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Objective: To test the hypothesis that beta-amyloid (Abeta) burden is associated with rates of brain atrophy.Methods: Forty-five subjects who had been prospectively studied, died, and had an autopsy diagnosis of low, intermediate, or high probability of Alzheimer's disease who had two volumetric head magnetic resonance imaging scans were identified. Compact and total (compact + diffuse) Abeta burden was measured using a computerized image analyzer with software program to detect the proportion of gray matter occupied by Abeta. Visual ratings of Abeta burden were also performed. The boundary shift integral was used to calculate change over time in whole-brain and ventricular volume. All boundary shift integral results were annualized by adjusting for scan interval. Demographics, cognitive measures, clinical diagnoses, apolipoprotein E genotype, neurofibrillary tangle (NFT) pathology, and vascular lesion burden were determined.Results: There was no correlation between compact or total Abeta burden, or visual Abeta ratings, and rates of brain loss or ventricular expansion in all subjects. However, significant correlations were observed between rates of brain loss and age, Braak NFT stage, and change over time in cognitive measures. These features also correlated with rates of ventricular expansion. The rates of brain loss and ventricular expansion were greater in demented compared with nondemented subjects.Interpretation: These findings suggest that rate of brain volume loss is not determined by the amount of insoluble Abeta in the gray matter. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to progression to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately 3 years before the diagnosis of AD, the second scan approximately 1 year before, and the third scan at the time of the diagnosis of AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were 3 years before the diagnosis of AD was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were 1 year before the diagnosis of AD. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had progressed to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least 3 years before progression to the diagnosis of AD. These results also suggest that 3D patterns of grey matter atrophy may help to predict the time to the first diagnosis of AD in subjects with aMCI. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are pathologically characterized by the deposition of abnormal proteins in the brain. It is likely that future treatment trials will target the underlying protein biochemistry and it is therefore increasingly important to be able to distinguish between different pathologies during life. The aim of this study was to determine whether rates of brain atrophy differ in neurodegenerative dementias that vary by pathological diagnoses and characteristic protein biochemistry. Fifty-six autopsied subjects were identified with a clinical diagnosis of dementia and two serial head MRI. Subjects were subdivided based on pathological diagnoses into Alzheimer's disease, dementia with Lewy bodies (DLB), mixed Alzheimer's disease/DLB, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes (FTLD-U), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Twenty-five controls were matched by age, gender and scan interval, to the study cohort. The boundary-shift integral was used to calculate change over time in whole brain (BBSI) and ventricular volume (VBSI). All BSI results were annualized by adjusting for scan interval. The rates of whole brain atrophy and ventricular expansion were significantly increased compared to controls in the Alzheimer's disease, mixed Alzheimer's disease/DLB, FTLD-U, CBD and PSP groups. However, atrophy rates in the DLB group were not significantly different from control rates of atrophy. The largest rates of atrophy were observed in the CBD group which had a BBSI of 2.3% and VBSI of 16.2%. The CBD group had significantly greater rates of BBSI and VBSI than the DLB, mixed Alzheimer's disease/DLB, Alzheimer's disease and PSP groups, with a similar trend observed when compared to the FTLD-U group. The FTLD-U group showed the next largest rates with a BBSI of 1.7% and VBSI of 9.6% which were both significantly greater than the DLB group. There was no significant difference in the rates of atrophy between the Alzheimer's disease, mixed Alzheimer's disease/DLB and PSP groups, which all showed similar rates of atrophy; BBSI of 1.1, 1.3 and 1.0% and VBSI of 8.3, 7.2 and 10.9%, respectively. Rates of atrophy therefore differ according to the pathological diagnoses and underlying protein biochemistry. While rates are unlikely to be useful in differentiating Alzheimer's disease from cases with mixed Alzheimer's disease/DLB pathology, they demonstrate important pathophysiological differences between DLB and those with mixed Alzheimer's disease/DLB and Alzheimer's disease pathology, and between those with CBD and PSP pathology. [ABSTRACT FROM AUTHOR]

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer's disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants. [ABSTRACT FROM AUTHOR]

The extent to which cerebral atrophy in Alzheimer's disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimer's disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

