Relationships between regional burden of tau pathology and age at death and disease duration in PSP.

BACKGROUND: A definitive diagnosis of progressive supranuclear palsy (PSP) can only be established through neuropathological evaluations where four cardinal tau lesions are identified. Relationships between regional tau burden and disease duration/age at death is unclear. OBJECTIVE: To investigate relationships between tau burden in different brain regions and disease duration and age at death in PSP and determine whether association are influenced by PSP subtype (subcortical/cortical) or co-pathologies. METHODS: We identified 45 patients with definite PSP who were evaluated at Mayo Clinic between 2009 and 2023, died and underwent histopathological evaluation. We performed semi-quantitative lesion count for each of four cardinal lesions (pretangles/globose neurofibrillary tangles, threads, tufted astrocytes, and coiled bodies) across 10 brain regions. We fit Bayesian linear hierarchical regression models to estimate the relationship between total pathological burden, and disease duration and age at death by region and the influence of subtype and co-pathologies. RESULTS: Of the 45 patients, 18 (40 %) were female. Median age at death was 75 (56-87) years and median disease duration was 8 (3,15) years. Younger age at death was associated with greater total tau burden in the pallidum, red nucleus, striatum, and subthalamic nucleus (all p ≤ 0.01). Shorter disease duration was associated with greater total tau burden in the red nucleus (p = 0.05). There was no evidence for a difference in association between lesion types. PSP subtype and co-pathologies did not influence associations. CONCLUSIONS: The findings from this study suggest that age and disease duration influence burden of tau pathology in subcortical regions in PSP.

Infrared spectral profiling of demyelinating activity in multiple sclerosis brain tissue.

Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. The highly dynamic nature of MS lesions has made them difficult to study using traditional histopathology due to the specificity of current stains. This requires numerous stains to track and study demyelinating activity in MS. Thus, we utilized Fourier transform infrared (FTIR) spectroscopy to generate holistic biomolecular profiles of demyelinating activities in MS brain tissue. Multivariate analysis can differentiate MS tissue from controls. Analysis of the absorbance spectra shows profound reductions of lipids, proteins, and phosphate in white matter lesions. Changes in unsaturated lipids and lipid chain length indicate oxidative damage in MS brain tissue. Altered lipid and protein structures suggest changes in MS membrane structure and organization. Unique carbohydrate signatures are seen in MS tissue compared to controls, indicating altered metabolic activities. Cortical lesions had increased olefinic lipid content and abnormal membrane structure in normal appearing MS cortex compared to controls. Our results suggest that FTIR spectroscopy can further our understanding of lesion evolution and disease mechanisms in MS paving the way towards improved diagnosis, prognosis, and development of novel therapeutics.

Flortaucipir PET uncovers relationships between tau and amyloid-ß in primary age-related tauopathy and Alzheimer's disease.

[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-ß. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-ß PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-ß phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-ß phase. Flortaucipir uptake linearly increased with the amyloid-ß phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-ß phase, and were useful for distinguishing different ADNC scores and PART.

Volumetric analysis of hippocampal subregions and subfields in left and right semantic dementia.

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.

Determinants of confrontation naming deficits on the Boston Naming Test associated with transactive response DNA-binding protein 43 pathology.

OBJECTIVE: To determine whether poorer performance on the Boston Naming Test (BNT) in individuals with transactive response DNA-binding protein 43 pathology (TDP-43+) is due to greater loss of word knowledge compared to retrieval-based deficits. METHODS: Retrospective clinical-pathologic study of 282 participants with Alzheimer's disease neuropathologic changes (ADNC) and known TDP-43 status. We evaluated item-level performance on the 60-item BNT for first and last available assessment. We fit cross-sectional negative binomial count models that assessed total number of incorrect items, number correct of responses with phonemic cue (reflecting retrieval difficulties), and number of "I don't know" (IDK) responses (suggestive of loss of word knowledge) at both assessments. Models included TDP-43 status and adjusted for sex, age, education, years from test to death, and ADNC severity. Models that evaluated the last assessment adjusted for number of prior BNT exposures. RESULTS: 43% were TDP-43+. The TDP-43+ group had worse performance on BNT total score at first (p = .01) and last assessments (p = .01). At first assessment, TDP-43+ individuals had an estimated 29% (CI: 7%-56%) higher mean number of incorrect items after adjusting for covariates, and a 51% (CI: 15%-98%) higher number of IDK responses compared to TDP-43-. At last assessment, compared to TDP-43-, the TDP-43+ group on average missed 31% (CI: 6%-62%; p = .01) more items and had 33% more IDK responses (CI: 1% fewer to 78% more; p = .06). CONCLUSIONS: An important component of poorer performance on the BNT in participants who are TDP-43+ is having loss of word knowledge versus retrieval difficulties.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aß)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide. DISCUSSION: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Molecular fragment characteristics and distribution of tangle associated TDP-43 (TATs) and other TDP-43 lesions in Alzheimer's disease.

