Neurofibrillary Tangle Scores Research Articles

Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.

Accumulation of pathological tau isoforms, especially hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers, has been demonstrated in the retinas of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous studies have noted a decrease in retinal ganglion cells (RGCs) in AD patients, but the presence and impact of pathological tau isoforms in RGCs and RGC integrity, particularly in early AD stages, have not been explored. To investigate this, we examined retinal superior temporal cross-sections from 25 patients with MCI (due to AD) or AD dementia and 16 cognitively normal (CN) controls, matched for age and gender. We utilized the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining to assess neuronal density in the ganglion cell layer (GCL). Our study found that hypertrophic RGCs containing pS396-tau and T22-positive tau oligomers were more frequently observed in MCI and AD patients compared to CN subjects. Quantitative analyses indicated a decline in RGC integrity, with 46-55% and 55-56% reductions of RBPMS+ RGCs (P<0.01) and Nissl+ GCL neurons (P<0.01-0.001), respectively, in MCI and AD patients. This decrease in RGC count was accompanied by increases in necroptotic-like morphology and the cleaved caspase-3 apoptotic marker in RGCs of AD patients. Furthermore, there was a 2.1 to 3.1-fold increase (P<0.05-0.0001) in pS396-tau-laden RGCs in MCI and AD patients, with a greater abundance observed in individuals with higher Braak stages (V-VI), more severe clinical dementia ratings (CDR=3), and lower mini-mental state examination (MMSE) scores. Strong correlations were noted between the decline in RGCs and the total amount of retinal pS396-tau and pS396-tau+ RGCs, with pS396-tau+ RGC counts correlating significantly with brain neurofibrillary tangle scores (r= 0.71, P= 0.0001), Braak stage (r= 0.65, P= 0.0009), and MMSE scores (r= -0.76, P= 0.0004). These findings suggest that retinal tauopathy, characterized by pS396-tau and oligomeric tau in hypertrophic RGCs, is associated with and may contribute to RGC degeneration in AD. Future research should validate these findings in larger cohorts and explore noninvasive retinal imaging techniques that target tau pathology in RGCs to improve AD detection and monitor disease progression.

Early tau detection in flortaucipir images: validation in autopsy-confirmed data and implications for disease progression

BackgroundThere is an increasing interest in utilizing tau PET to identify patients early in Alzheimer’s disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated.MethodsA total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (ADsignature) (Devous et al., J Nucl Med 59:937–43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944–51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/ADsignature+; Eτ+/ADsignature–; Eτ−/ADsignature−). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/ADsignature− group and B2 NFT scores were created for visual evaluation of uptake.ResultsSixty-four out of 390 analyzable subjects were identified as Eτ+/ADsignature–: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/ADsignature– status reflects an early stage of AD, Eτ+/ADsignature– subjects deteriorated significantly faster than Eτ–/ADsignature– subjects, but significantly slower than Eτ+/ADsignature+ subjects, on most measures (i.e., change in ADsignature SUVr, Eτ ROI cortical thickness, and MMSE). The ADsignature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/ADsignature–. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects.ConclusionThe Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/ADsignature–) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/ADsignature– subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ−/ADsignature− subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer’s disease.

Association of Tripartite Motif Containing 11 rs564309 With Tau Pathology in Progressive Supranuclear Palsy.

Intronic variant rs564309 in tripartite motif containing 11 (TRIM11) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP-Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes. Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi-quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies. 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309-A using multivariable linear regression models. TRIM11 rs564309-A was associated with increased neurofibrillary tangles pathology (P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores. TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society.

Association of MAPT Subhaplotypes With Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology

ImportanceThe association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease.ObjectiveTo comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases.Design, Setting, and ParticipantsA case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018.Main Outcomes and MeasuresPresence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases.ResultsFor 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95% CI, 1.43-2.42; P = 2 × 10−6), H1g (odds ratio, 3.64; 95% CI, 2.04-6.50; P = 2 × 10−6), and H1o (odds ratio, 2.60; 95% CI, 1.63-4.16; P = 2 × 10−5). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes.Conclusions and RelevanceThis study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP.

Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

Previous evidence linking diabetes to Alzheimer's disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries. To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults. In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. Astandardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic regression. We investigated effect modification of education, race, and APOE on these associations. Among 1,037 subjects (mean age = 74.4±11.5 y; mean education = 4.0±3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR = 1.12, 95% CI = 0.81-1.54, p = 0.48) or with CERAD (OR = 0.97, 95% CI = 0.68-1.38, p = 0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ɛ4 on the association between diabetes mellitus and BB scores. No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ɛ4 carriers, had higher odds of accumulation of neurofibrillary tangles.

New cerebrospinal fluid biomarkers in Alzheimer’s disease

New cerebrospinal fluid biomarkers in Alzheimer’s disease

Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies isCorrelated with Disease Severity andSoluble Aβ42 Load.

Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42. TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity. TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology

We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes. We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging-funded Alzheimer's Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic. Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01-1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69-0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16-0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17-0.45) compared with symptomatic subjects. Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.

α-Synuclein Lesions in Normal Aging, Parkinson Disease, and Alzheimer Disease: Evidence from the Baltimore Longitudinal Study of Aging (BLSA)

In a recent autopsy study, Mikolaenko et al (1), examining 117 elderly individuals, found α-synuclein (AS) lesions in a total of 25%, i.e. in 100% of PD cases (n = 7), 31.5% of brains with AD lesions (n = 56), and only 8.3% among older controls (n = 36). Among AD cases, the frequency of AS lesions was higher in those with higher neuritic plaque scores than in those with higher neurofibrillary tangle scores. While AS lesions were rare in aged controls, the coexistence of AS and Aβ pathologies in AD suggested similar pathogenic mechanisms. These data on the frequency of AS lesions are at variance to …

Alpha-Synuclein Lesions in Normal Aging, Parkinson Disease, and Alzheimer Disease: Evidence from the Baltimore Longitudinal Study of Aging (BLSA)

Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.