Josephs, Keith A.

AbstractBackgroundTransactive response DNA‐binding protein of 43 kDa (TDP‐43) is implicated in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Immunohistochemically stained TDP‐43 is linked to faster rates of hippocampal atrophy (HA) in AD. However, it is unclear whether phosphorylated TDP‐43 (pTDP‐43) measured using an immunoassay is also associated with HA. We explored associations between pTDP‐43 levels, TDP‐43 immunohistochemistry, and annual rate of HA in AD. We hypothesized that higher pTDP‐43 levels would be associated with positive TDP‐43 immunohistochemistry, and faster rates of HA.MethodThirty‐seven cognitively impaired participants from the Mayo Clinic Alzheimer’s Disease Research Center underwent serial brain MRIs and brain autopsy. Hippocampal TDP‐43 was detected histochemically, and pTDP‐43 was quantified using biochemical assay. Hippocampal volumes were measured using the longitudinal pipeline in FreeSurfer‐7 and annualized HA rates were calculated. Linear regression analyzed the relationship between HA and pTDP‐43 biochemical assay levels. pTDP‐43 was categorized as positive (=400) or negative (<400), and logistic regression tested the association of these levels with HA rates. The correlation between TDP‐43 immunohistochemistry status and biochemical assay levels was evaluated using descriptive statistics. All analyses were adjusted for potential confounders.ResultsThe mean age at death was 83.5 (±9.9) years with 49% females. Median scan interval was 3‐years. A negative relationship was observed between age at death and annual HA rate (ß=‐3.1; 95% CI [‐5.3,‐0.9]; p=0.007), and a positive relationship was observed between pTDP‐43 level and annual HA rate (ß=0.02; 95% CI [0.003,0.03]; p=0.015). A one‐unit increase in HA rate was associated with a 3% increase in the odds of being pTDP‐43 positive (=400) (odds ratio=1.03; CI [1.007,1.05]; p=0.014). Cases that tested positive for Immunohistochemistry TDP‐43 had significantly higher mean pTDP‐43 immunoassay levels (1508 ± 2072 vs. 202 ± 131; p=0.008). More cases with positive IHC TDP‐43 surpassed the pTDP‐43 immunoassay cut‐off level of 400 vs the negative participants (p=0.003).ConclusionHigher pTDP‐43 levels in the hippocampus are linked to faster HA in AD and correlated with immunohistochemistry TDP‐43 positivity. These findings underscore the role of TDP‐43 in AD neurodegeneration. The biological and clinical implications of these observations necessitate further exploration in subsequent studies.

AbstractBackgroundThe TAR DNA‐binding protein of 43 kDa (TDP‐43) is linked to hippocampal volume loss and faster rates of hippocampal atrophy in Alzheimer's disease and primary age‐related tauopathy (PART). Hence, TDP‐43 is becoming an important player in age‐related neurodegeneration. To advance our understanding of TDP‐43 effect on hippocampus, we conducted an imaging‐pathological study to determine which specific hippocampal subfields are affected by TDP‐43 in cases of PART.MethodOne‐hundred fifteen autopsied cases from Mayo Clinic Alzheimer Disease Center, Study of Aging and Neurodegenerative Research Group were analyzed. All had completed antemortem brain MRIs, underwent neuropathological examination per NIA and Alzheimer’s Association (NIA‐AA) criteria and had additional assessment for TDP‐43 deposition. Only cases meeting criteria for PART (Thal phases 0‐2 and Braak NFT stages I‐IV) were included. Hippocampal subfield segmentation was performed using FreeSurfer‐7. Brain volumes were normalized to total intracranial volume (TIV) when comparing TDP‐43 groups. Statistical analyses including logistic regression analyses were utilized to explore associations between TDP‐43 status and hippocampal subfield volumes.ResultForty‐nine of the 115 cases (43%) with PART were female. Thirty‐seven (32%) cases were TDP‐positive. Mean age at last MRI was 84 years. There were no differences in pathological characteristics between both groups except for presence of hippocampal sclerosis which was more frequent in the TDP(+) group (P <0.001). Whole hippocampal volume was significantly smaller in the TDP(+) group (176 ±31 vs. 188 ±27, p=0.049). After stratification of hippocampus into head, body, and tail, TDP‐positive cases had smaller volumes of hippocampal body (p=0.031) and tail (p=0.021) but did not reach significance for hippocampal head (p=0.129). When regions were subdivided into hippocampal subfields, TDP(+) cases showed smaller volumes of molecular layer of the hippocampal body (p=0.046), CA1 body (p=0.031), subiculum body (p=0.023), and presubiculum body (p=0.046) compared to TDP(‐) cases. Logistic regression analysis adjusting for TIV confirmed these associations.ConclusionThis study underscores the association between TDP‐43 and the hippocampus and provides further evidence that TDP‐43 targets multiple regions and subfields of the hippocampus in patients with PART. Intriguingly, regions targeted are those where TDP‐43 deposition is microscopically observed, suggesting a direct “hit” by TDP‐43 deposition.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

