (C9orf72RE). Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontotemporal dementia (FTD). We investigated group differences in cognitive function, gray matter volume through voxel-based morphometry, and white matter integrity by means of tract-based spatial statistics. We correlated cognitive change with underlying gray or white matter. Our data demonstrate lower scores on letter fluency, Stroop card I, and Stroop card III, accompanied by white matter integrity loss in tracts connecting the frontal lobe, the thalamic radiation, and tracts associated with motor functioning in presymptomatic C9orf72RE compared with HC. In a subgroup of C9orf72RE carriers above 40 years of age, we found gray matter volume loss in the thalamus, cerebellum, and parietal and temporal cortex. We found no significant relationship between subtle cognitive decline and underlying gray or white matter. This study demonstrates that a decline in cognitive functioning, white matter integrity, and gray matter volumes are present in presymptomatic C9orf72RE carriers. These findings suggest that neuropsychological assessment, T1-weighted MRI, and diffusion tensor imaging might be useful to identify early biomarkers in the presymptomatic stage of FTD or amyotrophic lateral sclerosis.

Effects of Multiple Genetic Loci on Age atOnset in Frontotemporal Dementia.

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia that show overlapping clinical symptoms. The aim of this study was to perform genetic analyses on GRN, VCP, CHMP2B, FUS, TARDBP, C9orf72 and MAPT genes in Chinese AD and FTD patients. We performed gene sequencing of the GRN, VCP, CHMP2B, FUS, TARDBP, MAPT and C9orf72 genes in 61 clinical AD and 38 FTD Chinese patients. We identified a known mutation of MAPT (p.Pro301Leu, c.902C>T) in four patients from an autosomal dominant FTD family with behavioral variant FTD (bvFTD) and progressive nonfluent aphasia (PNFA) phenotypes, and a novel mutation in MAPT (p.Leu48Val, c.142 G>C) in a sporadic progressive supranuclear palsy patient. Two novel variations in VCP (p.Thr127Ala, c. 379A>G; p.Asn401Ser, c.1202A>G) were present in both a sporadic FTD and an AD case, and a novel deletion in GRN (560del p.Leufs) was found in a sporadic primary progressive aphasia patient. Mutations of VCP, GRN and MAPT genes are present in Chinese FTD cases. In the case of the MAPT mutation, the family presented with both bvFTD and PNFA phenotypes, while the VCP mutation was also related to an early-onset AD phenotype.

C9ORF72 repeat expansion is not detected in sporadic ataxia patients in mainland China

Expansion of a GGGGCC hexanucleotide repeat in the gene C9ORF72 is a common pathogenic mutation in families with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In order to understand whether pathogenic GGGGCC expansions of C9ORF72 are associated with spinocerebellar ataxia (SCA) in mainland China, we performed an experiment to determine the prevalence of pathogenic hexanucleotide expansions of C9ORF72 in a large cohort of Chinese Han patients with SCA. 411 sporadic patients with SCA and 314 healthy controls were screened for pathogenic hexanucleotide expansions of C9ORF72 utilizing a repeat primed polymerase chain reaction assay. However, no pathological repeat expansion of C9ORF72 was detected in either patients or controls. We therefore conclude that an expansion in C9ORF72 may not play a significant role in SCA in our cohort. However, more studies are needed to draw conclusions for the general population.

Genetics in Degenerative Dementia

An increasing number of hereditary neurodegenerative diseases, including autosomal-dominant Alzheimer disease (AD), familial autosomal-dominant frontotemporal dementia (FTD), and heritable Lewy body disease (LBD) have been defined at the molecular level in recent years, making it possible to determine the genotype before the onset of symptoms. The identification of deterministic genes for these common adult-onset genetic diseases is moving the field of genetic counseling toward a new and challenging direction. With the identification of genes associated with AD and FTD, there is considerable interest in the clinical application of genetic information in genetic counseling and testing. Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians therefore increases the need for a better understanding of the multifaceted issues associated with genetic testing. The aims of this systematic review are: (1) to underline the need to consider a genetic etiology of AD, FTD, and LBD; (2) to provide clinicians with information necessary to effectively translate genetic diagnosis into clinical practice; and (3) to highlight gaps and uncertainties in the field which will need to be addressed by future research.

