Microtubule-associated Protein Tau Mutations Research Articles

Grey matter differences in genetic frontotemporal dementia: Results from the genfi study

Frontotemporal dementia (FTD) is the second most common early onset dementia. Around a third of cases are caused by an autosomal dominant mutation in one of three genes: Chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT). In this study, we examined structural grey matter (GM) differences in these three different genetic groups using voxel based morphometry on volumetric T1 magnetic resonance images (MRI) acquired as part of the multicentre Genetic FTD Initiative (GENFI). Participants were enrolled from 12 sites within the GENFI consortium. Those that had a volumetric T1 MRI of suitable quality and known genetic status were included in the study, resulting in 272 participants. Of these, 127 were mutation negative controls, 105 were presymptomatic mutation carriers, and 40 were symptomatic carriers (see Table). All image processing was performed using SPM12 with tissue segmentation, spatial normalization to a study specific template (modulating the warped GM maps), and finally smoothing using a 6mm full width half maximum Gaussian kernel. Statistical parametric maps were generated to determine GM differences between non-carriers and groups defined by mutation and clinical status (presymptomatic or symptomatic). The model corrected for acquisition site, total intracranial volume, gender, and age. In the symptomatic carriers, frontal and temporal atrophy was present in all three genetic groups compared with controls (p<0.05 FWE corrected for multiple comparisons). However differences were seen, with MAPT mutations having predominantly anterior temporal and orbitofrontal atrophy, GRN mutations having insula, prefrontal and striatal involvement, and the C9orf72 group having more widespread cortical as well as thalamus and superior cerebellar atrophy. In the presymptomatic carriers at a significance level of p<0.001 uncorrected, involvement of similar areas was seen in all three groups, with the most significant areas being in the temporal lobe in the MAPT mutation group, the frontal lobe in the GRN mutation group and the thalamus in the C9orf72 group. Presymptomatic atrophy can be seen in all three groups in similar areas to those seen in the symptomatic carriers but to a lesser extent. Different patterns are present in the three mutation groups.

A novel tau mutation, p.K317N, causes globular glial tauopathy

Globular glial tauopathies (GGTs) are 4-repeat tauopathies neuropathologically characterized by tau-positive, globular glial inclusions, including both globular oligodendroglial inclusions and globular astrocytic inclusions. No mutations have been found in 25 of the 30 GGT cases reported in the literature who have been screened for mutations in microtubule associated protein tau (MAPT). In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55-83 years) and mean age at symptomatic onset of 66 years (50-77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at amino acid residue 317 was used to assess functional significance of the variant on microtubule assembly and tau filament formation. Recombinant p.K317N tau had reduced ability to promote tubulin polymerization. Recombinant 3R and 4R tau bearing the p.K317N mutation showed decreased 3R tau and increased 4R tau filament assembly. These results strongly suggest that the p.K317N variant is pathogenic. Sequencing of MAPT should be considered in patients with GGT and a family history of dementia or movement disorder. Since several individuals in our series had a positive family history but no MAPT mutation, genetic factors other than MAPT may play a role in disease pathogenesis.

Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau.

LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after α-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than α-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or α-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms.

Dominant Frontotemporal Dementia Mutations in 140 Cases of Primary Progressive Aphasia and Speech Apraxia

Background: Mutations in three genes [chromosome 9 open-reading-frame 72 (C9ORF72); microtubule-associated protein tau (MAPT) and progranulin (GRN)] account for the vast majority of familial, and a proportion of sporadic, frontotemporal dementia (FTD) cases. Progressive apraxia of speech (PAOS) is a type of FTD characterized by speech production deficits without a known cause. Methods: We therefore assessed for genetic mutations in C9ORF72, MAPT and GRN in 40 prospectively recruited PAOS patients. For comparison, we also assessed these mutations in 100 patients with primary progressive aphasia (PPA), including logopenic PPA (n = 54), nonfluent/agrammatic PPA (n = 17), semantic PPA (n = 16), and unclassifiable PPA (n = 13). Results: The mean age at onset of PAOS patients was 66.7 years (± 9.3); 50% were women. Ten patients (25%) had ≥1 first-degree relative with a neurodegenerative disease. No mutations were found in any PAOS patient. In comparison, 36% of the PPA patients had a family history and 5 (5%) had a genetic mutation detected: MAPT (n = 0), GRN (n = 3) and C9ORF72 (n = 2). Conclusions: Although limited by an overrepresentation of logopenic PPA, which frequently predicts Alzheimer's disease pathology, this study suggests that mutations in the three genes most commonly associated with FTD are not associated with PAOS and are not commonly associated with PPA.

Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images.

The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n=21), GRN mutations (n=11), C9ORF72 repeat expansions (n=11) or sporadic FTD (n=15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia.

We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of MAPT (microtubule-associated protein tau) or GRN (progranulin) mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk of frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, structural MRI, and fMRI. We used voxel-based morphometry and tract-based spatial statistics for voxel-wise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsular, anterior midcingulate, and posterior cingulate cortices. Carriers (n = 39) and noncarriers (n = 36) had similar neuropsychological performance, except for lower Letter Digit Substitution Test scores in carriers. Worse performance on Stroop III, Rivermead Behavioral Memory Test, and Happé Cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy in the right uncinate fasciculus was found in carriers compared with controls. Reductions in functional connectivity between anterior midcingulate cortex and frontoinsula and several other brain regions were found in carriers compared with controls and correlated with higher age in carriers, but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found, except for a small cluster of higher volume in the precentral gyrus in carriers. This study demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia

The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients.

