Carlos, Arenn F.

Abstract INTRODUCTION Greater white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are seen with transactive response DNA‐binding protein 43 (TDP‐43) pathology in frontotemporal lobar degeneration (FTLD‐TDP). WMH associations with TDP‐43 pathology in Alzheimer's disease (AD‐TDP) remain unclear. METHODS A total of 157 participants from Mayo Clinic Rochester with autopsy‐confirmed AD, known TDP‐43 status, and antemortem fluid‐attenuated inversion recovery (FLAIR) MRI were included. Vascular risk factors were assessed. A semi‐automated WMH segmentation‐quantification process produced total and regional WMH volumes. Penalized linear regression models adjusting for age at MRI analyzed TDP‐43 associations (status and typing) with WMHs. RESULTS TDP‐43‐positive status was not associated with WMH burden overall because opposite effects were seen based on AD‐TDP typing. Despite similar antemortem vascular risk factors and postmortem vascular pathologies, AD‐TDP type‐ α showed greater total and regional WMH burden (particularly in subcortical frontotemporal and basal ganglia regions) than TDP‐43 negatives and AD‐TDP type‐ β . DISCUSSION AD‐TDP types may have different WMH pathomechanisms, with type‐ α having associations more like FTLD‐TDP than AD. Highlights In transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer's disease (AD‐TDP), TDP‐43 status alone is not associated with total or regional WMH burden AD‐TDP type‐ α shows greater total, frontotemporal subcortical, and basal ganglia white matter hyperintensities (WMHs) AD‐TDP type‐ β shows less total and subcortical occipital WMHs AD‐TDP type‐ α effect on WMH burden closely mimics the effects of frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) rather than AD Different relationships of AD‐TDP types with WMHs suggest different pathomechanisms

Abstract Progressive supranuclear palsy is a neurodegenerative disease characterized by the deposition of four-repeat tau in neuronal and glial lesions in the brainstem, cerebellar, subcortical and cortical brain regions. There are varying clinical presentations of progressive supranuclear palsy with different neuroimaging signatures, presumed to be due to different topographical distributions and burden of tau. The classic Richardson syndrome presentation is considered a subcortical variant, whilst progressive supranuclear palsy with predominant speech and language impairment is considered a cortical variant, although the pathological underpinnings of these variants are unclear. In this case-control study, we aimed to determine whether patterns of regional tau pathology differed between these variants and whether tau burden correlated with neuroimaging. Thirty-three neuropathologically confirmed progressive supranuclear palsy patients with either the Richardson syndrome (n = 17) or speech/language (n = 16) variant and ante-mortem magnetic resonance imaging were included. Tau lesion burden was semi-quantitatively graded in cerebellar, brainstem, subcortical and cortical regions and combined to form neuronal and glial tau scores. Regional magnetic resonance imaging volumes were converted to Z-scores using 33 age- and sex-matched controls. Diffusion tensor imaging metrics, including fractional anisotropy and mean diffusivity, were calculated. Tau burden and neuroimaging metrics were compared between groups and correlated using linear regression models. Neuronal and glial tau burden were higher in motor and superior frontal cortices in the speech/language variant. In the subcortical and brainstem regions, only the glial tau burden differed, with a higher burden in globus pallidus, subthalamic nucleus, substantia nigra and red nucleus in Richardson’s syndrome. No differences were observed in the cerebellar dentate and striatum. Greater volume loss was observed in the motor cortex in the speech/language variant and in the subthalamic nucleus, red nucleus and midbrain in Richardson’s syndrome. Fractional anisotropy was lower in the midbrain and superior cerebellar peduncle in Richardson’s syndrome. Mean diffusivity was greater in the superior frontal cortex in the speech/language variant and midbrain in Richardson’s syndrome. Neuronal tau burden showed associations with volume loss, lower fractional anisotropy and higher mean diffusivity in the superior frontal cortex, although these findings did not survive correction for multiple comparisons. Results suggest that a shift in the distribution of tau, particularly neuronal tau, within the progressive supranuclear palsy network of regions is driving different clinical presentations in progressive supranuclear palsy. The possibility of different disease epicentres in these clinical variants has potential implications for the use of imaging biomarkers in progressive supranuclear palsy.

