Publications by authors named "Stephen D Weigand"

128 Publications

NIA-AA Alzheimer's Disease Framework: Clinical Characterization of Stages.

Ann Neurol 2021 Mar 26. Epub 2021 Mar 26.

Department of Radiology, Mayo Clinic, Rochester, MN.

Background: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid.

Methods: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.

Results: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).

Interpretation: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26071DOI Listing
March 2021

Diffusion tensor imaging analysis in three progressive supranuclear palsy variants.

J Neurol 2021 Mar 12. Epub 2021 Mar 12.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Clinical variants of progressive supranuclear palsy (PSP) include the classic Richardson's syndrome (PSP-RS), as well as cortical presentations such as PSP-speech/language (PSP-SL) and subcortical presentations such as PSP-parkinsonism (PSP-P). Patterns of white matter tract degeneration underlying these variants, and the degree to which white matter patterns could differentiate these variants, is unclear.

Methods: Forty-nine PSP patients (28 PSP-RS, 12 PSP-P, and 9 PSP-SL) were recruited by the Neurodegenerative Research Group and underwent diffusion tensor imaging. Regional diffusion tensor imaging metrics were compared across PSP variants using Bayesian linear mixed-effects models, with inter-variant differentiation assessed using the area under the receiver operator characteristic curve (AUROC).

Results: All three variants showed degeneration of the body of the corpus callosum, posterior thalamic radiation, superior cerebellar peduncle, internal and external capsule, and superior fronto-occipital fasciculus. PSP-RS showed greater degeneration of superior cerebellar peduncle compared to PSP-P and PSP-SL, whereas PSP-SL showed greater degeneration of body and genu of the corpus callosum, internal capsule, external capsule, and superior longitudinal fasciculus compared to the other variants. Fractional anisotropy in body of the corpus callosum provided excellent differentiation of PSP-SL from both PSP-P and PSP-RS (AUROC = 0.91 and 0.92, respectively). Moderate differentiation of PSP-RS and PSP-P was achieved with fractional anisotropy in superior fronto-occipital fasciculus (AUROC = 0.68) and mean diffusivity in the superior cerebellar peduncle (AUROC = 0.65).

Conclusion: In this pilot study, patterns of white matter tract degeneration differed across PSP-RS, PSP-SL, and PSP-P, with the body of the corpus callosum showing some utility in the differentiation of PSP-SL from the other two variants.
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http://dx.doi.org/10.1007/s00415-020-10360-1DOI Listing
March 2021

CSF dynamics as a predictor of cognitive progression.

Neuroimage 2021 May 23;232:117899. Epub 2021 Feb 23.

Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117899DOI Listing
May 2021

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

J Alzheimers Dis 2021 ;80(2):683-693

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.

Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.

Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.

Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.

Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.
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http://dx.doi.org/10.3233/JAD-201166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020877PMC
January 2021

Iron Heterogeneity in Early Active Multiple Sclerosis Lesions.

Ann Neurol 2021 03 19;89(3):498-510. Epub 2020 Dec 19.

Department of Anatomy, Physiology, and Pharmacology/Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Objective: Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.

Methods: We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.

Results: Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17-127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3-64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = -40 to -14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron.

Interpretation: Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498-510.
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http://dx.doi.org/10.1002/ana.25974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986227PMC
March 2021

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Brain 2020 12;143(11):3463-3476

Department of Radiology (Radiology Research) Mayo Clinic, Rochester, MN, USA.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.
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http://dx.doi.org/10.1093/brain/awaa299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719030PMC
December 2020

Predicting future rates of tau accumulation on PET.

Brain 2020 10;143(10):3136-3150

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.
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http://dx.doi.org/10.1093/brain/awaa248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586089PMC
October 2020

Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers.

Neuroimage 2021 01 6;224:117433. Epub 2020 Oct 6.

Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860631PMC
January 2021

Sensitivity-Specificity of Tau and Amyloid β Positron Emission Tomography in Frontotemporal Lobar Degeneration.