Tau alternative splicing in familial and sporadic tauopathies

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.

Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS

BackgroundMutations in the microtubule associated protein tau (MAPT) and progranulin (PGRN) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT, PGRN, or C9orf72 mutations. MethodsMAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. ResultsWe found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72. Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. DiscussionMAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS.

Clinical Characteristics of Parkinsonism in Frontotemporal Dementia Syndromes Associated with Mutations in MAPT, PGRN, C9ORF72 (P06.075)

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.

FTDP-17: 2-Year Follow-Up of Motor and Cognitive Features After Autologous Stem-Cell Transplantation

FTDP-17: 2-Year Follow-Up of Motor and Cognitive Features After Autologous Stem-Cell Transplantation

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration–TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.

Phenotypic signatures of genetic frontotemporal dementia

Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Mutations in a number of genes are associated with FTD, although until recently only two [progranulin (GRN) and microtubule-associated protein tau (MAPT)] were known to be major causes of the disease. This review describes recent progress in identifying clinical and neuroanatomical phenotypes associated with autosomal-dominant FTD. Around a third to a half of FTD patients have an autosomal dominant pattern of inheritance. Up to 10% of patients have a mutation in GRN and a similar proportion have a mutation in MAPT. Recently a group of patients have been shown to have a hexanucleotide repeat expansion in the noncoding region of chromosome 9 open reading frame 72 (C9ORF72). A further group of patients have an autosomal dominant family history but no mutations in any of the known genes including a group of patients who have the same pathology as GRN mutations (type A TDP-43 pathology) but are negative for GRN mutations. Clinical phenotypes vary across the different mutations. Neuroimaging studies show that GRN and MAPT mutations have distinct patterns of atrophy--asymmetric fronto-temporo-parietal atrophy with GRN versus relatively symmetric medial temporal and orbitofrontal lobe atrophy with MAPT mutations. Neuroimaging of patients with an expansion in C9ORF72 has yet to be studied in detail. Genetic FTD is heterogeneous but certain phenotypic signatures of the major causative genes can be identified.

New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization

Frontotemporal lobar degeneration (FTLD) can be sporadic or familial. The genes encoding the microtubule-associated protein tau (MAPT) and progranulin (GRN) are the most relevant genes so far known causing the hereditary forms. Following genetic screening of patients affected by FTLD, we identified 2 new MAPT mutations, P364S and G366R, the former in a sporadic case. In the study we report the clinical and genetic features of the patients carrying these mutations, and the functional effects of the mutations, analyzed in vitro in order to investigate their pathogenic character. Both mutations resulted in reduced ability of tau to promote microtubule polymerization; the P364S protein variant also showed a high propensity to aggregate into filaments. These results suggest a high probability that these mutations are pathogenic. Our findings highlight the importance of genetic analysis also in sporadic forms of FTLD, and the role of in vitro studies to evaluate the pathologic features of new mutations.

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

Altered functional connectivity in asymptomatic MAPT subjects

To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.

Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN

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. 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. 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). 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.

Frontotemporal dementia and parkinsonism linked to chromosome 17 - the first Polish family

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder with various clinical phenotypes. We present the first Central-Eastern European family (Gdansk Family) with FTDP-17 because of a P301L mutation in microtubule-associated protein tau (MAPT). We have studied a family consisting of 82 family members, 39 of whom were genetically evaluated. The proband and her affected brother underwent detailed clinical and neuropsychological examinations. P301L mutation in MAPT was identified in two affected and five asymptomatic family members. New features included hemispatial neglect and unilateral resting tremor not previously reported for P301L MAPT mutation. Low blood folic acid levels were also detected. Our report suggests that FTDP-17 affects patients worldwide, but because of its heterogenous clinical presentation remains underrecognized.

Mutations in CHMP2B are not a cause of frontotemporal lobar degeneration in Finnish patients

Frontotemporal lobar degeneration (FTLD) is a genetically complex disorder. The majority of mutations linked to FTLD families are found in the microtubule-associated protein tau (MAPT) and progranulin (PGRN) genes. Mutations in the chromatin-modifying protein 2B gene (CHMP2B) have been identified in a few families. However, CHMP2B has been showed to be a rare cause of FTLD. Our aim was to determine the frequency of CHMP2B mutations in a clinical series of patients with FTLD in Northern Finland. We examined 72 (36 men) Finnish patients with FTLD. The mean age at onset was 58.9 (range 43–80). Symptoms of motor neuron disease (FTLDMND) were present in 12 patients (17%). Positive family history was detected in 28% of the patients. Mutations in MAPT and PGRN were excluded from these patients. All exons and exon–intron boundaries of the CHMP2B gene were sequenced. No pathogenic CHMP2B mutations were found. A rare polymorphism in the non-coding region of exon 1 (rs36098294) and three other previously reported polymorphisms were detected. Our results confirm that mutations in CHMP2B are not a common cause of FTLD. MAPT and PGRN mutations are also rare in Finnish population, suggesting that other, still unknown genetic factors may play a role in the pathogenesis of FTLD in Finnish population.

Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations

Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate–prefrontal–insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.