TAR DNA binding protein 43 (TDP-43) pathology is a defining feature of frontotemporal lobar degeneration (FTLD). In FTLD-TDP there is a moderate-to-high burden of morphologically distinctive TDP-43 immunoreactive inclusions distributed throughout the brain. In Alzheimer's disease (AD), similar TDP-43 immunoreactive inclusions are observed. In AD, however, there is a unique phenomenon of neurofibrillary tangle-associated TDP-43 (TATs) whereby TDP-43 intermingles with neurofibrillary tangles. Little is known about the characteristics and distribution of TATs, or how burden and distribution of TATs compares to burden and distribution of other FTLD-TDP-like lesions observed in AD. Here we characterize molecular fragment characteristics, burden and distribution of TATs and assess how these features compare to features of other TDP-43 lesions. We performed TDP-43 immunohistochemistry with anti-phosphorylated, C- and N-terminal TDP-43 antibodies in 20 high-probability AD cases and semi-quantitative burden of seven inclusion types within five brain regions (entorhinal cortex, subiculum, CA1 and dentate gyrus of hippocampus, occipitotemporal cortex). Hierarchical cluster analysis was used to analyze the dataset that consisted of 75 different combinations of neuropathological features. TATs were nonspherical with heterogeneous staining patterns and present in all regions except hippocampal dentate. All three antibodies detected TATs although N-terminal antibody sensitivity was low. Three clusters were identified: Cluster-1 had mild-moderate TATs, moderate-frequent neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions and fine neurites, and perivascular and granular inclusions identified only with the N-terminal antibody throughout the brain; Cluster-2 had scant TATs in limbic regions and Cluster-3 mild-moderate TATs and mild-moderate neuronal cytoplasmic inclusions and dystrophic neurites throughout the brain and moderate fine neurites. Only 17% of cluster 1 cases had the TMEM106b GG (protective) haplotype and 83% had hippocampal sclerosis. Both features differed across clusters (p=0.03 & p=0.01). TATs have molecular characteristics, distribution and burden, and genetic and pathologic associations like FTLD-TDP lesions.

Magnetic Susceptibility in Progressive Supranuclear Palsy Variants, Parkinson's Disease, and Corticobasal Syndrome.

BACKGROUND: Previous studies have shown that magnetic susceptibility is increased in several subcortical regions in progressive supranuclear palsy (PSP). However, it is still unclear how subcortical and cortical susceptibilities vary across different PSP variants, Parkinson's disease (PD), and corticobasal syndrome (CBS). OBJECTIVE: This study aims to clarify the susceptibility profiles in the subcortical and cortical regions in different PSP variants, PD, and CBS. METHODS: Sixty-four patients, 20 PSP-Richardson syndrome (PSP-RS), 9 PSP-parkinsonism (PSP-P), 7 PSP-progressive gait freezing, 4 PSP-postural instability, 11 PD, and 13 CBS, and 20 cognitively normal control subjects underwent a 3-Tesla magnetic resonance imaging scan to reconstruct quantitative susceptibility maps. Region-of-interest analysis was performed to obtain susceptibility in several subcortical and cortical regions. Bayesian linear mixed effect models were used to estimate susceptibility within group and differences between groups. RESULTS: In the subcortical regions, patients with PSP-RS and PSP-P showed greater susceptibility than control subjects in the pallidum, substantia nigra, red nucleus, and cerebellar dentate (P < 0.05). Patients with PSP-RS also showed greater susceptibility than patients with PSP-progressive gait freezing, PD, and CBS in the red nucleus and cerebellar dentate, and patients with PSP-P showed greater susceptibility than PD in the red nucleus. Patients with PSP-postural instability and CBS showed greater susceptibility than control subjects in the pallidum and substantia nigra. No significant differences were observed in any cortical region. CONCLUSIONS: The PSP variants and CBS had different patterns of magnetic susceptibility in the subcortical regions. The findings will contribute to our understanding about iron profiles and pathophysiology of PSP and may provide a potential biomarker to differentiate PSP variants, PD, and CBS. © 2023 International Parkinson and Movement Disorder Society.

