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1.  Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease 
Brain  2008;131(5):1268-1281.
Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimer's disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimer's disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimer's disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimer's disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders.
doi:10.1093/brain/awn047
PMCID: PMC2367697  PMID: 18362099
oculomotor; frontotemporal lobar degeneration; corticobasal syndrome; progressive supranuclear palsy; Alzheimer's disease
2.  Novel CSF biomarkers for frontotemporal lobar degenerations(e–Pub ahead of print) 
Neurology  2010;75(23):2079-2086.
Objective:
To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).
Methods:
CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD.
Results:
CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases.
Conclusions:
Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
GLOSSARY
= Alzheimer disease;
= Aguti-related protein;
= angiopoietin-2;
= adrenocorticotropic hormone;
= amyotrophic lateral sclerosis;
= apolipoprotein B;
= behavioral variant FTD;
= corticobasal syndrome;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with tau pathology;
= frontotemporal lobar degeneration with TDP-43 pathology;
= interleukin;
= macrophage-derived chemokine;
= progressive nonfluent aphasia;
= primary progressive aphasia;
= progressive supranuclear palsy;
= S100 calcium binding protein b;
= semantic dementia;
= tumor necrosis factor-related apoptosis-inducing ligand receptor 3.
doi:10.1212/WNL.0b013e318200d78d
PMCID: PMC2995537  PMID: 21048198
3.  Neuropathological background of phenotypical variability in frontotemporal dementia 
Acta Neuropathologica  2011;122(2):137-153.
Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.
doi:10.1007/s00401-011-0839-6
PMCID: PMC3232515  PMID: 21614463
Frontotemporal lobar degeneration; Progressive supranuclear palsy; Tau; TDP-43; FUS
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.  Two distinct subtypes of right temporal variant frontotemporal dementia 
Neurology  2009;73(18):1443-1450.
Background:
Right temporal frontotemporal dementia (FTD) is an anatomic variant of FTD associated with relatively distinct behavioral and cognitive symptoms. We aimed to determine whether right temporal FTD is a homogeneous clinical, imaging, and pathologic/genetic entity.
Methods:
In this case-control study, 101 subjects with FTD were identified. Atlas-based parcellation generated temporal, frontal, and parietal grey matter volumes which were used to identify subjects with a right temporal dominant atrophy pattern. Clinical, neuropsychological, genetic, and neuropathologic features were reviewed. The subjects with right temporal FTD were grouped by initial clinical diagnosis and voxel-based morphometry was used to assess grey matter loss in the different groups, compared to controls, and each other.
Results:
We identified 20 subjects with right temporal FTD. Twelve had been initially diagnosed with behavioral variant FTD (bvFTD), and the other 8 with semantic dementia (SMD). Personality change and inappropriate behaviors were more frequent in the bvFTD group, while prosopagnosia, word-finding difficulties, comprehension problems, and topographagnosia were more frequent in the SMD group. The bvFTD group showed greater loss in frontal lobes than the SMD group. The SMD group showed greater fusiform loss than the bvFTD group. All 8 bvFTD subjects with pathologic/genetic diagnosis showed abnormalities in tau protein (7 with tau mutations), while all three SMD subjects with pathology showed abnormalities in TDP-43 (p = 0.006).
Conclusions:
We have identified 2 subtypes of right temporal variant frontotemporal dementia (FTD) allowing further differentiation of FTD subjects with underlying tau pathology from those with TDP-43 pathology.
GLOSSARY
= Alzheimer Disease Patient Registry;
= Alzheimer Disease Research Center;
= behavioral variant frontotemporal dementia;
= Clinical Dementia Rating Scale sum of boxes;
= False Discovery Rate;
= frontotemporal dementia;
= Mini-Mental State Examination;
= Neuropsychiatric Inventory;
= semantic dementia;
= tissue probability map;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e3181bf9945
PMCID: PMC2779005  PMID: 19884571
6.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration 
Acta Neuropathologica  2007;114(1):5-22.
The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U sub-type. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.
doi:10.1007/s00401-007-0237-2
PMCID: PMC2827877  PMID: 17579875
Frontotemporal dementia; Semantic dementia; Progressive non-Xuent aphasia; Frontotemporal lobar degeneration; Motor neuron disease; Tauopathy; Ubiquitin; TDP-43 proteinopathy; Progranulin; Valosin-containing protein; Charged multivesicular body protein 2B; Neuronal intermediate filament inclusion disease; Neuropathologic diagnosis
7.  Clinicopathologic differences among patients with behavioral variant frontotemporal dementia 
Neurology  2007;69(11):1113-1121.
