Accurately measuring the cortical mean diffusivity (MD) derived from diffusion tensor imaging (DTI) at the comprehensive lobe, gyral and voxel level of young, elderly healthy brains and those with Alzheimer's disease (AD) may provide insights on heterogeneous cortical microstructural changes caused by aging and AD. Due to partial volume effects (PVE), the measurement of cortical MD is overestimated with contamination of cerebrospinal fluid (CSF). The bias is especially severe for aging and AD brains because of significant cortical thinning of these brains. In this study, we aimed to quantitatively characterize the unbiased regional cortical MD changes due to aging and AD and delineate the effects of cortical thinning of elderly healthy and AD groups on MD measurements. DTI and T1-weighted images of 14 young, 15 elderly healthy subjects and 17 AD patients were acquired. With the parcellated cortical gyri and lobes from T1 weighted image transformed to DTI, regional cortical MD of all subjects before and after PVE correction were measured. CSF contamination model was used to correct bias of MD caused by PVE. Compared to cortical MD of young group, significant increases of corrected MD for elderly healthy and AD groups were found only in frontal and limbic regions, respectively, while there were significant increases of uncorrected MD all over the cortex. Uncorrected MD are significantly higher in limbic and temporal gyri in AD group, compared to those in elderly healthy group but higher MD only remained in limbic gyri after PVE correction. Cortical thickness was also measured for all groups. The correlation slopes between cortical MD and thickness for elderly healthy and AD groups were significantly decreased after PVE correction compared to before correction while no significant change of correlation slope was detected for young group. It suggests that the cortical thinning in elderly healthy and AD groups is a significant contributor to the bias of uncorrected cortical MD measurement. The established comprehensive unbiased cortical MD profiles of young, elderly healthy subjects and AD patients at the lobe, gyral and voxel level may serve as clinical references for cortical microstructure.
DTI; Cortex; Mean diffusivity; Aging; Alzheimer's disease; Unbiased; Partial volume effects
Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusions. To address this challenge, the Michael J. Fox Foundation for Parkinson's Research generated a number of monoclonal antibodies targeting epitopes across the LRRK2 protein. In the present paper, we report optimized protocols and results for ten monoclonal antibodies for immunoblotting, immunohistochemistry, immunoprecipitation and kinase activity assays, in rat, mouse and human brain tissue. Several efficacious antibodies were identified, but results demonstrate that the mouse monoclonal N241A/34 is suitable for most applications, with the best overall rabbit monoclonal antibody being c41-2. These antibodies produced a dominant band of the expected size via immunoblotting and a lack of labelling in tissue derived from LRRK2-knockout animals under optimized conditions. A significant proportion of LRRK2 protein localizes to insoluble fractions and no evidence of truncated LRRK2 protein was detected in any fraction from rodent or human tissues. An assay was developed for the robust detection of LRRK2 kinase activity directly from frozen mouse and human brain tissue, but precipitous declines in activity were observed that corresponded to increasing post-mortem intervals and processing times. Finally, we demonstrate the highest levels of brain-localized LRRK2 in the striatum, but note differential expression patterns between rat and mouse in both striatum and cortex. Anti-LRRK2 monoclonal antibodies that are unlimited in availability together with the proposed standardized protocols should aid in the definition of LRRK2 function in both health and disease.
immunohistochemistry; kinase assay; leucine-rich repeat kinase 2 (LRRK2); Parkinson’s disease; DAB, 3,3′-diaminobenzidine; DMEM, Dulbecco’s modified Eagle’s medium; eGFP, enhanced green fluorescent protein; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HEK, human embryonic kidney; KO, knockout; LRRK2, leucine-rich repeat kinase 2; MEF, mouse embryonic fibroblast; MJFF, Michael J. Fox Foundation for Parkinson’s Research; PD, Parkinson’s disease; PEI, polyethyleneimine; PFA, paraformaldehyde; UTSW, University of Texas Southwestern; VDAC, voltage-dependent anion channel; WT, wild-type
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.
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.
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
The purpose of this study is to determine the value of Tc-99m HMPAO SPECT in the diagnosis of the dementias. Tc-99m HMPAO was used with a 3-camera scanner to produce 5 sets of sectional images of the brain. Images were further processed using Statistical Parametric Mapping. Diagnosis was made by a physician blinded to the clinical diagnosis. Results in 73 subjects were compared with a neuropathologic study of the brain at autopsy. Data were analyzed for sensitivity, specificity, positive and negative predictive values and accuracy. These results are compared with several other studies performed with Tc-99m HMPAO SPECT with histopathologic correlation. This procedure is widely available and relatively inexpensive and may be of value in patients with dementias and problematic diagnoses. Further, a degree of differential diagnosis between Alzheimer's and Frontotemporal diseases may be effected. The study was approved by our Institutional Review Board.
The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type α-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of 10 brain regions from 417 subjects stained immunohistochemically for α-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson’s disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer’s disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson’s Disease Rating Scale Part 3. Additionally there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.
Parkinson’s disease; parkinsonism; dementia with Lewy bodies; Alzheimer’s disease; incidental Lewy bodies; α-synuclein; olfactory bulb; amgydala; limbic; brainstem; neocortex
Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the unified Parkinson's Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.