There are recognized neuroimaging regions of interest in typical Alzheimer's disease which have been used to track disease progression and aid prognostication. However, there is a need for validated baseline imaging markers to predict clinical decline in atypical Alzheimer's Disease. We aimed to address this need by producing models from baseline imaging features using penalized regression and evaluating their predictive performance on various clinical measures. Baseline multimodal imaging data, in combination with clinical testing data at two time points from 46 atypical Alzheimer's Disease patients with a diagnosis of logopenic progressive aphasia (N = 24) or posterior cortical atrophy (N = 22), were used to generate our models. An additional 15 patients (logopenic progressive aphasia = 7, posterior cortical atrophy = 8), whose data were not used in our original analysis, were used to test our models. Patients underwent MRI, FDG-PET and Tau-PET imaging and a full neurologic battery at two time points. The Schaefer functional atlas was used to extract network-based and regional gray matter volume or PET SUVR values from baseline imaging. Penalized regression (Elastic Net) was used to create models to predict scores on testing at Time 2 while controlling for baseline performance, education, age, and sex. In addition, we created models using clinical or Meta Region of Interested (ROI) data to serve as comparisons. We found the degree of baseline involvement on neuroimaging was predictive of future performance on cognitive testing while controlling for the above measures on all three imaging modalities. In many cases, model predictability improved with the addition of network-based neuroimaging data to clinical data. We also found our network-based models performed superiorly to the comparison models comprised of only clinical or a Meta ROI score. Creating predictive models from imaging studies at a baseline time point that are agnostic to clinical diagnosis as we have described could prove invaluable in both the clinical and research setting, particularly in the development and implementation of future disease modifying therapies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Primary age-related tauopathy (PART) is characterized by neurofibrillary tangles and minimal β-amyloid deposition, diagnosed postmortem. This study investigates  18 F-flortaucipir (FTP) PET imaging for antemortem PART diagnosis., Methods: We analyzed FTP PET scans from 50 autopsy-confirmed PART and 13 control subjects. Temporal lobe uptake was assessed both qualitatively and quantitatively. Demographic and clinicopathological characteristics and voxel-level uptake using SPM12 were compared between FTP-positive and FTP-negative cases. Intra-reader reproducibility was evaluated with Krippendorff's alpha., Results: Minimal/mild and moderate FTP uptake was seen in 32% of PART cases and 62% of controls, primarily in the left inferior temporal lobe. No demographic or clinicopathological differences were found between FTP-positive and FTP-negative cases. High intra-reader reproducibility (α = 0.83) was noted., Discussion: FTP PET imaging did not show a specific uptake pattern for PART diagnosis, indicating that in vivo PART identification using FTP PET is challenging. Similar uptake in controls suggests non-specific uptake in PART., Highlights: 18 F-flortaucipir (FTP) PET scans were analyzed for diagnosing PART antemortem. 32% of PART cases had minimal/mild FTP uptake in the left inferior temporal lobe. Similar to PART FTP uptake was found in 62% of control subjects. No specific uptake pattern was found, challenging in vivo PART diagnosis., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: Declaration of competing interest As the corresponding author I confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere. We have no declaration of competing interest pertinent to this study. I confirm that I take full responsibility for the data, the analyses and interpretation, and the conduct of the research. I further confirm that the manuscript has been read and approved for submission by all named authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Transcribing disordered speech can be useful when diagnosing motor speech disorders such as primary progressive apraxia of speech (PPAOS), who have sound additions, deletions, and substitutions, or distortions and/or slow, segmented speech. Since transcribing speech can be a laborious process and requires an experienced listener, using automatic speech recognition (ASR) systems for diagnosis and treatment monitoring is appealing. This study evaluated the efficacy of a readily available ASR system (wav2vec 2.0) in transcribing speech of PPAOS patients to determine if the word error rate (WER) output by the ASR can differentiate between healthy speech and PPAOS and/or among its subtypes, whether WER correlates with AOS severity, and how the ASR's errors compare to those noted in manual transcriptions., Method: Forty-five patients with PPAOS and 22 healthy controls were recorded repeating 13 words, 3 times each, which were transcribed manually and using wav2vec 2.0. The WER and phonetic and prosodic speech errors were compared between groups, and ASR results were compared against manual transcriptions., Results: Mean overall WER was 0.88 for patients and 0.33 for controls. WER significantly correlated with AOS severity and accurately distinguished between patients and controls but not between AOS subtypes. The phonetic and prosodic errors from the ASR transcriptions were also unable to distinguish between subtypes, whereas errors calculated from human transcriptions were. There was poor agreement in the number of phonetic and prosodic errors between the ASR and human transcriptions., Conclusions: This study demonstrates that ASR can be useful in differentiating healthy from disordered speech and evaluating PPAOS severity but does not distinguish PPAOS subtypes. ASR transcriptions showed weak agreement with human transcriptions; thus, ASR may be a useful tool for the transcription of speech in PPAOS, but the research questions posed must be carefully considered within the context of its limitations., Supplemental Material: https://doi.org/10.23641/asha.26359417.