Objective
To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy.
Methods
This study reviewed all patients entered as clinical bvFTD in the National Alzheimer’s Coordinating Center’s database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups.
Results
The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems.
Conclusion
During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD.
doi:10.1212/01.wnl.0000267701.58488.69
PMCID: PMC3545400  PMID: 17522386
8.  Clinicopathologic differences among patients with behavioral variant frontotemporal dementia 
Neurology  2013;80(6):561-568.
Objective:
To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy.
Methods:
This study reviewed all patients entered as clinical bvFTD in the National Alzheimer's Coordinating Center's database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups.
Results:
The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems.
Conclusion:
During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD.
doi:10.1212/WNL.0b013e3182815547
PMCID: PMC3589292  PMID: 23325909
9.  Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72 
Acta Neuropathologica  2011;122(6):673-690.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
doi:10.1007/s00401-011-0907-y
PMCID: PMC3277860  PMID: 22083254
10.  Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease 
BMC Neurology  2006;6:32.
Background
Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.
Methods
We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII.
Results
No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity.
Conclusion
We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.
doi:10.1186/1471-2377-6-32
PMCID: PMC1570137  PMID: 16945149
11.  TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration 
Acta Neuropathologica  2008;116(2):141-146.
Autopsy studies have shown that about 55% of patients with frontotemporal lobar degeneration (FTLD) and 25% of patients with Alzheimer’s disease (AD) harbour TDP-43 immunoreactive pathological changes in their brains. Using ELISA, we investigated whether we could detect the presence, or increased amounts, of TDP-43 in plasma of patients with FTLD and AD compared to normal control subjects. We detected elevated levels of TDP-43 protein in plasma of 46% patients with FTLD with clinical frontotemporal dementia (FTD) and 22% patients with AD, compared to 8% of control subjects. The proportions of patients with FTD and AD showing raised plasma TDP-43 levels correspond closely to those proportions known from autopsy studies to contain TDP-43 pathological changes in their brains. Raised TDP-43 plasma levels may thereby index TDP-43 pathology within the brain. Plasma TDP-43 levels may be a biomarker that can provide a laboratory test capable of identifying the presence of TDP-43 brain pathology in neurodegenerative disease during life. It may help to distinguish those cases of FTLD with ubiquitin/TDP-43 pathology in their brains from those with tauopathy. As a predictive test, plasma TDP-43 level may have great practical value in directing therapeutic strategies aimed at preventing or removing tau or TDP-43 pathological changes from the brain in FTLD and AD.
doi:10.1007/s00401-008-0389-8
PMCID: PMC2464623  PMID: 18506455
Frontotemporal lobar degeneration; Alzheimer’s disease; TDP-43; Plasma; Biomarker
12.  Frontotemporal dementia: An updated overview 
Indian Journal of Psychiatry  2009;51(Suppl1):S65-S69.
Frontotemporal dementia (FTD) is a progressive neurodegenerative syndrome occurring between 45 and 65 years. The syndrome is also called frontotemporal lobar degeneration (FTLD). However, FTLD refers to a larger group of disorders FTD being one of its subgroups. The other subgroups of FTLD are progressive nonfluent aphasia (PFNA), and semantic dementia (SD). FTLD is characterized by atrophy of prefrontal and anterior temporal cortices. FTD occurs in 5-15% of patients with dementia and it is the third most common degenerative dementia. FTD occurs with equal frequency in both sexes. The age of onset is usually between 45 and 65 years though it may range anywhere from 21 to 81 years. The usual course is one of progressive clinicopathological deterioration with mortality within 6-8 years. Unlike Alzheimer’s disease (AD), this condition has a strong genetic basis and family history of FTD is seen in 40-50% of cases. FTD is a genetically complex disorder inherited as an autosomal dominant trait with high penetrance in majority of cases. Genetic linkage studies have revealed FTLD loci on chromosome 3p, 9, 9p, and 17q. The most prevalent genes are PGRN (progranulin) and MAPT (microtubule-associated protein tau), both located on chromosome 17q21. More than 15 different pathologies can underlie FTD and related disorders and it has four major types of pathological features: (1) microvacuolation without neuronal inclusions, (2) microvacuolation with ubiquitinated rounded intraneuronal inclusions and dystrophic neurites FTLD-ubiquitinated (FTLD-U), (3) transcortical gliosis with tau-reactive rounded intraneuronal inclusions, (4) microvacuolation and taupositive neurofibrillary tangles. Behavior changes are the most common initial symptom of FTD (62%), whereas speech and language problems are most common in NFPA (100%) and SD (58%). There are no approved drugs for the management of FTD and trials are needed to find effective agents. Non-pharmacological treatment and caregiver training are important in the management of FTD.