Parkinson's disease, surgery; Deep brain stimulation; Gene therapy; Transplantation; Dementia with Lewy bodies, diagnosis, therapy, clinical trial; α-Synuclein, Lewy bodies, incidental Lewy body disease; Biopsy; Olfactory bulb
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
Frontotemporal dementia; FTD; granulin; progranulin; GRN; PGRN
A pathologic hallmark of Huntington disease (HD) is the presence of intraneuronal aggregates of polyglutamine-containing huntingtin protein (Htt) fragments. Monoclonal antibody 1C2 is a commercial antibody to normal human TATA-binding protein that detects long stretches of glutamine residues. Using 1C2 as a surrogate marker for mutant Htt, we immunostained 19 HD cases, 10 normal controls, and 10 cases of frontotemporal degeneration with ubiquitinated inclusions as disease controls. In the HD cases there was consistent 1C2 immunoreactivity in the neocortex, striatum, hippocampus, lateral geniculate body, basis pontis, medullary reticular formation, and cerebellar dentate nucleus. The normal and disease controls demonstrated 1C2 immunoreactivity only in the substantia nigra, locus coeruleus, and pituitary gland. Staining of 5 HD cases and 5 normal controls revealed a less consistent and less diagnostically useful morphologic immunoreactivity profile. These results indicate that widespread 1C2 immunoreactivity is present in diverse central nervous system areas in HD and that in the appropriate setting 1C2 staining can be a useful tool in the postmortem diagnosis of HD when neuromelanin-containing neuronal populations are avoided.
1C2; Frontotemporal degeneration with ubiquitinated inclusions; inclusions; Huntington disease; Immunohistochemistry; Neuromelanin; Polyglutamine
To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.
The use of α-synuclein immunohistochemistry has altered our concepts of the cellular pathology, anatomical distribution and prevalence of Lewy body disorders. However, the diversity of methodology between laboratories has led to some inconsistencies in the literature. Adoption of uniformly sensitive methods may resolve some of these differences. Eight different immunohistochemical methods for demonstrating α-synuclein pathology, developed in eight separate expert laboratories, were evaluated for their sensitivity for neuronal elements affected by human Lewy body disorders. Identical test sets of formalin-fixed, paraffin-embedded sections from subjects diagnosed neuropathologically with or without Lewy body disorders were stained with the eight methods and graded by three observers for specific and nonspecific staining. The methods did not differ significantly in terms of Lewy body counts, but varied considerably in their ability to reveal neuropil elements such as fibers and dots. One method was clearly superior for revealing these neuropil elements and the critical factor contributing to its high sensitivity was considered to be its use of proteinase K as an epitope retrieval method. Some methods, however, achieved relatively high sensitivities with optimized formic acid protocols combined with a hydrolytic step. One method was developed that allows high sensitivity with commercially available reagents.
Tight junctions (TJs) play a crucial role in the establishment of cell polarity and regulation of paracellular permeability in epithelia. Here, we show that upon calcium-induced junction biogenesis in Madin-Darby canine kidney cells, ABαC, a major protein phosphatase (PP)2A holoenzyme, is recruited to the apical membrane where it interacts with the TJ complex. Enhanced PP2A activity induces dephosphorylation of the TJ proteins, ZO-1, occludin, and claudin-1, and is associated with increased paracellular permeability. Expression of PP2A catalytic subunit severely prevents TJ assembly. Conversely, inhibition of PP2A by okadaic acid promotes the phosphorylation and recruitment of ZO-1, occludin, and claudin-1 to the TJ during junctional biogenesis. PP2A negatively regulates TJ assembly without appreciably affecting the organization of F-actin and E-cadherin. Significantly, inhibition of atypical PKC (aPKC) blocks the calcium- and serum-independent membrane redistribution of TJ proteins induced by okadaic acid. Indeed, PP2A associates with and critically regulates the activity and distribution of aPKC during TJ formation. Thus, we provide the first evidence for calcium-dependent targeting of PP2A in epithelial cells, we identify PP2A as the first serine/threonine phosphatase associated with the multiprotein TJ complex, and we unveil a novel role for PP2A in the regulation of epithelial aPKC and TJ assembly and function.
PP2A; aPKC; ZO-1; occludin; claudin
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (AD-NLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.
Parkinson’s disease; Parkinsonism; Dementia with Lewy bodies; Alzheimer’s disease; Incidental Lewy bodies; α-Synuclein; Spinal cord; Sympathetic nervous system; Peripheral nervous system; Autonomic nervous system; Enteric nervous system; Submandibular gland; Esophagus; Adrenal gland; Heart; Stomach; Gastrointestinal system
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.
Primary progressive aphasia; Frontotemporal dementia; Alzheimer disease; FTLD-TDP; TDP-43 proteinopathy; Hippocampal sclerosis
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.
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
TDP-43 is a major component of the inclusions in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We studied TDP-43-pathology in the hippocampus and frontal cortex of autopsy brains with FTLD-U (n=68), dementia lacking distinctive histopathology (n=4), other neurodegenerative diseases (n=23), and controls (n=12). A marked enhancement of TDP-43-positive dystrophic neurites (DN) was obtained by using a sensitive immunohistochemistry protocol. Two previously unrecognized patterns of pathology were observed: frequent long DN in the CA1 region and frequent dot-like DN in the neocortical layer II, which were seen in 39% and 15% of the FTLD-U cases, respectively. Four FTLD-U cases showed no TDP-43 pathology and were reclassified as FTLD-U, non-TDP-43 proteinopathy. Frequent long DN, but not dot-like DN, were significantly associated with progranulin mutations. Three of the DLDH cases were reclassified as FTLD-U. Of the cases with other neurodegenerative diseases, 43% showed TDP-43-pathology in the hippocampus but only 4% in the frontal cortex. No TDP-43-pathology was seen in controls. These results indicate that the sensitivity of the TDP-43 immunohistochemistry method affects both the quantity of the pathology and the types of pathology that can be detected. Involvement of both the hippocampus and frontal cortex may be a diagnostically important feature in FTLD-U.
Frontotemporal lobar degeneration with ubiquitinated inclusions; frontotemporal lobar degeneration with motor neuron disease; dementia lacking distinctive histopathology; progranulin; TAR DNA-binding protein 43; dystrophic neurites; autopsy; immunohistochemistry