Whitwell, Jennifer L.

AbstractINTRODUCTIONAlzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete.METHODSThirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups.RESULTSA+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups.DISCUSSIONAmyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients.Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.

ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta‐amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP‐43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [ 18 F] fluorodeoxyglucose positron emission tomography (FDG‐PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP‐43. In this context, we observed an 86‐year‐old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG‐PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico‐imaging findings and histopathology. In addition to TDP‐43, we identified three other pathological processes in the medial temporal lobe: sequestosome‐1/p62, argyrophilic grain disease (AGD), and primary age‐related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP‐43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.

Background and Objectives: Hearing loss is relatively common in older individuals, and individuals with frontotemporal lobar degeneration (FTLD) are no exception; this can exacerbate communication difficulties stemming from speech-language impairments. The co-occurrence of these symptoms can contribute to increased frustration and isolation for patients and their communication partners. The objective of this study was to evaluate the feasibility of self-administered hearing testing. Ultimately, this could be administered remotely, which would increase access to assessment and inform management for this population. Method: Seventeen patients with underlying FTLD, clinically presenting with progressive apraxia of speech with and without agrammatic aphasia, independently completed the Home Hearing Test supervised while in office. Results: Three patients self-reported hearing loss, but results for 100% recommended formal evaluation. Eleven patients demonstrated good test accuracy. Six patients had “poor” or not computable accuracy; among them, five had evidence of cognitive impairment and/or behavioral changes, and one had known severe hearing loss, although differences between those with good and poor test accuracy were not significant. Patients with poor test accuracy had more difficulty with limb praxis. Conclusions: Most participants independently completed the test, though some had reduced test accuracy that may have been associated with cognitive impairment and/or limb apraxia. This study supports the need for hearing screenings in all patients with progressive apraxia of speech and aphasia and highlights both the feasibility and caution required in implementing self-administered testing protocols. Further work should evaluate the feasibility of in-home hearing screenings in a broader range of FTLD phenotypes and directly compare sensitivity and specificity of hearing loss detection with in-clinic administration. Supplemental Material: https://doi.org/10.23641/asha.28306613

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

AbstractBackgroundCorticobasal syndrome (CBS) is a progressive neurodegenerative syndrome that can result from several underlying neuropathologies, including Alzheimer’s disease (AD). Little is known about the utility of blood plasma measures to predict PET biomarker confirmed AD in CBS.MethodEighteen CBS patients (8 PET Aβ+; 10 PET Aβ‐) and 8 cognitively unimpaired Aβ‐ individuals (CU) were recruited by the Neurodegenerative Research group from the Department of Neurology, Mayo Clinic, Rochester, MN, underwent Aβ (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181, total tau, Aβ 42/40, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) using the Quanterix Simoa platform. Plasma concentrations were compared between Aβ‐, and Aβ+ CBS and controls using Kruskal‐Wallis corrected for multiple comparisons using Dunn’s test, with effect size measured with area under the receiver operating characteristic curve (AUROC) analysis. Spearman correlations were calculated to assess relationships between plasma concentrations and Aβ and tau PET uptake.ResultThe CBS Aβ+ group showed reduced Aβ42/40 ratio, with elevated p‐tau 181, GFAP and NfL plasma concentrations compared to CU, while the CBS Aβ‐ group only showed elevated NfL concentration compared to CU (Figure 1). Both p‐tau 181 (AUROC=0.95) and GFAP (AUROC=0.91) plasma concentrations were able to differentiate CBS Aβ‐ from CBS Aβ+. Plasma p‐tau 181 and GFAP concentrations showed a positive correlation to both Aβ and tau PET uptake, and the Aβ42/40 ratio showed a negative correlation to Aβ PET uptake (Figure 2). No correlations were observed between NfL and Aβ and tau PET.ConclusionThis study supports the use of plasma p‐tau 181 and GFAP to detect AD in CBS, while NfL shows potential as a nonspecific disease biomarker of CBS regardless of underlying pathology. Plasma concentrations of these biomarkers may potentially be incorporated into clinical trials targeting CBS patients with underlying AD pathology.