PMCID: PMC3038533  PMID: 21416021
Frontotemporal dementia; frontotemporal lobar degeneration; progressive nonfluent aphasia; neurodegenerative disorders
13.  Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration 
Neurology  2009;72(19):1653-1660.
Objective:
Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy.
Methods:
Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed.
Results:
The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy.
Conclusions:
While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.
GLOSSARY
= Alzheimer disease;
= behavioral variant frontotemporal dementia;
= frontotemporal dementia;
= Alzheimer pathology with semantic dementia;
= frontotemporal dementia with tau inclusions;
= frontotemporal dementia with ubiquitin inclusions;
= frontotemporal lobar degeneration;
= Mini-Mental State Examination;
= progressive nonfluent aphasia;
= semantic dementia;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e3181a55fa2
PMCID: PMC2827263  PMID: 19433738
14.  Making the Diagnosis of Frontotemporal Lobar Degeneration 
Context
Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the morphologic hallmark of Pick disease. Pick disease is a type of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD. The 2 major categories of pathologic FTLD are tauopathies (FTLD-tau) and ubiquitinopathies (FTLD-U). Pick disease is one of the FTLD-tau subtypes and is termed FTLD-tau (PiD).
Objective
To “demystify” FTLDs, and to demonstrate that subtypes of FTLD-tau and FTLD-U can be easily determined by following a logical, stepwise, histochemical, and immunohistochemical investigation of the FTD autopsy brain.
Data Sources
Previously published peer-reviewed articles.
Conclusions
The hope is that this article will be a useful reference for the general pathologist faced with performing a brain autopsy on a decedent with frontotemporal dementia.
doi:10.5858/arpa.2012-0075-RA
PMCID: PMC3629720  PMID: 23451743
15.  A new subtype of frontotemporal lobar degeneration with FUS pathology 
Brain  2009;132(11):2922-2931.
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.
doi:10.1093/brain/awp214
PMCID: PMC2768659  PMID: 19674978
frontotemporal lobar degeneration; frontotemporal dementia; FUS; fused in sarcoma; TLS; translocated in liposarcoma
16.  Medial Versus Lateral Frontal Lobe Contributions to Voluntary Saccade Control as Revealed by the Study of Patients with Frontal Lobe Degeneration 
Deficits in the ability to suppress automatic behaviors lead to impaired decision making, aberrant motor behavior, and impaired social function in humans with frontal lobe neurodegeneration. We have studied patients with different patterns of frontal lobe dysfunction resulting from frontotemporal lobar degeneration or Alzheimer's disease, investigating their ability to perform visually guided saccades and smooth pursuit eye movements and to suppress visually guided saccades on the antisaccade task. Patients with clinical syndromes associated with dorsal frontal lobe damage had normal visually guided saccades but were impaired relative to other patients and control subjects in smooth pursuit eye movements and on the antisaccade task. The percentage of correct antisaccade responses was correlated with neuropsychological measures of frontal lobe function and with estimates of frontal lobe gray matter volume based on analyses of structural magnetic resonance images. After controlling for age, gender, cognitive status, and potential interactions between disease group and oculomotor function, an unbiased voxel-based morphometric analysis identified the volume of a segment of the right frontal eye field (FEF) as positively correlated with antisaccade performance (less volume equaled lower percentage of correct responses) but not with either pursuit performance or antisaccade or visually guided saccade latency or gain. In contrast, the volume of the presupplementary motor area (pre-SMA) and a portion of the supplementary eye fields correlated with antisaccade latency (less volume equaled shorter latency) but not with the percentage of correct responses. These results suggest that integrity of the presupplementary motion area/ supplementary eye fields is critical for supervisory processes that slow the onset of saccades, facilitating voluntary saccade targeting decisions that rely on the FEF.
doi:10.1523/JNEUROSCI.0549-06.2006
PMCID: PMC2551317  PMID: 16763044
antisaccade; smooth pursuit; frontotemporal lobar degeneration; presupplementary motor area; supplementary eye field; frontal eye field; brain volume
17.  Neuropsychiatric symptom profile differs based on pathology in patients with clinically diagnosed behavioral variant frontotemporal dementia 
Background/Aims
Behavioral variant frontotemporal dementia (bvFTD) is pathologically heterogeneous. With emerging therapeutics, determining underlying pathology during life is increasingly important. Neuropsychiatric symptoms are prevalent and diagnostic in bvFTD.
