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Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau).

ABSTRACT: Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of corticobasal degeneration (CBD; n?=?49), progressive supranuclear palsy (PSP; n?=?109), and Pick's disease (PiD; n?=?22). Nearly two-thirds of patients (n?=?115 of 180, 63.8%) with FTLD-tau had some degree of comorbid AD-tau pathology and 20.5% of the FTLD-tau cohort had Braak stage ?B2, consistent with medium-to-high-level AD neuropathological change (ADNPC). The PSP group had the highest frequency of medium-high AD-tau pathology compared to other tauopathies (PSP?=?31/109, 28.4%; Picks?=?2/22, 9.1%, CBD?=?4/49, 8.2%) but neuropathological diagnosis was not found to be a significant independent predictor of medium-high AD Braak stage in a multivariate model after accounting for age at death (OR?=?1.09; 95% CI?=?1.03-1.15; p?=?0.002) and CERAD plaque scores (OR?=?3.75, 95% CI?=?1.58-8.89; p?=?0.003), suggesting there is no predilection for a specific FTLD tauopathy to develop AD-tau co-pathology after accounting for age. Patients with FTLD-tau who had, clinically significant, medium-high AD-tau pathology had significantly higher antemortem CSF levels of both total-tau (t-tau; mean?=?89.98?pg/ml, SD?=?36.70?pg/ml) and phosphorylated-tau (p-tau; mean?=?20.45?pg/ml, SD?=?9.31?pg/ml) compared to patients with negligible-low AD-tau, t-tau (mean?=?43.04?pg/ml, SD?=?25.40?pg/ml) and p-tau (mean?=?11.90?pg/ml, SD?=?4.48?pg/ml) (p???0.001 both). Finally, in an exploratory analysis in our largest pathology group (PSP) we find an association of GT-38?AD-tau Braak stage with lower baseline MMSE (p?=?0.03). Together, these finding validate the use of GT-38 to selectively detect AD-tau pathology in the context of FTLD-tau and provides a novel tool to investigate associations of clinical phenotypes amongst co-morbid tauopathies.

SUBMITTER: Gibbons GS

PROVIDER: S-EPMC6399892 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau).

Gibbons Garrett S GS Kim Soo-Jung SJ Robinson John L JL Changolkar Lakshmi L Irwin David J DJ Shaw Leslie M LM Lee Virginia M-Y VM Trojanowski John Q JQ

Acta neuropathologica communications 20190304 1

Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of cortico ...[more]

PMID: 30832741

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Project description:Frontotemporal lobar degeneration with ? pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or ?-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.

Project description:An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration associated with TDP-43 pathology (FTLD-TDP). In addition to TDP-43-positive neuronal and glial inclusions, C9ORF72-linked FTLD-TDP has characteristic TDP-43-negative neuronal cytoplasmic and intranuclear inclusions as well as dystrophic neurites in the hippocampus and cerebellum. These lesions are immunopositive for ubiquitin and ubiquitin-binding proteins, such as sequestosome-1/p62 and ubiquilin-2. Studies examining the frequency of the C9ORF72 mutation in clinically probable Alzheimer's disease (AD) have found a small proportion of AD cases with the mutation. This prompted us to systematically explore the frequency of Alzheimer-type pathology in a series of 17 FTLD-TDP cases with mutations in C9ORF72 (FTLD-C9ORF72). We identified four cases with sufficient Alzheimer-type pathology to meet criteria for intermediate-to-high-likelihood AD. We compared AD pathology in the 17 FTLD-C9ORF72 to 13 cases of FTLD-TDP linked to mutations in the gene for progranulin (FTLD-GRN) and 36 cases of sporadic FTLD (sFTLD). FTLD-C9ORF72 cases had higher Braak neurofibrillary tangle stage than FTLD-GRN. Increased tau pathology in FTLD-C9ORF72 was assessed with thioflavin-S fluorescent microscopy-based neurofibrillary tangle counts and with image analysis of tau burden in temporal cortex and hippocampus. FTLD-C9ORF72 had significantly more neurofibrillary tangles and higher tau burden compared with FTLD-GRN. The differences were most marked in limbic regions. On the other hand, sFTLD and FTLD-C9ORF72 had a similar burden of tau pathology. These results suggest FTLD-C9ORF72 has increased propensity for tau pathology compared to FTLD-GRN, but not sFTLD. The accumulation of tau as well as lesions immunoreactive for ubiquitin and ubiquitin-binding proteins (p62 and ubiquilin-2) suggests that mutations in C9ORF72 may involve disrupted protein degradation that favors accumulation of multiple different proteins.

Project description:Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.

Project description:Frontotemporal lobar degeneration (FTLD) has been associated with toxic intracellular aggregates of hyperphosphorylated tau (FTLD-tau). Moreover, genetic studies identified mutations in the MAPT gene encoding tau in familial cases of the disease. In this review, we cover a range of aspects of tau function, both in the healthy and diseased brain, discussing several in vitro and in vivo models. Tau structure and function in the healthy brain is presented, accentuating its distinct compartmentalization in neurons and its role in microtubule stabilization and axonal transport. Furthermore, tau-driven pathology is discussed, introducing current concepts and the underlying experimental evidence. Different aspects of pathological tau phosphorylation, the protein's genomic and domain organization as well as its spreading in disease, together with MAPT-associated mutations and their respective models are presented. Dysfunction related to other post-transcriptional modifications and their effect on normal neuronal functions such as cell cycle, epigenetics and synapse dynamics are also discussed, providing a mechanistic explanation for the observations made in FTLD-tau cases, with the possibility for therapeutic intervention. In this review, we cover aspects of tau function, both in the healthy and diseased brain, referring to different in vitro and in vivo models. In healthy neurons, tau is compartmentalized, with higher concentrations found in the distal part of the axon. Cargo molecules are sensitive to this gradient. A disturbed tau distribution, as found in frontotemporal lobar degeneration (FTLD-tau), has severe consequences for cellular physiology: tau accumulates in the neuronal soma and dendrites, leading among others to microtubule depolymerization and impaired axonal transport. Tau forms insoluble aggregates that sequester additional molecules stalling cellular physiology. Neuronal communication is gradually lost as toxic tau accumulates in dendritic spines with subsequent degeneration of synapses and synaptic loss. Thus, by providing a mechanistic explanation for the observations made in FTLD-tau cases, arises a possibility for therapeutic interventions. This article is part of the Frontotemporal Dementia special issue.

Project description:Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

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

Dataset Information

Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau).

Publications

Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau).

Similar Datasets

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