Introduction: FTLD-FET is a newly described subtype of frontotemporal lobar degeneration (FTLD characterized by pathologic inclusions of FET proteins: fused in sarcoma (FUS), Ewing sarcoma, and TATA-binding protein-associated factor 2N (TAF15)). Severe caudate volume loss on MRI has been linked to FTLD-FUS, yet glucose hypometabolism in FTLD-FET has not been studied. We assessed [ 18 F] fluorodeoxyglucose PET (FDG-PET) hypometabolism in FTLD-FET subtypes and compared metabolism to FTLD-tau and FTLD-TDP., Methods: We retrospectively reviewed medical records of 26 autopsied FTLD patients (six FTLD-FET, ten FTLD-Tau, and ten FTLD-TDP) who had completed antemortem FDG-PET. We evaluated five regions, caudate nucleus, medial frontal cortex, lateral frontal cortex, and medial temporal using a 0-3 visual rating scale and validated our findings quantitatively using CORTEX-ID suite Z scores., Results: Of the six FTLD-FET cases (three females) with median age at onset = 36, three were atypical FTLD-U (aFTLD-U) and three were neuronal intermediate filament inclusion disease (NIFID). bvFTD was the most common presentation. Four of the six FTLD cases (3 aFTLD-U + 1 NIFID) showed prominent caudate hypometabolism relatively early in the disease course. FTLD-tau and FTLD-TDP did not show early prominent caudate hypometabolism. Hypometabolism in medial and lateral temporal cortex was associated with FTLD-TDP, while FTLD-tau had normal-minimal regional metabolism., Discussion: Prominent caudate hypometabolism, especially early in the disease course, appears to be a hallmark feature of the aFTLD-U subtype of FTLD-FET. Assessing caudate and temporal hypometabolism on FDG-PET will help to differentiate FTLD-FET from FTLD-tau and FTLD-TDP., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances., Objective: This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS)., Methods: Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution., Results: The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001)., Conclusions: This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objectives: Nonverbal oral apraxia (NVOA) is the inability to plan, sequence, and execute voluntary oromotor movements in the absence of weakness. In the context of neurodegenerative disease, it remains unclear whether it is linked to a specific underlying pathologic, clinical, or neuroimaging finding. Thus, we aimed to assess the clinicopathologic and neuroimaging associations of NVOA., Methods: We conducted a retrospective study of autopsy-confirmed patients previously assessed through an NVOA evaluation tool with a previously published cutpoint to screen for NVOA. We compared demographic and clinical characteristics and postmortem pathology between those who developed NVOA and those who did not. We also compared clinicopathologic characteristics in mild vs greater than mild NVOA and early vs late-emerging NVOA. SPM12 was used to assess patterns of gray matter loss in NVOA vs non-NVOA with age and sex included as covariates., Results: A total of 104 patients (median age at symptom onset 63 years, 43% female) were included in the study. 63 (60.6%) developed NVOA. NVOA appeared at a median of 4.3 years from symptom onset. 29% developed NVOA within the first 3 years. Primary progressive apraxia of speech and the nonfluent variant of primary progressive aphasia were the most common baseline diagnoses in the NVOA group while progressive supranuclear palsy (PSP) syndrome and logopenic progressive aphasia (LPA) were the most common in patients without NVOA. Atrophy of the left lateral and medial posterior frontal cortex was related to NVOA. The most common pathologies associated with NVOA were PSP (36.5%) and corticobasal degeneration (CBD) (33.3%). In patients without NVOA, PSP (26.8%) and other pathologies (26.8%) were the most frequent. 11% of patients with NVOA had persistently mild NVOA and were more likely to have baseline diagnoses of LPA, PSP syndrome, or semantic dementia. The most frequent pathologies in this group were Alzheimer disease and PSP. The pathologic associations of greater than mild NVOA were CBD and PSP., Discussion: NVOA is present in several clinical syndromes. It is most associated with PSP and CBD. NVOA is a manifestation of left lateral and medial posterior frontal cortex damage rather than a particular pathology.