Ann Neurol 2020 11 12;88(5):1009-1022. Epub 2020 Sep 12.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: To examine associations between tau and amyloid β (Aβ) molecular positron emission tomography (PET) and both Alzheimer-related pathology and 4-repeat tau pathology in autopsy-confirmed frontotemporal lobar degeneration (FTLD).

Methods: Twenty-four patients had [ F]-flortaucipir-PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD-TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)-PET. Braak staging, Aβ plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta-ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden.

Results: Nine cases (37.5%) had Aβ plaques. Global PiB SUVR correlated with Aβ plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty-one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta-ROI SUVRs were not elevated in Braak IV or primary age-related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions.

Interpretation: Molecular PET shows expected correlations with Alzheimer-related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009-1022.
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http://dx.doi.org/10.1002/ana.25893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861121PMC
November 2020

CSF biomarkers in Olmsted County: Evidence of 2 subclasses and associations with demographics.

Neurology 2020 07 26;95(3):e256-e267. Epub 2020 Jun 26.

From the Departments of Neurology (A.C.V.H., M.M.M., D.S.K., R.C.P.), Health Sciences Research (H.J.W., S.D.W., M.M.M., W.K.K., R.C.P.), Laboratory Medicine and Pathology (R.B.D.), and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center Amsterdam UMC (A.C.V.H.), the Netherlands; and Roche Diagnostics (U.E., R.B.-U., A.A.-S.), Basel, Switzerland.

Objective: We studied interrelationships between CSF biomarkers and associations with ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.

Methods: We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.

Results: Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.

Conclusion: We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.
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http://dx.doi.org/10.1212/WNL.0000000000009874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455353PMC
July 2020

Association between transactive response DNA-binding protein of 43 kDa type and cognitive resilience to Alzheimer's disease: a case-control study.

Neurobiol Aging 2020 08 15;92:92-97. Epub 2020 Apr 15.

Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Association between the transactive response DNA-binding protein of 43 kDa (TDP-43), its newly described types (type α/type β), and resilience to Alzheimer's disease neuropathological change (ADNC) defined as preservation of normal cognitive functioning despite advanced ADNC has been evaluated in this case-control study of 63 older adults. Twenty-one resilient to ADNC individuals were matched 1:2 to nonresilient (Alzheimer's dementia) using propensity scores, accounting for age at death, neuritic plaque density, and neurofibrillary tangle stage. Resilient and matched nonresilient participants were similar in terms of gender, apolipoprotein E ε4 carriership, education, occupation, AD, and other pathologies. Resilient participants had lower frequency of TDP-43 co-pathology compared to nonresilient (19% vs. 62%, p = 0.002). Among TDP-43-positive cases, TDP-43 type α inclusions were absent in resilient to ADNC participants and were dominant in matched nonresilient cases (65%, p = 0.03). TDP-43 and TDP-43 types appear to be one of the key pathological determinants of loss of cognitive resilience to ADNC and hence are important in the understanding of the clinical expression of ADNC.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682814PMC
August 2020

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous.

Ann Clin Transl Neurol 2020 05 15;7(5):707-721. Epub 2020 Apr 15.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Objective: To assess the relationships between MRI volumetry and [ F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by decade).

Methods: Five-hundred and sixty-four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer's dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and C-PiB; all 166 Alzheimer's participants were beta-amyloid positive and all controls were beta-amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal-to-neocortical and entorhinal-to-neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50-59, 60-69, and 70+). Voxel-level analyses were also performed.

Results: For 50-59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel-level analysis. For 60-69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60-69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes.

Interpretation: MRI volumetry versus flortaucipir PET relationships differ across Alzheimer's clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta-amyloid and tau-positive biomarker defined Alzheimer's disease.
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http://dx.doi.org/10.1002/acn3.51038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261766PMC
May 2020

Longitudinal Amyloid-β PET in Atypical Alzheimer's Disease and Frontotemporal Lobar Degeneration.