Abstract Two variants of semantic dementia are recognized based on the laterality of temporal lobe involvement: a left-predominant variant associated with verbal knowledge impairment and a right-predominant variant associated with behavioural changes and non-verbal knowledge loss. This cross-sectional clinicoradiologic study aimed to assess whole hippocampal, subregion, and/or subfield volume loss in semantic dementia versus controls and across its variants. Thirty-five semantic dementia participants and 15 controls from the Neurodegenerative Research Group at Mayo Clinic who had completed 3.0-T volumetric magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography were included. Classification as left-predominant (n = 25) or right-predominant (n = 10) variant was based on temporal lobe hypometabolism. Volumes of hippocampal subregions (head, body, and tail) and subfields (parasubiculum, presubiculum, subiculum, cornu ammonis 1, cornu ammonis 3, cornu ammonis 4, dentate gyrus, molecular layer, hippocampal–amygdaloid transition area, and fimbria) were obtained using FreeSurfer 7. Subfield volumes were measured separately from head and body subregions. We fit linear mixed-effects models using log-transformed whole hippocampal/subregion/subfield volumes as dependent variables; age, sex, total intracranial volume, hemisphere and a group-by-hemisphere interaction as fixed effects; and subregion/subfield nested within hemisphere as a random effect. Significant results (P < 0.05) are hereby reported. At the whole hippocampal level, the dominant (predominantly involved) hemisphere of both variants showed 23–27% smaller volumes than controls. The non-dominant (less involved) hemisphere of the right-predominant variant also showed volume loss versus controls and the left-predominant variant. At the subregional level, both variants showed 17–28% smaller dominant hemisphere head, body, and tail than controls, with the right-predominant variant also showing 8–12% smaller non-dominant hemisphere head than controls and left-predominant variant. At the subfield level, the left-predominant variant showed 12–36% smaller volumes across all dominant hemisphere subfields and 14–15% smaller non-dominant hemisphere parasubiculum, presubiculum (head and body), subiculum (head) and hippocampal–amygdaloid transition area than controls. The right-predominant variant showed 16–49% smaller volumes across all dominant hemisphere subfields and 14–22% smaller parasubiculum, presubiculum, subiculum, cornu ammonis 3, hippocampal–amygdaloid transition area (all from the head) and fimbria of non-dominant hemisphere versus controls. Comparison of dominant hemispheres showed 16–29% smaller volumes of the parasubiculum, presubiculum (head) and fimbria in the right-predominant than left-predominant variant; comparison of non-dominant hemispheres showed 12–15% smaller cornu ammonis 3, cornu ammonis 4, dentate gyrus, hippocampal–amygdaloid transition area (all from the head) and cornu ammonis 1, cornu ammonis 3 and cornu ammonis 4 (all from the body) in the right-predominant variant. All hippocampal subregion/subfield volumes are affected in semantic dementia, although some are more affected in both dominant and non-dominant hemispheres of the right-predominant than the left-predominant variant by the time of presentation. Involvement of hippocampal structures is apparently more subregion dependent than subfield dependent, indicating possible superiority of subregion volumes as disease biomarkers.

Abstract Disruption of the default mode network is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of Alzheimer’s disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer’s disease participants diagnosed with posterior cortical atrophy (n = 33) or logopenic progressive aphasia (n = 28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer’s disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer’s disease participants, 26 amnestic Alzheimer’s disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1–2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer’s disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer’s disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer’s disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical Alzheimer’s disease. Connectivity in the ventral default mode network declined over time in atypical Alzheimer’s disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer’s disease variants, and discriminated Alzheimer’s disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau pathology.

AbstractBackgroundThe language and visual variants are two common clinical phenotypes of atypical Alzheimer’s disease (AD). There are reports of overlap between these clinical phenotypes, however, the extent and frequency of overlap, and its neuroanatomical underpinnings remain unclear.MethodEighty‐two patients with biomarker‐confirmed AD who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits were recruited by the Neurodegenerative Research Group and underwent neurological and neuropsychological testing, MRI and [18F]flortaucipir‐PET. The clinical examination included testing for simultanagnosia, Gerstmann’s syndrome, ideomotor apraxia, visuospatial‐visuoperceptual function, confrontational naming, sentence repetition and letter and animal fluency. Cut‐points for abnormality were defined for each test and used to classify the following groups: language‐pure (no visual‐function deficit), language‐plus (impaired on one visual‐function), language‐mixed (impaired on two visual‐functions), visual‐pure (no language‐function deficit), visual‐plus (impaired on one language‐function) and visual‐mixed (impaired on two language‐functions). Patterns of relative volume loss and flortaucipir uptake were assessed using SPM12.ResultOf the 82 patients, 11 (13%) were language‐pure, 16 (20%) language‐plus, 7 (8%) language‐mixed, 10 (12%) visual‐pure, 17 (21%) visual‐plus and 21 (26%) visual‐mixed, with no difference in disease duration across groups. Visual deficits in the language‐plus group consisted of mild simultanagnosia in 29%, Gerstmann’s syndrome in 24%, and mild visuospatial deficits. In the language‐mixed group 86% had simultanagnosia and 43% had Gerstmann’s syndrome, with visuospatial‐visuoperceptual deficits comparable to the visual‐pure group. Language deficits in the visual‐plus group consisted of mild anomia and reduced letter and animal fluency. The visual‐mixed group reported naming and repetition deficits, and reduced fluency, comparable to the language‐predominant groups. All three language groups showed left temporal volume loss and flortaucipir uptake, with greater involvement of the parieto‐occipital and frontal lobes in language‐plus and language‐mixed groups. All three visual groups showed occipital volume loss and flortaucipir uptake, with greater involvement of the parieto‐temporal and frontal lobes in visual‐plus and visual‐mixed groups.ConclusionOnly 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping. Syndromic overlap was associated with neuroanatomical overlap and more widespread patterns of atrophy and tau deposition.

AbstractBackgroundPosterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show overlapping patterns of hypometabolism affecting posterior regions of the brain. Both syndromes show disruptions in functional connectivity, but it is unknown how patterns of disruption within and between networks compare between PCA and DLB.MethodThirty amyloid‐positive PCA, 27 amyloid‐positive DLB (DLB+), 24 amyloid‐negative DLB (DLB‐) patients and 30 cognitively normal amyloid‐negative (CN) individuals were recruited at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore nine networks: visual, sensorimotor, dorsal‐attention, cerebellar, frontoparietal, memory, language, salience, and default mode networks (DMN). Multivariate linear regression models corrected for multiple comparisons and adjusted for age and sex were fit to analyze within‐network connectivity (Fisher’s R‐to‐Z transformations). Between‐network connectivity was assessed with group level difference maps (two‐sample t‐test) corrected for false discovery rate at p<0.05.ResultMultivariate linear regression models showed reduced within‐network connectivity across all DMN components, sensorimotor, and dorsal‐attention networks, with trends for the visual network in PCA compared to CN. Both DLB‐ and DLB+ showed reduced within‐network connectivity for the cerebellar network, with DLB+ showing reduced connectivity in the posterior‐DMN, memory, and salience networks compared to CN. DLB‐ showed increased connectivity in dorsal‐attention and DMN, while DLB+ showing reduced connectivity in the memory network compared to PCA. Between‐network analysis showed an increase in cerebellar‐to‐sensorimotor connectivity in all three groups, with increase in cerebellar‐to‐dorsal‐attention connectivity in DLB‐ and PCA compared to CN. DLB‐ showed a decrease in posterior‐DMN‐to‐sensorimotor connectivity, while PCA showed reduced connectivity between all DMN components and dorsal‐attention‐to‐sensorimotor connectivity compared to CN. There was an increase in connectivity between all DMN components and a reduction in dorsal‐DMN‐to‐sensorimotor connectivity in both DLB‐ and DLB+ compared to PCA.ConclusionPCA was associated with connectivity disruptions across all DMN components, sensorimotor, dorsal‐attention and visual networks, while both DLB groups showed disruptions in cerebellar networks, with DLB+ showing further disruptions in posterior‐DMN, memory and salience networks. These findings suggest that both PCA and DLB have unique brain network disruptions, with amyloid status influencing connectivity in DLB.

AbstractBackgroundPosterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are atypical variants of Alzheimer’s disease which typically show different cross‐sectional patterns of atrophy and tau deposition. Patterns of atrophy remain distinct longitudinally. A direct comparison of rates of atrophy and tau accumulation between these syndromes has not yet been reported.MethodWe evaluated 20 PCA and 20 LPA patients; all were amyloid‐positive on [11C]PiB‐PET. Structural MRI and tau‐PET were performed at baseline and one‐year follow‐up. Annualized rates of change in grey matter volume (log Jacobians from tensor‐based morphometry) and flortaucipir‐PET SUVRs were calculated at the lobar level. A global tau SUVR was calculated using parietal, temporal, and occipital regions. Lobar rates were compared between PCA and LPA with linear models, accounting for education, sex, age, baseline global tau SUVR (for tau‐PET), with significance set at p = 0.05. SPM voxel‐level comparisons were performed, with the same covariates, with significance set at p = 0.001.ResultGroups did not differ in age, Apoe status, baseline global tau SUVR or whole brain volume, or their annualized rates of change. LPA had shorter disease duration. In the lobar models, PCA had faster rates of atrophy in the occipital lobe and there were no significant differences on rates of tau accumulation, but a trend for LPA having faster rates of tau accumulation in all lobes. Baseline global tau SUVR was negatively associated with rate of tau accumulation in parietal and temporal lobes. Age was negatively associated with rates of tau accumulation in frontal, temporal and occipital lobes and with rates of atrophy in frontal and parietal lobes. Voxel‐level analysis confirmed these results, with PCA showing faster rates of occipital atrophy, and LPA showing subtle evidence for diffuse faster rates of tau accumulation (Figure 1).ConclusionLongitudinal patterns of neuroimaging abnormalities differ between PCA and LPA, although with divergent results for tau accumulation and atrophy that may reflect differences in disease stage. Rates of change are strongly influenced by age and severity of baseline tau, with faster rates of tau accumulation in patients with younger age and lower baseline tau deposition.