AbstractBackgroundDiscussion surrounding the nomenclature of the “nonfluent/agrammatic” spectrum of progressive speech‐language disorders has largely focused on the clinical‐pathological and neuroimaging correlations, with some attention paid to the prognostication afforded by differentiating clinical phenotypes. Progressive apraxia of speech (AOS), with or without agrammatic aphasia, is generally associated with an underlying tauopathy; however, patients have offered a unique perspective on the importance of distinguishing between difficulties with speech and language that extends beyond pathological specificity. This study aimed to provide insight into the experience of patients with primary progressive AOS (PPAOS), with particular attention to their diagnostic journey.MethodA qualitative research approach was used. Structured interviews were conducted with three prosodic and one phonetic predominant PPAOS patients, judged representative of our research cohort, who were previously received other diagnoses, including primary progressive aphasia (PPA). A current PPAOS diagnosis and willingness to discuss the details of their diagnostic workup and reflect upon their experience were the inclusion criteria. One patient preferred to provide written responses. Each interview was reviewed, and the collective contents were examined using thematic analysis.ResultThe primary themes were identity, community, and planning. Patients expressed: 1) the importance of the alignment of AOS with their difficulties, specifically that they had no difficulty with thinking of words or with comprehension (i.e., no aphasia); 2) not sharing attributes with PPA patients and their observed clinical presentations; and 3) the desire to capitalize upon their retained skills for treatment, for example “I intend to retain my ‘voice’ even as I lose my speaking ability.”ConclusionUnderstanding the experiences of PPAOS patients may inform future iterations of progressive speech‐language spectrum diagnostic criteria and the consistency of their use, along with intervention recommendations. The specificity of a PPAOS diagnosis is meaningful to patients as it relates to their identity, sense of community, and approach to future planning. Further work will evaluate the experience of patients with a broader spectrum of progressive speech‐language disorders along with their care partners. More work is underway to outline the predictive value of an AOS diagnosis, relative to co‐occurring aphasia severity, to inform better prognostication.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.

We report a patient who presented clinically with progressive supranuclear palsy (PSP) but was pathologically diagnosed as having primary lateral sclerosis (PLS) with magnetic resonance imaging (MRI) with a quantitative susceptibility mapping (QSM) protocol. A 70‐year‐old man was clinically diagnosed with PSP due to early falls and unresponsiveness to levodopa therapy. Postmortem pathological examination revealed mild loss of Betz cells, gliosis, and transactive response DNA binding protein of 43 kDa (TDP‐43)‐positive inclusions in the motor cortex, leading to the pathological diagnosis of PLS. To explore methods for differentiating PLS from PSP, ante‐mortem QSM images were visually and quantitatively assessed for abnormal increases in magnetic susceptibility in the motor cortex. Prussian blue and Luxol fast blue combined with periodic acid‐Schiff staining were also performed to understand the source of the susceptibility increases. QSM showed clear hyperintense signals in the motor cortex. Magnetic susceptibility in the motor cortex was higher in the PLS patient (Z = 4.7, p < 0.001) compared to normal controls and pathologically diagnosed PSP patients. Pathological examination of the region showed intracortical myelin loss, as well as iron deposition. Underlying pathological processes for the increased magnetic susceptibility include not only iron deposition but also intracortical myelin. Our case suggests that QSM is a potential tool to differentiate PLS from PSP, providing insights for accurate diagnosis and enhancing clinical decision‐making.

Purpose: Speakers with primary progressive apraxia of speech (PPAOS) have an insidious onset of motor speech planning/programming difficulties. As the disease progresses, the apraxia of speech (AOS) becomes more severe and a co-occurring dysarthria often emerges. Here, longitudinal data from speakers with phonetic- and prosodic-predominant PPAOS are used to characterize the progression of their motor speech impairment, including the development of dysarthria and mutism. Method: Data are presented from 52 speakers who had PPAOS at enrollment (i.e., progressive AOS in the absence of aphasia, cognitive, or other neurologic symptoms). Twenty-one had predominantly phonetic features, whereas 31 had primarily prosodic features. All participants underwent a comprehensive motor speech evaluation at their enrollment visit and each annual return visit, with a median of three visits per participant. Results: Almost 25% of the speakers with PPAOS presented with dysarthria at their enrollment visit (median disease duration of 3.65 years), whereas more than 70% of them had developed dysarthria by their last visit (median disease duration of 6.85 years). Neither the likelihood to develop dysarthria nor the disease duration at which it was detected differed significantly between the phonetic and prosodic groups. However, muteness emerged sooner for speakers with phonetic-predominant PPAOS; the median disease duration at which they became mute was 1.5 years shorter than for their prosodic counterparts. Conclusions: Clinically, these results facilitate more accurate prognostication of motor speech symptoms in speakers with PPAOS, allowing for timely introduction of alternative means of communication. The results also support the differentiation between progressive AOS and dysarthria as distinct motor speech disorders that often co-occur in these individuals.

Abstract BACKGROUND [ 18 F] flortaucipir (FTP) binding to paired helical filament (PHF) tau in Alzheimer's disease (AD) is well accepted. Binding to 3R and 4R tau in frontotemporal lobar degeneration (FTLD) is controversial. We aimed to investigate whether an FTP fluorescent analog (T726) can help shed light on this controversy. METHOD We assessed T726 binding to amyloid beta (Aβ) and different tau isoforms in nine subjects (one control, three with Alzheimer's disease [AD], and five with FTLD) with different 3R and 4R tauopathies using fluorescence confocal microscopy. RESULTS T726 did not colocalize with Aβ but showed significant co‐localization with PHF tau in AD. We also observed some, albeit limited, co‐localization of T726 with 3R and 4R tau lesions in FTLD. DISCUSSION This study's findings support FTP binding to some 3R and 4R tau lesions in FTLD. Further studies are needed to understand the biology of why FTP binds some but not all FTLD tau lesions. Highlights Flortaucipir analog (T726) showed significant co‐localization with paired helical filament (PHF) tau in Alzheimer's disease (AD). Colocalization between T726 with 3R and 4R tau lesions was observed in frontotemporal lobar degeneration (FTLD). Not all 4R tau lesions bind to T726 across different FTLD brain regions.