AbstractBackgroundBlood plasma metrics provide excellent biomarkers of the presence of Alzheimer’s disease (AD) pathology in population cohorts. However, it is less clear whether plasma metrics correlate with PET measures of AD pathology in cohorts of patients with advanced AD disease, particularly in those with atypical clinical presentations of AD.MethodSeventy‐seven patients (visual variant=43, language variant=32, motor variant=1 and dysexecutive variant=1) with PET biomarker‐confirmed atypical AD were recruited by the Neurodegenerative Research group at Mayo Clinic, Rochester, MN, underwent Aβ (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181 and Aβ42/40 ratio concentrations using the Quanterix Simoa platform. Multivariate linear regression models assessed the relationship between plasma concentrations and both global Aβ, atypical AD summary and regional tau PET measures. For each PET measure, two separate models were fit to assess the influence of each plasma biomarker separately, while the third model included all plasma measures to assess the combined influence of all biomarkers on PET uptake. To investigate differences in plasma concentrations between atypical AD phenotypes, we performed Mann‐Whitney’s test across the visual and language variants of AD.ResultPlasma Aβ42/40 ratio showed positive associations with tau PET uptake, specifically within precuneus, parietal and temporal regions and was not associated with Aβ PET. There was no relationship between plasma p‐tau 181 and Aβ or tau PET uptake. However, the model that included both plasma biomarkers showed that with the addition of p‐tau 181, all significant associations between Aβ42/40 ratio and regional tau uptake were weakened to trends. The Aβ42/40 ratio continued to show no relationship with global Aβ‐PET uptake and plasma p‐tau 181 showed no relationship to PET measures (Figure 1). Lastly, no significant difference in plasma Aβ42/40 and p‐tau 181 levels was noted between the visual and language variants of AD (Figure 2).ConclusionThe lack of associations between plasma concentrations and PET measures of Aβ and tau in this relatively advanced AD cohort may suggest that plasma concentrations have greater utility as diagnostic biomarkers of early AD as compared to advanced AD.

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 (β=‐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 (β=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.

AbstractBackgroundCorticobasal syndrome (CBS) is a progressive neurodegenerative syndrome that can result from several underlying neuropathologies, including Alzheimer’s disease (AD). Little is known about the utility of blood plasma measures to predict PET biomarker confirmed AD in CBS.MethodEighteen CBS patients (8 PET Aß+; 10 PET Aß‐) and 8 cognitively unimpaired Aß‐ individuals (CU) were recruited by the Neurodegenerative Research group from the Department of Neurology, Mayo Clinic, Rochester, MN, underwent Aß (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181, total tau, Aß 42/40, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) using the Quanterix Simoa platform. Plasma concentrations were compared between Aß‐, and Aß+ CBS and controls using Kruskal‐Wallis corrected for multiple comparisons using Dunn’s test, with effect size measured with area under the receiver operating characteristic curve (AUROC) analysis. Spearman correlations were calculated to assess relationships between plasma concentrations and Aß and tau PET uptake.ResultThe CBS Aß+ group showed reduced Aß42/40 ratio, with elevated p‐tau 181, GFAP and NfL plasma concentrations compared to CU, while the CBS Aß‐ group only showed elevated NfL concentration compared to CU (Figure 1). Both p‐tau 181 (AUROC=0.95) and GFAP (AUROC=0.91) plasma concentrations were able to differentiate CBS Aß‐ from CBS Aß+. Plasma p‐tau 181 and GFAP concentrations showed a positive correlation to both Aß and tau PET uptake, and the Aß42/40 ratio showed a negative correlation to Aß PET uptake (Figure 2). No correlations were observed between NfL and Aß and tau PET.ConclusionThis study supports the use of plasma p‐tau 181 and GFAP to detect AD in CBS, while NfL shows potential as a nonspecific disease biomarker of CBS regardless of underlying pathology. Plasma concentrations of these biomarkers may potentially be incorporated into clinical trials targeting CBS patients with underlying AD pathology.

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.

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.