J Alzheimers Dis 2020 ;74(1):377-389

Department of Neurology, Division of Behavioral Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer's dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer's disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD).

Objective: We aimed tocharacterize longitudinal Aβ accumulation anddetermine the influence of age, apolipoprotein E (APOE) genotype, disease duration, and sexin atypical AD and FTLD.

Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serialPiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ.

Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOEɛ4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET≤4 years. Female sex was associated with faster rates of accumulation in atypical AD.

Conclusion: Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influence accumulation in these diseases providing insight into potentially different biological mechanisms of Aβ deposition.
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http://dx.doi.org/10.3233/JAD-190699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078031PMC
January 2020

Brain volume and flortaucipir analysis of progressive supranuclear palsy clinical variants.

Neuroimage Clin 2020 28;25:102152. Epub 2019 Dec 28.

Department of Neurology, Mayo Clinic, Rochester, MN, United States.

Background And Purpose: Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that is associated with different clinical variants, including PSP-Richardson's syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-corticobasal syndrome (PSP-CBS), PSP-frontal (PSP-F), PSP-progressive gait freezing (PSP-PGF) and PSP-speech/language (PSP-SL). While PSP-RS has been well-characterized on neuroimaging, the characteristics of the other atypical variants are less well defined and it is unknown how they compare to each other or relate to neuropathology. We aimed to assess and compare regional atrophy on MRI and [F]flortaucipir uptake on PET across PSP variants.

Materials And Methods: 105 PSP patients (53 PSP-RS, 23 PSP-SL, 12 PSP-P, 8 PSP-CBS, 5 PSP-F and 4 PSP-PGF) underwent volumetric MRI, with 59 of these also undergoing flortaucipir PET. Voxel-level and region-level analyses were performed comparing PSP variants to 30 controls and to each other. Semi-quantitative tau burden measurements were also performed in 21 patients with autopsy-confirmed PSP.

Results: All variants showed evidence for atrophy or increased flortaucipir uptake in striatum, globus pallidus and thalamus. Superior cerebellar peduncle volume loss was only observed in PSP-RS, PSP-CBS and PSP-F. Volume loss in the frontal lobes was observed in PSP-SL, PSP-CBS and PSP-F, with these variants also showing highest cortical tau burden at autopsy. The PSP-P and PSP-PGF variants showed more restricted patterns of neurodegeneration predominantly involving striatum, globus pallidus, subthalamic nucleus and thalamus. The PSP-SL variant showed greater volume loss and flortaucipir uptake in supplementary motor area and motor cortex compared to all other variants, but showed less involvement of subthalamic nucleus and midbrain. Compared to PSP-RS, PSP-P had larger midbrain volume and greater flortaucipir uptake in putamen.

Conclusion: The PSP variants have different patterns of involvement of subcortical circuitry, perhaps suggesting different patterns of disease spread through the brain. These findings will be important in the development of appropriate neuroimaging biomarkers for the different PSP variants.
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http://dx.doi.org/10.1016/j.nicl.2019.102152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961761PMC
December 2020

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer's Disease Neuropathological Changes.

J Alzheimers Dis 2020 ;73(4):1511-1523

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer's disease (AD), but whether the association is modified by other factors is unknown.

Objective: To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE) ɛ4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage.

Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOEɛ4, presence of LBs, Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models.

Results: Older age, female gender, APOEɛ4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOEɛ4 carriers (p = 0.04).

Conclusion: Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.
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http://dx.doi.org/10.3233/JAD-191040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081101PMC
January 2020

The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes.

Brain 2019 10;142(10):3230-3242

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-β and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.
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http://dx.doi.org/10.1093/brain/awz268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763736PMC
October 2019

Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer's Association Research Framework.

JAMA Neurol 2019 Jul 15. Epub 2019 Jul 15.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

Importance: A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms.

