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1.  Frontotemporal dementia in a Brazilian Caucasian kindred with the C9orf72 mutation 
Archives of neurology  2012;69(9):1149-1153.
Objective
Describe the clinical features of a Brazilian C9orf72 frontotemporal dementia – amyotrophic lateral sclerosis (FTD-ALS) kindred, and compare them to other reported C9orf72 families and FTD-ALS causing mutations.
Design
Report of a kindred.
Setting
Dementia center at an University hospital.
Patients
One kindred encompassing 3 generations.
Results
The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed PCR and Southern blot. The observed phenotypes were behavioral variant FTD and ALS with dementia, with significant variability in age of onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations and more posterior atrophy on neuroimaging than is typical for FTD were seen.
Conclusions
bvFTD due to C9orf72 expansions displays some phenotypic heterogeneity, and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede by many years the diagnosis of dementia and may be a distinguishing feature of this mutation.
doi:10.1001/archneurol.2012.650
PMCID: PMC3625641  PMID: 22964910
2.  Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer’s disease 
Archives of neurology  2012;69(4):509-517.
Objective
Deficits in the generation and control of saccades have been described in clinically-defined frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses, we sought to determine the saccade abnormalities associated with autopsy-defined cases of FTLD and AD.
Participants and design
An infrared eye tracker was used to record visually guided saccades to ten degree targets and antisaccades in 28 autopsy-confirmed FTD and 10 AD subjects, an average of 35.6 ± 10 months prior to death and 27 age-matched normal controls (NC). 12 FTD subjects had FTLD-TDP pathology, 15 had FTLD-tau pathology and one showed FTLD-FUS pathology. Receiver operating curve (ROC) statistics were used to determine diagnostic value of oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry (VBM).
Results
All FTD and AD subjects were impaired relative to NC on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually-guided saccade abnormalities. AD cases displayed prominent increases in horizontal saccade latency that differentiated them from FTD cases. Impairments in velocity and gain were most severe in individuals with Progressive Supranuclear Palsy (PSP) but were also present in other tauopathies. Vertical and horizontal saccade velocity and gain were able to differentiate PSP cases from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.
Conclusion
Decreased visually-guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of PSP.
doi:10.1001/archneurol.2011.1021
PMCID: PMC3423186  PMID: 22491196
Frontotemporal Dementia; Corticobasal Degeneration; Progressive Supranuclear Palsy; Ocular Motility
3.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
4.  The Spectrum of Mutations in Progranulin 
Archives of neurology  2010;67(2):161-170.
Background
Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.
Objectives
To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.
Design
Case-control study.
Setting
Clinical and neuropathology dementia research studies at 8 academic centers.
Participants
Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.
Main Outcome Measures
Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.
Results
We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.
Conclusions
Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.
doi:10.1001/archneurol.2009.328
PMCID: PMC2901991  PMID: 20142524
5.  Apathy Symptom Profile and Behavioral Associations in Frontotemporal Dementia vs. Alzheimer's Disease 
Archives of neurology  2009;66(7):888-893.
Objective:
Apathy is a very common and significant problem in patients with dementia, regardless of etiology. Observations on frontosubcortical circuit (FSC) syndromes indicate that apathy may have affective, behavioral or cognitive manifestations. We explored whether the apathy manifested in frontotemporal dementia (FTD) with its predominantly anterior brain neuropathology differs from the apathy in Alzheimer's disease (DAT) with its predominantly hippocampal and temporoparietal-based neuropathology. We also sought to determine whether other behavioral disturbances reported in FSC syndromes correlate with apathy.
Design:
Survey. Analyses included individual items within Neuropsychiatric Inventory (NPI) subscale items. Items of the Apathy/Indifference subscale were designated by consensus as: A) affective = lacking in emotions, B) behavioral = inactive, chores abandoned or C) cognitive = no interest in others' activities. Proportions of correlated non-apathy NPI items were calculated and displayed using Chernoff faces to facilitate comparison of apathy domains and dementia diagnoses.
Setting and Patients:
Several neurology specialty clinics contributed to our dataset of 92 participants with FTD and 457 with DAT.
Results:
Apathy was more prevalent in FTD than DAT, but when present, the specific apathy symptoms in both dementias were rarely restricted to one of the three domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in FTD. Participants with affective apathy more frequently co-presented with an orbitofrontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also co-presented with uncooperative agitation, anger, and physical agitation in both dementias.
Conclusions:
Apathy is common in FTD and in DAT, although it is more common in FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to impact on patient safety, independence and quality of life.
doi:10.1001/archneurol.2009.92
PMCID: PMC2875777  PMID: 19597092
Alzheimer's Disease; Apathy; Frontotemporal Dementia; Frontotemporal Degeneration
6.  Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia 
Archives of neurology  2008;65(10):1368-1374.
Background
Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found.
Objective
To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease.
Design, Setting, and Participants
Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer’s Genetics Study).
Results
Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2−68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer’s Genetics sample showed the same direction of association as the case-control sample.
Conclusions
To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.
doi:10.1001/archneur.65.10.1368
PMCID: PMC2841136  PMID: 18852354
7.  Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies 
Archives of neurology  2009;66(2):180-189.
Objective
To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.
Design
Performance of immunohistochemical whole–central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.
Setting
An academic medical center.