Effects of de-facing software mri_reface on utility of imaging biomarkers used in Alzheimer's disease research.

Brain imaging research studies increasingly use "de-facing" software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer's Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri_reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent.

Defining the natural history of tumefactive demyelination: A retrospective cohort of 257 patients.

OBJECTIVE: To describe demographic, clinical, and radiographic features of tumefactive demyelination (TD) and identify factors associated with severe attacks and poor outcomes. METHODS: Retrospective review of TD cases seen at Mayo Clinic, 1990-2021. RESULTS: Of 257 patients with TD, 183/257 (71%) fulfilled the 2017 multiple sclerosis (MS) McDonald criteria at the last follow-up, 12/257 (5%) had myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), 0 had aquaporin-4-IgG seropositive neuromyelitis optic spectrum disorders (AQP4+ NMOSD), and 62/257 (24%) were cryptogenic. Onset before age 18 was present in 18/257 (7%). Female to male ratio was 1.3:1. Cerebrospinal fluid oligoclonal (CSF) bands were present in 95/153 (62%). TD was the first demyelinating attack in 176/257 (69%). At presentation, 59/126 (47%) fulfilled Barkhof criteria for dissemination in space, 59/100 (59%) had apparent diffusion coefficient (ADC) restriction, and 57/126 (45%) had mass effect. Despite aggressive clinical presentation at onset, 181/257 (70%) of patients remained fully ambulatory (Expanded Disability Status Scale [EDSS] ≤4) after a 3.0-year median follow-up duration. Severe initial attack-related disability (EDSS ≥4) was more common in patients with motor symptoms (81/143 vs. 35/106, p < 0.0001), encephalopathy (20/143 vs. 2/106, p < 0.0001) and ADC restriction on initial MRI (42/63 vs. 15/33, p = 0.04). Poor long-term outcome (EDSS ≥4) was more common in patients with older onset age (41.9 ± 15 vs. 36.8 ± 15.6, p = 0.02) and motor symptoms at onset (49/76 vs. 66/171, p < 0.0001). INTERPRETATION: Most TD patients should be considered part of the MS spectrum after excluding MOGAD and NMOSD. Motor symptoms and older age at presentation portend a poor outcome.

ADC restriction is not associated with clinical response to plasma exchange following a cerebral attack of multiple sclerosis.

BACKGROUND: MS is the most common CNS inflammatory demyelinating disease. Plasma exchange (PLEX) has well-demonstrated efficacy in acute corticosteroid-refractory attacks of demyelination but identifying the factors that predict favorable PLEX response remains elusive. We aimed to determine if apparent diffusion coefficient (ADC) restriction on brain MRI predicts clinical response to PLEX in individuals with an acute cerebral attack of MS. METHODS: Retrospective chart review of individuals with a cerebral attack of MS who underwent PLEX at Mayo Clinic. RESULTS: We identified 34 individuals who fulfilled the inclusion criteria. Twenty-seven (79%) responded to plasma exchange, with 16/34 (47%) having moderate and 11/34 (32%) marked improvement. Twenty-three (68%) people had ADC restriction on brain MRI prior to PLEX.  ADC restriction did not predict response (p = 0.51). Several other pre-PLEX factors, including sex, Expanded Disability Status Scale (EDSS) at initial attack, time to PLEX, and concurrent spinal cord attack, also failed to predict response. Plasma-exchange responders had less disability at 6-month follow-up compared to non-responders (median EDSS 2.5 (range 1.0-10.0) vs. 7.5 (5.5-10.0), p<0.001). CONCLUSION: Acute cerebral attacks of MS have a high rate of plasma exchange response resulting in a lower EDSS at 6-months. ADC restriction does not predict response to plasma exchange.

Long-term clinical, imaging and cognitive outcomes association with MS immunopathology.