The missing tau mutation: + 15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17

WCN 2013 No: 2532 Topic: 2 — Movement Disorders The missing tau mutation: +15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17 R. Lonergan, A. McCarthy, S. O'Dowd, B. Magennis, E. Fallon, M. Spillantini, M. Hutton, T. Lynch. Neurology, Mater Misericordiae Hospital, Dublin, Ireland; Molecular Neurology, Addenbrooke's Hospital, Cambridge, UK; Eli Lilly and Company, London, UK Background: Up to 40% of families with autosomal dominant frontotemporal dementia with parkinsonism (AD FTDP-17) carry pathogenic 5′ splice site mutations in the Microtubule-Associated Protein Tau (MAPT) gene. Several stem-loop mutations of tau exon 10 were identified, but the +15 mutation remained elusive. Aim: We present a family with the ‘missing’ +15 mutation. Case: A 44 year old man developed progressive disinhibition, apathy and simultaneous amnestic syndrome. Neurological examination normal (primitive reflexes/disinhibition). Pedigree: autosomal dominant young-onset dementia. Investigations: MRI brain — moderate bitemporal atrophy; PET CT — low anterior temporal activity. CSF — raised protein: phosphorylated tau/beta-amyloid normal. Fluorescent sequencing analysis for familial tau variant: sequence variant c.915 + 15A N C, at exon 10/intron 10 boundary of MAPT gene. Identical variant in first cousin. Discussion: In 1998, Hutton described 5′ splice site mutations in tau, associated with FTDP-17, destabilising a stem-loop structure, causing alternate splicing of exon 10. The predicted +15 A N C mutation at intron 10 was ‘missing’ until now. In this unique family, the proband had profound short-term amnesia and behavioral change, suggesting atypical familial Alzheimer disease or atypical FTDP-17. Detection of novel +15 mutation clarified diagnosis of FTDP-17 and informed genetic counselling. Finding this mutation 14 years after prediction highlights value of pursuing complete family history to guide appropriate molecular genetic testing. doi:10.1016/j.jns.2013.07.549 Abstract — WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline M. Yucel, H. Akgun, S. Tasdemir, S. Alay, O. Oz, E. Eroglu, S. Demirkaya. Department of Neurology, Kasimpasa Military Hospital, Istanbul, Turkey; Department of Neurology, Etimesgut Military Hospital, Ankara, Turkey; Department of Neurology, Gulhane Military Medical Academy, Ankara, Turkey Background: Orthostatic tremor is known as a lower extremity tremor occurring when standing. When a person stands, typical high frequency (13–18 Hz) tremor develops, and disappears with walking, sitting or continuous volatile leg movement. Objective: In this report we presented a patient with tremor on the lower limbs diagnosed with Parkinson's disease. Patients and methods: A 58-year-old female patient presented to our outpatient clinic with complaints of trembling in the body when standing, lasting for 1 year. The neurological examination revealed bradykinesia of the lower and upper right limbs, rigidity and rest tremor of the right hand and trembling of the lower limbs when standing. Results: The brain MRI and the routine nerve conduction studies were normal. The superficial electrode recordings of femoris, anterior tibialis, biceps femoris muscles documented a tremor of 13 Hz. The patient was diagnosed with Parkinson's disease accompanied by orthostatic tremor and was started 2 mg of Rasagiline. Significant improvement was noted. Conclusion: We found this case worth reporting because of the rare presentation of Parkinson's disease in the literature with orthostatic symptoms as a first sign. doi:10.1016/j.jns.2013.07.550 Abstract — WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea D. Petrlenicova, M. Kucharik, M. Saling. 2nd Dept. of Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava, Bratislava,