Objectives: To estimate the sex- and age-specific prevalence of 3 imaging biomarker-based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease.

Design, Setting, And Participants: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019.

Main Outcomes And Measures: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease).

Results: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women.

Conclusions And Relevance: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.
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http://dx.doi.org/10.1001/jamaneurol.2019.1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632154PMC
July 2019

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia.

JAMA 2019 06;321(23):2316-2325

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers.

Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information.

Design, Setting, And Participants: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018.

Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles.

Main Outcomes And Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only.

Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier.

Conclusions And Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.
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http://dx.doi.org/10.1001/jama.2019.7437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582267PMC
June 2019

Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults.

Neurology 2019 07 30;93(1):e29-e39. Epub 2019 May 30.

From the Departments of Radiology (V.J.L., T.J.B., H.-K.M., P.F., M.L.S., M.K.P., K.K., D.T.J., P.V., C.G.S., C.R.J.), Health Sciences Research (H.J.W., S.D.W., T.M.T., M.M. Mielke, R.O.R.), Information Technology (M.L.S.), Neurology (B.F.B., K.A.J., D.T.J., J.G.-R., M.M. Mielke, D.S.K., R.C.P.), Neuroscience (M.E.M.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN.

Objective: To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.

Methods: Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49.

Results: Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+.

Conclusions: Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.
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http://dx.doi.org/10.1212/WNL.0000000000007728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659005PMC
July 2019

Brain atrophy in primary age-related tauopathy is linked to transactive response DNA-binding protein of 43 kDa.

Alzheimers Dement 2019 06 2;15(6):799-806. Epub 2019 May 2.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Introduction: Primary age-related tauopathy (PART) is characterized by the presence of neurofibrillary tangles and absent-minimal β-amyloid deposition. Transactive response DNA-binding protein of 43 kDa (TDP-43), a third protein, has recently garnished a lot of attention in Alzheimer's disease where it is associated with memory loss and amygdala and hippocampal atrophy. We aimed to determine whether TDP-43 is associated with brain atrophy in PART.

Methods: We assessed the frequency of TDP-43 in PART and performed voxel-level analysis in SPM12, as well as region-of-interest analysis using linear regression modeling, controlling for variables of interest, to assess for associations between TDP-43 and brain atrophy.

Results: Of 116 PART cases, 31 (26.7%) had TDP-43. The presence of TDP-43 was associated with significantly greater amygdala, hippocampal, and anterior temporal atrophy in both the region-of-interest and the voxel level analyses.

Discussion: TDP-43 is associated with greater brain atrophy in PART.
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http://dx.doi.org/10.1016/j.jalz.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556401PMC
June 2019

The role of age on tau PET uptake and gray matter atrophy in atypical Alzheimer's disease.

Alzheimers Dement 2019 05 8;15(5):675-685. Epub 2019 Mar 8.

Department of Neurology, Mayo Clinic, Rochester MN, USA.

Introduction: Little is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD).

Methods: Regional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model.

Results: Age was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance.

Discussion: Age is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.
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http://dx.doi.org/10.1016/j.jalz.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511453PMC
May 2019

The influence of tau, amyloid, alpha-synuclein, TDP-43, and vascular pathology in clinically normal elderly individuals.

Neurobiol Aging 2019 05 21;77:26-36. Epub 2019 Jan 21.

Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Many individuals live to older ages without clinical impairment. It is unknown whether brain pathologies in these individuals are associated with subtle clinical deficits. We analyzed the brains of 161 clinically normal (Clinical Dementia Rating score = 0) older individuals enrolled in the Mayo Clinic Patient Registry or Study of Aging. We assessed for the presence and burden of beta-amyloid, tau, alpha-synuclein, TDP-43, and vascular pathology. We investigated whether pathologies were associated with antemortem cognitive and motor function, depression, MRI volumetric measures, or the apolipoprotein E (APOE) ε4 allele. Eighty-six percent had at least 1 pathology, and 63% had mixed pathologies. Tau and vascular pathology were associated with poorer memory scores. Tau was also associated with poorer general cognition scores and smaller amygdala, hippocampi, and entorhinal cortex volumes. Beta-amyloid neuritic plaque burden was associated with greater depression scores. The presence of a greater number of pathologies was associated with APOE e4 carrier status and with poorer memory performance. Some dementia-related pathologies are associated with poorer performance in clinical measures and brain atrophy in the unimpaired elderly.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486870PMC
May 2019