AbstractBackgroundIncreasing evidence suggests that transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer’s Disease (AD), or AD‐TDP, can be diffuse or limbic‐predominant. Understanding whether diffuse AD‐TDP has genetic, clinical, and pathological features that differ from limbic AD‐TDP could have clinical and research implications. We aimed to better characterize the clinicopathologic features of diffuse AD‐TDP and differentiate it from limbic‐predominant AD‐TDP pathology.MethodThree hundred sixty‐three participants were prospectively recruited and followed in the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group and died between May 1999 and August 2021. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. At postmortem evaluation, they showed Alzheimer’s disease neuropathologic changes and TDP‐43‐immunoreactive inclusions. The distribution of TDP‐43 pathology was assessed using the Josephs 6‐stage scheme. Participants with TDP‐43 stages 1‐3 were classified as Limbic, while those with stages 4‐6 were classified as Diffuse. Neuropathologically defined frontotemporal lobar degeneration cases were excluded. Multivariable logistic regression was used to identify clinicopathological features that predicted diffuse TDP‐43 pathology at postmortem. We hypothesized that the Diffuse group would show impairment in cognitive domains beyond episodic memory and more hippocampal sclerosis.ResultsThe cohort was 61% female and old at onset (median:76 years [IQR:70‐82]) and death (median:88 years [IQR:82‐92]). Fifty‐four percent (n = 197) were classified as Limbic and 46% (n = 166) as Diffuse. A “clinical” multivariate logistic regression fit to 85 participants with all clinical variables of interest showed that later age at onset (OR:1.09, 95%CI:1.01‐1.19;P = 0.03), longer disease duration (OR:1.17, 95%CI:1.02‐1.36;P = 0.03) and higher Neuropsychiatric Inventory scores (OR:1.14, 95%CI:1.01‐1.28;P = 0.03) all independently increased the odds of being Diffuse, while higher Trails Making Test‐B (OR:0.99, 95%CI:0.98‐0.99;P = 0.02) and Block Design Test scores (OR:0.91, 95%CI:0.85‐0.99;P = 0.023) independently decreased the odds of being Diffuse. A “pathology” multivariate logistic regression fit to 233 cases with all neuropathological data revealed that widespread amyloid‐β pathology corresponding to Thal phases 3‐5 all significantly decreased the odds of diffuse pathology by 80‐90%, while hippocampal sclerosis increased it sixfold (OR:6.18, 95% CI:2.93‐13.03;P<0.001).ConclusionsDiffuse AD‐TDP shows clinicopathological features that differ from Limbic AD‐TDP, which could have public health implications relating to treatment and research on AD and dementia.

AbstractBackgroundPosterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are atypical variants of Alzheimer’s disease which typically show different cross‐sectional patterns of atrophy and tau deposition. Patterns of atrophy remain distinct longitudinally. A direct comparison of rates of atrophy and tau accumulation between these syndromes has not yet been reported.MethodWe evaluated 20 PCA and 20 LPA patients; all were amyloid‐positive on [11C]PiB‐PET. Structural MRI and tau‐PET were performed at baseline and one‐year follow‐up. Annualized rates of change in grey matter volume (log Jacobians from tensor‐based morphometry) and flortaucipir‐PET SUVRs were calculated at the lobar level. A global tau SUVR was calculated using parietal, temporal, and occipital regions. Lobar rates were compared between PCA and LPA with linear models, accounting for education, sex, age, baseline global tau SUVR (for tau‐PET), with significance set at p = 0.05. SPM voxel‐level comparisons were performed, with the same covariates, with significance set at p = 0.001.ResultGroups did not differ in age, Apoe status, baseline global tau SUVR or whole brain volume, or their annualized rates of change. LPA had shorter disease duration. In the lobar models, PCA had faster rates of atrophy in the occipital lobe and there were no significant differences on rates of tau accumulation, but a trend for LPA having faster rates of tau accumulation in all lobes. Baseline global tau SUVR was negatively associated with rate of tau accumulation in parietal and temporal lobes. Age was negatively associated with rates of tau accumulation in frontal, temporal and occipital lobes and with rates of atrophy in frontal and parietal lobes. Voxel‐level analysis confirmed these results, with PCA showing faster rates of occipital atrophy, and LPA showing subtle evidence for diffuse faster rates of tau accumulation (Figure 1).ConclusionLongitudinal patterns of neuroimaging abnormalities differ between PCA and LPA, although with divergent results for tau accumulation and atrophy that may reflect differences in disease stage. Rates of change are strongly influenced by age and severity of baseline tau, with faster rates of tau accumulation in patients with younger age and lower baseline tau deposition.