Orthostatic tremor responding to Rasagiline

WCN 2013 No: 2532 Topic: 2 — Movement Disorders The missing tau mutation: +15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17 R. Lonergan, A. McCarthy, S. O'Dowd, B. Magennis, E. Fallon, M. Spillantini, M. Hutton, T. Lynch. Neurology, Mater Misericordiae Hospital, Dublin, Ireland; Molecular Neurology, Addenbrooke's Hospital, Cambridge, UK; Eli Lilly and Company, London, UK Background: Up to 40% of families with autosomal dominant frontotemporal dementia with parkinsonism (AD FTDP-17) carry pathogenic 5′ splice site mutations in the Microtubule-Associated Protein Tau (MAPT) gene. Several stem-loop mutations of tau exon 10 were identified, but the +15 mutation remained elusive. Aim: We present a family with the ‘missing’ +15 mutation. Case: A 44 year old man developed progressive disinhibition, apathy and simultaneous amnestic syndrome. Neurological examination normal (primitive reflexes/disinhibition). Pedigree: autosomal dominant young-onset dementia. Investigations: MRI brain — moderate bitemporal atrophy; PET CT — low anterior temporal activity. CSF — raised protein: phosphorylated tau/beta-amyloid normal. Fluorescent sequencing analysis for familial tau variant: sequence variant c.915 + 15A N C, at exon 10/intron 10 boundary of MAPT gene. Identical variant in first cousin. Discussion: In 1998, Hutton described 5′ splice site mutations in tau, associated with FTDP-17, destabilising a stem-loop structure, causing alternate splicing of exon 10. The predicted +15 A N C mutation at intron 10 was ‘missing’ until now. In this unique family, the proband had profound short-term amnesia and behavioral change, suggesting atypical familial Alzheimer disease or atypical FTDP-17. Detection of novel +15 mutation clarified diagnosis of FTDP-17 and informed genetic counselling. Finding this mutation 14 years after prediction highlights value of pursuing complete family history to guide appropriate molecular genetic testing. doi:10.1016/j.jns.2013.07.549 Abstract — WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline M. Yucel, H. Akgun, S. Tasdemir, S. Alay, O. Oz, E. Eroglu, S. Demirkaya. Department of Neurology, Kasimpasa Military Hospital, Istanbul, Turkey; Department of Neurology, Etimesgut Military Hospital, Ankara, Turkey; Department of Neurology, Gulhane Military Medical Academy, Ankara, Turkey Background: Orthostatic tremor is known as a lower extremity tremor occurring when standing. When a person stands, typical high frequency (13–18 Hz) tremor develops, and disappears with walking, sitting or continuous volatile leg movement. Objective: In this report we presented a patient with tremor on the lower limbs diagnosed with Parkinson's disease. Patients and methods: A 58-year-old female patient presented to our outpatient clinic with complaints of trembling in the body when standing, lasting for 1 year. The neurological examination revealed bradykinesia of the lower and upper right limbs, rigidity and rest tremor of the right hand and trembling of the lower limbs when standing. Results: The brain MRI and the routine nerve conduction studies were normal. The superficial electrode recordings of femoris, anterior tibialis, biceps femoris muscles documented a tremor of 13 Hz. The patient was diagnosed with Parkinson's disease accompanied by orthostatic tremor and was started 2 mg of Rasagiline. Significant improvement was noted. Conclusion: We found this case worth reporting because of the rare presentation of Parkinson's disease in the literature with orthostatic symptoms as a first sign. doi:10.1016/j.jns.2013.07.550 Abstract — WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea D. Petrlenicova, M. Kucharik, M. Saling. 2nd Dept. of Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava, Bratislava,

Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.

Frontotemporal Dementia Caused by CHMP2B Mutations

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.

Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p

Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.