OBJECTIVE: In this observational study on a cohort of biopsy-proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early-active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function. METHODS: Seventy-five patients had at least one early-active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow-up was 11 years, median age at biopsy - 41, EDSS - 4.0. At last follow-up, the median age was 50, EDSS - 3.0. Clinical examination, cognitive assessment (CogState battery), and 3-Tesla-MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained. RESULTS: IP-I was identified in 14/75 (19%), IP-II was identified in 41/75 (56%), and IP-III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow-up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing-remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP-III patients recalling one word less on average. INTERPRETATION: In this study, immunopathological heterogeneity of early-active MS lesions identified at biopsy does not correlate with different long-term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.

TDP-43 pathology effect on volume and flortaucipir uptake in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18 F-flortaucipir-positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA-binding protein 43 (TDP-43) was contributing to this volume-uptake mismatch. METHODS: Seventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. RESULTS: Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age. DISCUSSION: TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants. HIGHLIGHTS: TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.

Optimum Differentiation of Frontotemporal Lobar Degeneration from Alzheimer Disease Achieved with Cross-Sectional Tau Positron Emission Tomography.

OBJECTIVE: This study was undertaken to assess cross-sectional and longitudinal [18 F]-flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC). METHODS: One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated. RESULTS: Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%). INTERPRETATION: There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029.

Histologic lesion type correlates of magnetic resonance imaging biomarkers in four-repeat tauopathies.

Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

CSF phosphorylated tau as an indicator of subsequent tau accumulation.

We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aß42 or amyloid PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aß42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage.

APOE ε4 influences medial temporal atrophy and tau deposition in atypical Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD. METHODS: An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE Îµ4 on cross-sectional and longitudinal regional metrics. RESULTS: At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus. DISCUSSION: APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.

Tractography of supplementary motor area projections in progressive speech apraxia and aphasia.

Progressive apraxia of speech (AOS) is a motor speech disorder affecting the ability to produce phonetically or prosodically normal speech. Progressive AOS can present in isolation or co-occur with agrammatic aphasia and is associated with degeneration of the supplementary motor area. We aimed to assess breakdowns in structural connectivity from the supplementary motor area in patients with any combination of progressive AOS and/or agrammatic aphasia to determine which supplementary motor area tracts are specifically related to these clinical symptoms. Eighty-four patients with progressive AOS or progressive agrammatic aphasia were recruited by the Neurodegenerative Research Group and underwent neurological, speech/language, and neuropsychological testing, as well as 3 T diffusion magnetic resonance imaging. Of the 84 patients, 36 had apraxia of speech in isolation (primary progressive apraxia of speech, PPAOS), 40 had apraxia of speech and agrammatic aphasia (AOS-PAA), and eight had agrammatic aphasia in isolation (progressive agrammatic aphasia, PAA). Tractography was performed to identify 5 distinct tracts connecting to the supplementary motor area. Fractional anisotropy and mean diffusivity were assessed at 10 positions along the length of the tracts to construct tract profiles, and median profiles were calculated for each tract. In a case-control comparison, decreased fractional anisotropy and increased mean diffusivity were observed along the supplementary motor area commissural fibers in all three groups compared to controls. PPAOS also had abnormal diffusion in tracts from the supplementary motor area to the putamen, prefrontal cortex, Broca's area (frontal aslant tract) and motor cortex, with greatest abnormalities observed closest to the supplementary motor area. The AOS-PAA group showed abnormalities in the same set of tracts, but with greater involvement of the supplementary motor area to prefrontal tract compared to PPAOS. PAA showed abnormalities in the left prefrontal and frontal aslant tracts compared to both other groups, with PAA showing greatest abnormalities furthest from the supplementary motor area. Severity of AOS correlated with tract metrics in the supplementary motor area commissural and motor cortex tracts. Severity of aphasia correlated with the frontal aslant and prefrontal tracts. These findings provide insight into how AOS and agrammatism are differentially related to disrupted diffusivity, with progressive AOS associated with abnormalities close to the supplementary motor area, and the frontal aslant and prefrontal tracts being particularly associated with agrammatic aphasia.

Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.

BACKGROUND AND OBJECTIVE: Individuals with biomarker evidence of ß-amyloid (Aß) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aß-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. METHODS: Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aß PET positivity was defined based on ADNI cutpoints. We identified all Aß-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aß PET (amyloid with low tau [ALT] group) and all Aß-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aß Centiloid, and hippocampal volume. RESULTS: We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aß Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aß Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. DISCUSSION: Aß-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aß cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.