The influence of β-amyloid on [F]AV-1451 in semantic variant of primary progressive aphasia.

Neurology 2019 02 11;92(7):e710-e722. Epub 2019 Jan 11.

From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.

Objective: To compare [F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ).

Methods: Thirty-one participants with svPPA underwent MRI and Pittsburgh compound B-PET scanning, and 17 of these also underwent [F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(-) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(-) controls.

Results: Of the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(-) participants. svPPA showed elevated [F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia.

Conclusion: Although [F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [F]AV-1451 in svPPA is related to binding paired helical filament tau.
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http://dx.doi.org/10.1212/WNL.0000000000006913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382367PMC
February 2019

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains.

Acta Neuropathol 2019 02 2;137(2):227-238. Epub 2019 Jan 2.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (- 10.6% [- 17.6%, - 3.5%]; p = 0.003) and hippocampal (- 14.4% [- 21.6%, - 7.3%]; p < 0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (- 7.77%, - 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.
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http://dx.doi.org/10.1007/s00401-018-1951-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358471PMC
February 2019

Predicting Progression to Mild Cognitive Impairment.

Ann Neurol 2019 01 7;85(1):155-160. Epub 2019 Jan 7.

Department of Radiology, Mayo Clinic, Rochester, MN.

Despite much attention to the use of biomarkers for predicting Alzheimer disease, little information is available at the individual level. We used the population-based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75-year-old with abnormal amyloid and cortical thinning biomarkers has about a 20% chance of cognitive impairment by age 80 years, whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. ANN NEUROL 2019;85:155-160.
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http://dx.doi.org/10.1002/ana.25388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504922PMC
January 2019

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia.

J Alzheimers Dis 2018 ;64(4):1227-1233

Background: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown.

Objective: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD.

Methods: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features.

Results: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43.

Conclusion: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.
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http://dx.doi.org/10.3233/JAD-180169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258191PMC
July 2019

Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer's disease.

Alzheimers Dement 2018 08 30;14(8):1005-1014. Epub 2018 Mar 30.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Introduction: Neuroimaging modalities can measure different aspects of the disease process in Alzheimer's disease, although the relationship between these modalities is unclear.

Methods: We assessed subject-level regional correlations between tau on [F]AV-1451 positron emission tomography (PET), β amyloid on Pittsburgh compound B PET, hypometabolism on [F] fluorodeoxyglucose PET, and cortical thickness on magnetic resonance imaging in 96 participants with typical and atypical Alzheimer's disease presentations. We also assessed how correlations between modalities varied according to age, presenting syndrome, tau-PET severity, and asymmetry.

Results: [F]AV-1451 uptake showed the strongest regional correlation with hypometabolism. Correlations between [F]AV-1451 uptake and both hypometabolism and cortical thickness were stronger in participants with greater cortical tau severity. In addition, age, tau asymmetry, and clinical diagnosis influenced the strength of the correlation between [F]AV-1451 uptake and cortical thickness.

Discussion: These findings support a close relationship between tau and hypometabolism in Alzheimer's disease but show that correlations between neuroimaging modalities vary across participants.
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http://dx.doi.org/10.1016/j.jalz.2018.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097955PMC
August 2018

Longitudinal tau PET in ageing and Alzheimer's disease.

Brain 2018 05;141(5):1517-1528

Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.
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http://dx.doi.org/10.1093/brain/awy059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917767PMC
May 2018

[ F]AV-1451 tau-PET and primary progressive aphasia.