Rs5848 polymorphism and serum progranulin level

Objective To assess the influence of rs5848 polymorphism in serum progranulin (PGRN) level in a cohort of subjects with Alzheimer and related dementias from a tertiary referral clinic. Background Mutations in the GRN gene cause autosomal dominant frontotemporal dementia (FTD) with TDP-43 pathology (FTLD-TDP) through haploinsufficiency. It has recently been shown that homozygous carriers of the T allele of rs5848 have an elevated risk of developing FTD, and this polymorphism may play a role in the pathogenesis of other dementia by modifying progranulin level. We hypothesize that genotype of rs5848 may influence serum PGRN level in AD, FTD, and other dementias. Methods Blood samples were obtained from patients with cognitive impairment and dementia referred to a tertiary dementia clinic, as well as samples from a cohort of healthy controls. Serum PGRN level was measured using an ELISA assay, and rs5848 genotype was determined by a TaqMan assay. Results We found that rs5848 SNP significantly influenced serum PGRN level, with TT genotype having the lowest levels, and CC as the highest. This relationship is observed in each of the subgroups. We also confirmed that GRN mutation carriers had significantly lower serum PGRN levels than all other groups. Conclusions The rs5848 polymorphism significantly influences serum PGRN with TT carriers having a lower level of serum PGRN then CT and CC carriers. This is consistent with the finding that miR-659 binding to the high risk T allele of rs5848 may augment translational inhibition of GRN and alter risk of FTD and possibly other dementias.

Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia

Autosomal dominant frontotemporal dementia (FTD) due to mutations in the MAPT gene is referred to as FTD with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). Typically the disease begins in the sixth decade of life. We report a novel exon 12 mutation in MAPT (S356T), in a family with an exceptionally early age at onset (27 and 29 years), causing familial behavioural variant frontotemporal dementia. Both the proband and the proband's father were initially diagnosed as having schizophrenia. Pathological examination showed frontotemporal lobar degeneration with extensive neuronal and glial tau deposition. This mutation is one of a small group of MAPT mutations (including P301S, G335V and S352L) that cause very early onset FTDP-17T. It is likely that the early age at onset reflects a marked pathogenic effect of the mutation involving a disturbance of microtubule binding, tau phosphorylation or a major acceleration of tau aggregation.

Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS)

BackgroundAmyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3–10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis.Methodology/Principal FindingsSequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B.Conclusions/SignificanceWe conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS.We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.

A Reassessment of the Neuropathology of Frontotemporal Dementia Linked to Chromosome 3

A large Danish family has previously been reported in which autosomal dominant frontotemporal dementia (FTD) is genetically linked to chromosome 3 (FTD-3). A mutation was recently identified in the CHMP2B gene that is probably responsible for causing disease in this family. Because of its neuropathologic findings, FTD-3 was originally categorized as a subtype of frontotemporal lobar degeneration, termed "dementia lacking distinctive histopathology." We now report a reevaluation of the neuropathologic changes in this family. Postmortem material from 4 affected family members was available for examination. Gross examination revealed generalized cortical atrophy that was most severe in frontal and temporal cortices. Microscopy showed loss of cortical neurons, microvacuolation of layer II, mild gliosis, and demyelination of the deep white matter. Results of immunohistochemical staining for alpha-synuclein, prion protein, neurofilament, and tau protein were unremarkable. Variable numbers of small, round, ubiquitin-positive cytoplasmic inclusions were present in the dentate granule layer of the hippocampus in all 4 cases. Rare ubiquitin-positive inclusions were also found in frontal and temporal cortical neurons. These inclusions were also positive for p62 but not for TDP-43. The finding of ubiquitin- and p62-positive, TDP-43-negative cytoplasmic inclusions in the hippocampus and neocortex suggests reclassification of the neuropathology of FTD-3 as a unique subtype of frontotemporal lobar degeneration with ubiquitin-positive inclusions that are TDP-43-negative.

Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation

Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia

Mutations in the CHMP2B gene have been recently identified in a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). We report the frequency of CHMP2B mutations in 162 FTD patients recruited from a large population-based study of FTD carried out in The Netherlands. Our results suggest that mutations in CHMP2B are a rare cause of FTD as compared to MAPT mutations.