Background and Objective: No epidemiologic studies have formally assessed the incidence of primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS). Thus, we decided to assess the incidence of these disorders in Olmsted County, MN, between 2011 and 2022, and to characterize clinical, radiographic, and pathologic characteristics of these patients., Methods: This was a retrospective examination of data from a population-based cohort of patients with PPA and PPAOS prospectively identified in Olmsted County, MN, from 2011 to 2022. The incidence of PPA among adults (older than 18 years) was calculated for Olmsted County as the number of patients per 100,000 person-years during the study period. The adult population of Olmsted County was determined by the annual catchment population reported by the Rochester Epidemiological Project for each year 2011-2022. A behavioral neurologist verified the clinical diagnoses and determined subtypes., Results: We identified 10 patients (60% female) within the study period (median age of symptoms onset: 70 years; range: 66-73), 8 with PPA and 2 with PPAOS. Of the 8 patients with PPA (6 female patients, 2 male patients), 2 met criteria for non-fluent variant PPA (nfvPPA), 3 for logopenic variant PPA (lvPPA), and 3 for semantic variant (svPPA). Speech evaluation confirmed the clinical diagnoses in all patients and all showed typical imaging findings consistent with their respective subtype. Six patients (2 PPAOS, 2 nfvPPA, 2 lvPPA) died and 3 underwent autopsy (2 PPAOS, 1 nfvPPA), confirming the pathologic diagnosis of progressive supranuclear palsy. The incidence of PPA + PPAOS was 0.70 persons per 100,000 person-years (95% CI 0.34-1.29 persons per 100,000) during the study period. The incidence of PPAOS was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55 persons per 100,000), whereas for the 8 patients with PPA, the incidence was 0.56 persons per 100,000 person-years (95% CI 0.24-1.10 cases per 100,000). The incidence of nfvPPA was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55), 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for lvPPA, and 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for svPPA., Discussion: As a group, PPA and PPAOS are a relatively rare group of diseases. PPAOS has a slightly lower incidence than PPA as a group but similar incidence to the individual PPA variants.

Background: Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction., Methods: We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k -nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database., Results: PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies., Conclusions: Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology., Competing Interests: Competing interests: DSK serves on a Data Safety Monitoring Board for the DIAN study. He served on a Data Safety Monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is a site investigator in the Biogen aducanumab trials. He is an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Roche and Alzeca Biosciences but receives no personal compensation. RCP serves as a consultant for Roche, Genentech, Nestle, Eli Lilly and Co and Eisai, and receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate. BFB receives honoraria for SAB activities for the Tau Consortium; is a site investigator for clinical trials sponsored by Alector, Biogen and Transposon; and receives research support from NIH. GSD serves as a consultant for Parabon NanoLabs, as a topic editor (Dementia) for DynaMed (EBSCO) and as the clinical director of the Anti-NMDA Receptor Encephalitis Foundation (Canada, uncompensated). He is the co-Project PI for a clinical trial in Anti-NMDA Receptor Encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media and Continuing Education. He owns stock in ANI Pharmaceuticals. GSD’s institution has received support from Eli Lilly for GSD’s development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer's disease. WKK was supported in part by NIH funding. DWD, DTJ, KAJ and JLW received research funding from the NIH and declared no competing financial interests. MEM is a consultant for AVID Radiopharmaceuticals. She receives support from the NIH/NIA and Eli Lilly. NRG-R receives royalties from UpToDate, has participated in multicentre therapy studies sponsored by Biogen, TauRx, AbbVie, Novartis and Lilly, and he receives research support from NIH. JAF is on the OSMB for the SWAN-Aging Study, serves as a consultant for Medtronic and received NIH funding. JG-R serves on the DSMB for STROKENET, is a site investigator for a trial sponsored by Eisai and the NIH, and he receives research support from the NIH., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P)., Objective: Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP., Methods: Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects., Results: Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores., Conclusions: Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS., (© 2024 International Parkinson and Movement Disorder Society.)