Methods
We assessed the neuropsychiatric profile in patients with clinically diagnosed bvFTD as a function of pathology at autopsy. Patients with a clinical diagnosis of bvFTD at initial visit were selected from the National Alzheimer's Coordinating Center database. Neuropsychiatric symptoms endorsed on the Neuropsychiatric Inventory Questionnaire were analyzed.
Results
Of 149 patients with clinically diagnosed bvFTD, pathology was primarily Alzheimer's disease in 20.5%. These patients differed from those with underlying frontotemporal lobar degeneration: patients with AD pathology (plaques and tangles) were more likely to have hallucinations, delusions, or agitation. Patients were further differentiated into tau positive (30 % of cases, including Pick's disease, frontotemporal dementia and parkinsonism with tau-positive, and other tauopathies) or tau-negative (70% of cases including bvFTD tau-negative ubiquitin-positive inclusions). These patients also differed in some of the neuropsychiatric symptoms seen. Tau-negative cases were more likely to demonstrate depression, delusions, and changes in appetite and eating.
Conclusions
These preliminary findings contribute to our increasing ability to predict, using simple clinical tools the neuropathological underpinnings of bvFTD during life.
doi:10.1159/000354368
PMCID: PMC4041327  PMID: 24135712
Behavioral variant frontotemporal dementia (bvFTD); Neuropsychiatric Inventory Questionnaire (NPI-Q); Neuropathology; NACC; Behavior-neuropathological correlation
18.  CSF neurofilament concentration reflects disease severity in frontotemporal degeneration 
Annals of neurology  2014;75(1):116-126.
Objective
Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD.
Methods
CSF NfL, amyloid-β42 (Aβ42), tau and phosphorylated tau (ptau) concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer’s disease, 6 Parkinson’s disease and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural MR images determined the relationship between brain volume and CSF NfL.
Results
Mean CSF NfL concentrations were higher in bvFTD, SD and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, and not in other diagnostic groups. Analyses in two independent FTD cohorts and a group of autopsy verified or biomarker enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with highest NfL levels exhibited the most atrophy.
Interpretation
CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.
doi:10.1002/ana.24052
PMCID: PMC4020786  PMID: 24242746
19.  Distinctive Features of Saccadic Intrusions and Microsaccades in Progressive Supranuclear Palsy 
The eyes do not stay perfectly still during attempted fixation; fixational eye movements and saccadic intrusions (SIs) continuously change the position of gaze. The most common type of SI, square-wave jerk (SWJ), consists of saccade pairs that appear purely horizontal on clinical inspection: the first saccade moves the eye away from the fixation target and, after a short interval, the second saccade brings it back towards the target. SWJs are prevalent in certain neurological disorders, including progressive supranuclear palsy (PSP). Here we developed an objective method to identify SWJs. We found that SWJs are more frequent, larger and more markedly horizontal in PSP patients than in healthy human subjects. Further, the loss of a vertical component in fixational saccades and SWJs was the eye movement feature that best distinguished PSP patients from controls. We moreover determined that in PSP patients and controls, the larger the saccade the more likely it was part of a SWJ. Further, saccades produced by PSP patients had equivalent properties whether they were part of a SWJ or not, suggesting that normal fixational saccades (microsaccades) are rare in PSP. We propose that fixational saccades and SIs are generated by the same neural circuit, and that, both in PSP patients and in controls, SWJs result from a coupling mechanism that generates a second corrective saccade shortly after a large fixation saccade. Due to brainstem and/or cerebellum impairment, fixational saccades in PSP are abnormally large, and thus more likely to trigger a corrective saccade, giving rise to SWJs.
doi:10.1523/JNEUROSCI.2600-10.2011
PMCID: PMC3111217  PMID: 21430139
Fixational eye movements; microsaccades; saccadic palsy; square wave jerks; parkinsonian disorders
20.  Abnormalities of optokinetic nystagmus in progressive supranuclear palsy 
Objectives: To measure vertical and horizontal responses to optokinetic (OK) stimulation and investigate directional abnormalities of quick phases in progressive supranuclear palsy (PSP).
Methods: Saccades and OK nystagmus were studied in six PSP patients, five with Parkinson's disease (PD), and 10 controls. The OK stimulus subtended 72° horizontally, 60° vertically, consisted of black and white stripes, and moved at 10–50°/s.