Participants
We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.
Main Outcome Measure
Neuronal and glial TDP-43 pathology.
Results
We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.
Conclusion
These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.
doi:10.1001/archneurol.2008.558
PMCID: PMC2774117  PMID: 19204154
8.  Frontal Paralimbic Network Atrophy in Very Mild Behavioral Variant Frontotemporal Dementia 
Archives of neurology  2008;65(2):249-255.
Background:
Behavioral variant frontotemporal dementia (bvFTD) strikes hardest at the frontal lobes, but the sites of earliest injury remain unclear.
Objective:
To determine atrophy patterns in distinct clinical stages of bvFTD, testing the hypothesis that the mildest stage is restricted to frontal paralimbic cortex.
Design:
A bvFTD cohort study.
Setting:
University hospital dementia clinic.
Participants:
Patients with bvFTD with Clinical Dementia Rating (CDR) scale scores of 0.5 (n=15), 1 (n=15), or 2 to 3 (n=15) age and sex matched to each other and to 45 healthy controls.
Main Outcome Measures:
Magnetic resonance voxel-based morphometry estimated gray matter and white matter atrophy at each disease stage compared with controls.
Results:
Patients with a CDR score of 0.5 had gray matter loss in frontal paralimbic cortices, but atrophy also involved a network of anterior cortical and subcortical regions. A CDR score of 1 showed more extensive frontal gray matter atrophy and white matter losses in corpus callosum and brainstem. A CDR score of 2 to 3 showed additional posterior insula, hippocampus, and parietal involvement, with white matter atrophy in presumed frontal projection fibers.
Conclusions:
Very mild bvFTD targets a specific subset of frontal and insular regions. More advanced disease affects white matter and posterior gray matter structures densely interconnected with the sites of earliest injury.
doi:10.1001/archneurol.2007.38
PMCID: PMC2544627  PMID: 18268196
9.  Patterns of White Matter Atrophy in Frontotemporal Lobar Degeneration 
Archives of neurology  2007;64(11):1619-1624.
Background
Structural magnetic resonance imaging (MRI) has been used to investigate the in vivo pathology of frontotemporal lobar degeneration. However, few neuroimaging studies have focused on white matter (WM) alterations in this disease.
Objectives
To use volumetric MRI techniques to identify the patterns of WM atrophy in vivo in 2 clinical variants of frontotemporal lobar degeneration—fronto-temporal dementia (FTD) and semantic dementia—and to compare the patterns of WM atrophy with those of gray matter (GM) atrophy in these diseases.
Design
Structural MRIs were obtained from patients with FTD (n=12) and semantic dementia (n=13) and in cognitively healthy age-matched controls (n=24). Regional GM and WM were classified automatically from high-resolution T1-, T2-, and proton density-weighted MRIs with Expectation-Maximization Segmentation and compared between the groups using a multivariate analysis of covariance model that included age and WM lesion volumes as covariates.
Results
Patients with FTD had frontal WM atrophy and frontal, parietal, and temporal GM atrophy compared with controls, who had none. Patients with semantic dementia had temporal WM and GM atrophy and patients with FTD had frontal GM atrophy. Adding temporal WM volume to temporal GM volume significantly improved the discrimination between semantic dementia and FTD.
Conclusions
These results show that patients with frontotemporal lobar degeneration who are in relatively early stages of the disease (Clinical Dementia Rating score, 1.0-1.2) have WM atrophy that largely parallels the pattern of GM atrophy typically associated with these disorders.
doi:10.1001/archneur.64.11.1619
PMCID: PMC2443735  PMID: 17998444
10.  Novel Tau Polymorphisms, Tau Haplotypes, and Splicing in Familial and Sporadic Frontotemporal Dementia 
Archives of neurology  2003;60(5):698-702.
Background
A subset of familial cases (FTDP-17) of frontotemporal dementia (FTD) are caused by mutations in the tau gene. The role of tau gene mutations and haplotypes in sporadic FTD and the functional consequences of tau polymorphisms are unknown.
Objectives
To investigate (1) the frequency of known FTDP-17 mutations in familial and sporadic FTD and compare these results with previous studies; (2) whether the tau H1 haplotype is associated with FTD; and (3) the functional effect of intronic tau sequence variations.
Patients and Methods
Patients with familial and sporadic FTD were screened for mutations in the microtubule-binding region of tau. The frequencies of tau haplotypes and genotypes were compared between patients with FTD and control subjects. We analyzed the splicing effect of novel intronic polymorphisms associated with FTD.
Results
The P301L mutation was detected in 11% of familial FTD cases. The H1 haplotype was not overrepresented in patients with FTD, but the P301L mutation appeared on the background of the H2 tau haplotype. We identified 4 novel single nucleotide polymorphisms in intron 9 and a 9–base pair deletion in intron 4A. A C-to-T transition 177 base pairs upstream from exon 10 was significantly increased in patients with FTD compared with controls. Direct analysis of brain tissue from a patient with this variant showed an increase in exon 10–containing tau transcripts.
Conclusions
Sequence variations in intronic or regulatory regions of tau may have previously unrecognized consequences leading to tau dysfunction and neurodegeneration.
doi:10.1001/archneur.60.5.698
PMCID: PMC2072863  PMID: 12756133

Results 1-10 (10)