Introduction: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype., Methods: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments., Results: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations., Discussion: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients., Highlights: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Patients who have a yes-no reversal respond "yes" when they mean no and vice versa. The unintentional response can be made both verbally and with gestures (e.g., head shake or nod, thumbs up or down). Preliminary reports associate this phenomenon with 4-repeat tauopathies including primary progressive apraxia of speech (PPAOS), nonfluent/agrammatic primary progressive aphasia, and corticobasal syndrome; however, the significance and timing of this symptom relative to others are not well understood. Whereas some accounts associate yes-no reversals with other binary reversals (e.g., up/down, hot/cold) and attribute the reversals to disturbances of selection within the language system, others implicate more general inhibitory control processes. Here, we compared clinical and neuroimaging findings across 30 patients with PPAOS (apraxia of speech in the absence of aphasia), 15 of whom had a yes-no reversal complaint and 15 who did not. The two groups did not differ on any of the language or motor speech measures; however, patients who had the yes-no reversal received lower scores on the Frontal Assessment Battery and motor assessments. They also had greater hypometabolism in the left supplementary motor area and bilateral caudate nuclei on [ 18 F]-fluorodeoxyglucose PET, but only the right caudate nucleus cluster survived correction for multiple comparisons. We interpret these results to suggest that the yes-no reversal phenomenon is associated with cognitive abilities that are supported by the frontostriatal network; more specifically, impaired response inhibition., Competing Interests: Declaration of competing interest The authors do not have any relevant conflicts of interest to disclose at the time of submission., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS., Methods: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy., Results: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS., Conclusion: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Keith A. Josephs reports financial support was provided by National Institute on Deafness and Other Communication Disorders. Jennifer L. Whitwell reports financial support was provided by National Institute on Deafness and Other Communication Disorders. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Purpose: Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP., Methods: Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18 F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated., Results: Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74)., Conclusions: Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

[ 18 F]-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-β. 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 [ 18 F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-β PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-β 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-β phase. Flortaucipir uptake linearly increased with the amyloid-β 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-β phase, and were useful for distinguishing different ADNC scores and PART.

Purpose: We describe the communication challenges of four patients with a neurodegenerative disorder consistent with behavioral variant frontotemporal dementia (bvFTD), characterized by early behavioral and personality changes. By describing their clinical profiles, we identify common barriers to functional communication in this population and provide recommendations for how speech-language pathologists (SLPs) might contribute to minimizing them., Method: Four patients with bvFTD were selected from a cohort of patients with progressive communication impairments. Three of them returned for at least one follow-up visit. Case histories are presented along with the results of comprehensive speech and language, neuropsychological, and neurological testing., Results: At the time of initial evaluation, patients were between the ages of 54 and 66 years and had been experiencing symptoms for 1.5-6 years. Consistent with their bvFTD diagnoses, all patients had prominent behavioral and personality changes that impacted communication. Patients 1 and 2 also had mild aphasia at enrollment, primarily characterized by anomia and loss of word meaning. Patients 3 and 4 both had apraxia of speech and moderate-to-severe aphasia at enrollment with prominent anomia and agrammatism. All four patients had impaired executive functioning and relative sparing of visuospatial skills; episodic memory was also impaired for Patients 2 and 4. Even though functional communication was progressively limited for all patients, none of them received regular support from an SLP., Conclusions: This case series adds to a scant, but growing, literature demonstrating that patients with bvFTD have communication impairments. SLPs are uniquely positioned to identify barriers to functional communication and to provide tailored strategy training to the patients and their care partners over the course of their disease. Systematic evaluation of the efficacy of treatment in this population would be valuable., Supplemental Material: https://doi.org/10.23641/asha.25933762.

Objective: Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction., Methods: Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB)., Results: 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB., Conclusions: Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS., Methods: We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12., Results: Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time., Discussion: An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

Introduction: Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS., Methods: A cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake., Results: CBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aβ- from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake., Discussion: This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology., Highlights: Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)- from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ- and Aβ+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)