Ann Neurol 2018 03 13;83(3):599-611. Epub 2018 Mar 13.

Department of Neuroradiology, Mayo Clinic, Rochester, MN.

Objectives: To assess [ F]AV-1451 tau-PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [ F]AV-1451 independent of clinical diagnosis, and compare the diagnostic utility of [ F]AV-1451, [ F]-fluorodeoxygluclose (FDG)-PET and MRI (magnetic resonance imaging) to differentiate the PPA variants.

Methods: We performed statistical parametric mapping of [ F]AV-1451 across 40 PPA patients (logopenic-PPA = 14, semantic-PPA = 13, and agrammatic-PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B-negative controls, age and gender matched 2:1. Principal component analysis of regional [ F]AV-1451 tau-PET standard uptake value ratio was performed to understand underlying patterns of [ F]AV-1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility.

Results: Logopenic-PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic-PPA, and agrammatic-PPA. Semantic-PPA and agrammatic-PPA showed milder patterns of focal [ F]AV-1451 uptake. Semantic-PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic-PPA. Agrammatic-PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic-PPA. The principal component analysis of regional [ F]AV-1451 indicated two primary dimensions, a severity dimension that distinguished logopenic-PPA from agrammatic-PPA and semantic-PPA, and a frontal versus temporal contrast that distinguishes agrammatic-PPA and semantic-PPA cases. Diagnostic utility of [ F]AV-1451was superior to MRI and at least equal to FDG-PET.

Interpretation: [ F]AV-1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [ F]AV-1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [ F]AV-1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599-611.
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http://dx.doi.org/10.1002/ana.25183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896771PMC
March 2018

Sex differences in cerebrovascular pathologies on FLAIR in cognitively unimpaired elderly.

Neurology 2018 02 17;90(6):e466-e473. Epub 2018 Jan 17.

From the Departments of Radiology (F.F., K.K., G.M.P., C.R.J., P.V.), Health Sciences Research (S.D.W., S.A.P., R.O.R., M.M. Mielke), Neurology (J.G.-R., D.S.K., R.O.R., M.M. Mielke, R.C.P.), and Psychology (M.M. Machulda), Mayo Clinic Rochester; and School of Medicine (F.F.), University of Minnesota, Minneapolis.

Objective: To examine sex differences in cerebrovascular pathologies (CVPs) as seen on fluid-attenuated inversion recovery (FLAIR) MRI and in cardiovascular and metabolic risk factors in a population-based cognitively unimpaired cohort and to examine whether sex is independently associated with FLAIR findings after accounting for differences in important midlife risk factors.

Methods: We identified 1,301 cognitively normal participants (663 men and 638 women) enrolled in the Mayo Clinic Study of Aging (age ≥70 years) who had FLAIR MRI and ascertained total burden of white matter (WM) hyperintensities (WMH), subcortical infarctions, and cortical infarctions. We compared CVPs and midlife and late-life vascular risk factors between men and women. We fit regression models with each CVP as an outcome, treating age, sex, and midlife risk factors as predictors.

Results: Women had significantly greater WMH volume relative to their WM volume compared to men (2.8% vs 2.4% of WM, < 0.001), while men had a greater frequency of cortical infarctions compared to women (9% vs 4%, < 0.001). Subcortical infarctions were equally common in men and women (20%). In regression modeling after adjustment for WM volume, the mean WMH volume difference between men and women was of the same magnitude as a 7-year difference in age. In contrast, men had 2.2-greater relative odds of having a cortical infarction compared to women. These sex differences persisted even after adjustment for midlife vascular risk factors.

Conclusions: There were important sex differences in CVP findings on FLAIR in cognitively unimpaired elderly. Understanding these sex differences could aid in the development of sex-specific preventive strategies.
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http://dx.doi.org/10.1212/WNL.0000000000004913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818016PMC
February 2018