Results: All PSP patients showed slowed voluntary vertical saccades and nystagmus quick phases compared with PD or controls. Small, paired, horizontal saccadic intrusions (SWJ) were more frequent and larger in PSP during fixation. Vertical saccades were transiently faster at the time of SWJ and horizontal saccades in PSP. During vertical OK nystagmus, small quick phases were often combined with horizontal SWJ in all subjects; in PSP the vector was closer to horizontal. Vertical OK slow phase gain was reduced in PSP but, in most PD patients, was similar to normals. The average position of gaze shifted in the direction of vertical OK stimulus in PSP patients with preserved slow phase responses but impaired quick phases.
Conclusions: Vertical OK responses in PSP show impaired slow phase responses, and quick phases that are slowed and combined with SWJ to produce an oblique vector. SWJ facilitate vertical saccades and quick phases in PSP, but it is unclear whether this is an adaptive process or a result of the disease. A large OK stimulus is useful to induce responses that can be quantitatively analysed in patients with limited voluntary range of vertical gaze.
doi:10.1136/jnnp.2003.027367
PMCID: PMC1738726  PMID: 15377682
21.  Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP 
Neurology  2013;81(22):1945-1952.
Objectives:
To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau).
Methods:
Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined.
Results:
In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity.
Conclusion:
A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies.
Classification of evidence:
This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
doi:10.1212/01.wnl.0000436625.63650.27
PMCID: PMC3843382  PMID: 24174584
22.  Atypical, slowly progressive behavioral variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion 
Background
Some patients meeting behavioral variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy, and have thus been referred to as bvFTD “phenocopies” or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have found no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, we describe two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions.
Methods
Three hundred and eighty-four patients with FTD clinical spectrum and Alzheimer’s disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns assessed using voxel-based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.
Results
Both patients were age 48 at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over seven years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over two years, her neuropsychological and functional scores as well as brain atrophy remained stable.
Conclusions
C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
doi:10.1136/jnnp-2011-301883
PMCID: PMC3388906  PMID: 22399793
C9ORF72; C9FTD/ALS; frontotemporal dementia; genetics; dementia
23.  Frontotemporal Dementia: Implications for Understanding Alzheimer Disease 
Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease.
Mutations in the tau (MAPT) gene account for ∼5% of frontotemporal dementia cases. They give rise to characteristic protein inclusions, providing insight into tau pathology in Alzheimer disease.
doi:10.1101/cshperspect.a006254
PMCID: PMC3281593  PMID: 22355793
24.  New Perspective on Parkinsonism in Frontotemporal Lobar Degeneration 
Frontotemporal dementia (FTD) is the second most common type of presenile dementia. Three clinical prototypes have been defined; behavioral variant FTD, semantic dementia, and progressive nonfluent aphasia. Progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease may possess clinical and pathological characteristics that overlap with FTD, and it is possible that they may all belong to the same clinicopathological spectrum. Frontotemporal lobar degeneration (FTLD) is a clinicopathological syndrome that encompasses a heterogenous group of neurodegenerative disorders. Owing to the advancement in the field of molecular genetics, diagnostic imaging, and pathology, FTLD has been the focus of great interest. Nevertheless, parkinsonism in FTLD has received relatively less attention. Parkinsonism is found in approximately 20–30% of patients in FTLD. Furthermore, parkinsonism can be seen in all FTLD subtypes, and some patients with familial and sporadic FTLD can present with prominent parkinsonism. Therefore, there is a need to understand parkinsonism in FTLD in order to obtain a better understanding of the disease. With regard to the clinical characteristics, the akinetic rigid type of parkinsonism has predominantly been described. Parkinsonism is frequently observed in familial FTD, more specifically, in FTD with parkinsonism linked to chromosome 17q (FTDP-17). The genes associated with parkinsonism are microtubule associated protein tau (MAPT), progranulin (GRN or PGRN), and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion. The neural substrate of parkinsonism remains to be unveiled. Dopamine transporter (DAT) imaging revealed decreased uptake of DAT, and imaging findings indicated atrophic changes of the basal ganglia. Parkinsonism can be an important feature in FTLD and, therefore, increased attention is needed on the subject.
doi:10.14802/jmd.13001
PMCID: PMC4027647  PMID: 24868417
Frontotemporal dementia; Frontotemporal lobar degeneration; Parkinsonism
25.  Right temporal variant frontotemporal dementia with motor neuron disease 
Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including DTI sequence in one patient, and FDG PET scan, revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in 2 patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer's disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.
doi:10.1016/j.jocn.2011.06.007
PMCID: PMC3248959  PMID: 22051030
Frontotemporal dementia; Motor neuron disease; TDP-43; Voxel based morphometry (VBM); positron emission tomography (PET

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