Publications by authors named "Keith A Josephs"

378 Publications

Assessing Change in Communication Limitations in Primary Progressive Apraxia of Speech and Aphasia: A 1-Year Follow-Up Study.

Am J Speech Lang Pathol 2021 Sep 7:1-11. Epub 2021 Sep 7.

Department of Neurology, Mayo Clinic, Rochester, MN.

Purpose Individuals with primary progressive apraxia of speech have apraxia of speech (AOS) as the initial and predominant symptom. Many develop aphasia and/or dysarthria later in the disease course. It was previously demonstrated that patients with neurodegenerative AOS experience reduced participation in communication that is further exacerbated by co-occurring language deficits (Utianski et al., 2020). Measures of disease severity did not necessarily correlate with measures of participation restrictions. The aim of this follow-up study was to describe changes in communication limitations in these patients, again measured by (a) the patient via the Communicative Participation Item Bank (CPIB) and (b) the speech-language pathologist via the American Speech-Language-Hearing Association's (ASHA's) Functional Communication Measures (FCMs) and an adapted motor speech disorder (MSD) severity rating to determine if there are significant changes in these and other objective speech and language measures at follow-up after 1 year. Method Of the 24 patients reported in the study of Utianski et al. (2020), 17 (10 men, seven women) returned for a second visit approximately 1 year following the first visit. Identical procedures were utilized; the communication measures collected at each visit were statistically compared. Correlations were calculated between the participation ratings and other clinical assessment measures at the second visit and for the change in scores on those measures between the first and second visits. Results There were statistically significant differences in AOS and aphasia severity between visits. There were significant changes in clinical assessments, MSD severity rating, and all ASHA FCMs between visits, but not the CPIB. Correlation analyses suggest the relationships among clinical and participation measures are complex; overall, patients with more severe changes in AOS experienced greater changes in participation restrictions. Conclusions The findings of this study support the use of patient-reported outcome measures as they may better reflect the patient experience, including the influence of factors such as ongoing speech therapy and the emergence of neuropsychiatric features, and associated changes in day-to-day functioning, when other measures may simply index the progression of the disease. Supplemental Material https://doi.org/10.23641/asha.16528512.
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http://dx.doi.org/10.1044/2021_AJSLP-20-00402DOI Listing
September 2021

Survival Analysis in Primary Progressive Apraxia of Speech and Agrammatic Aphasia.

Neurol Clin Pract 2021 Jun;11(3):249-255

Department of Radiology (JLW), Department of Health Sciences Research (PM), Division of Speech Pathology (JRD, HMC, RLU, EAS), and Division of Behavioral Neurology (HB, KAJ), Department of Neurology, and Department of Psychiatry and Psychology (MMM), Mayo Clinic, Rochester, MN.

Objective: To compare survival among patients with different combinations of apraxia of speech (AOS) and agrammatic aphasia, including those with isolated AOS (primary progressive AOS, PPAOS), both AOS and agrammatic aphasia (AOS + progressive agrammatic aphasia [PAA]), and isolated agrammatic aphasia (PAA).

Methods: One hundred nine patients were recruited who had any combination of AOS and agrammatic aphasia (42 PPAOS, 56 AOS + PAA, and 11 PAA) and were followed longitudinally, with 57 patients having since died. Cox proportional hazard models were used to quantify the relative risk of death across diagnoses. Adjusted survival curves are presented based on this model. We also assessed the influence of AOS and aphasia severity on survival.

Results: PPAOS had the longest survival (median survival of 5.97 years from the baseline visit), followed by PAA (5.26 years) and then AOS + PAA (4.33 years). AOS + PAA had a greater risk of death than PPAOS, with a hazard ratio of 3.01 (lower/upper confidence interval = 1.66/5.46, < 0.001). Risk of death did not differ between PAA and the other groups. All results accounted for age and time from onset to baseline visit. AOS severity, independent of syndromic diagnosis, was associated with greater risk of death, with a hazard ratio of 1.35 for a 1-point increase in severity. Aphasia severity was not associated with risk of death.

Conclusions: Individuals with PPAOS have better survival and reduced risk of death compared with individuals with AOS + PAA. This finding will help improve prognostic estimates for these patients and supports the value of distinguishing PPAOS from AOS + PAA.
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http://dx.doi.org/10.1212/CPJ.0000000000000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382380PMC
June 2021

Laboratory based assessment of gait and balance impairment in patients with progressive supranuclear palsy.

J Neurol Sci 2021 Aug 25;429:118054. Epub 2021 Aug 25.

Department of Orthopedic Surgery, Rochester, MN, United States of America.

Background: Gait and balance abnormalities are a significant source of morbidity and mortality in progressive supranuclear palsy (PSP). Gait impairment in PSP is primarily assessed clinically on exam or with the use of rating scales. Three dimensional video based gait and balance analysis performed in a laboratory setting is a highly accurate method of motion analysis (Wren et al., 2020), however limited data is available in patients with PSP.

Research Question: In this study we assess the objective features of postural control, kinematics, kinetic and temporal-spatial gait metrics in PSP, using three-dimensional video motion analysis in a laboratory setting compared to normal controls.

Methods: Three-dimensional motion was captured using a 10-camera motion capture system, 41 body markers and ground embedded force plates in 16 patients with PSP patients and compared to motorically normal controls.

Results: Spatiotemporal, kinematic, and kinetic gait measures effectively differentiated patients with PSP from controls. Patients had slower gait velocity, lower cadence, increased double support time and abnormal antero-posterior sway. Joint kinematics and kinetics were reduced and showed less variation among patients with PSP compared to controls which is suggestive of bradykinesia. Objective gait measures of abnormality correlated with clinical disease severity. Postural sway metrics distinguished PSP from controls and captured gait imbalance.

Significance: Objective measures of gait and balance abnormalities in patients with PSP provide an outcome measure that can be potentially used for early disease detection, in clinical trials and to validate portable motion capture devices in the future.
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http://dx.doi.org/10.1016/j.jns.2021.118054DOI Listing
August 2021

Gray and White Matter Correlates of Dysphagia in Progressive Supranuclear Palsy.

Mov Disord 2021 Aug 23. Epub 2021 Aug 23.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Dysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death.

Objective: The aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity.

Methods: Thirty-eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging. Penalized linear regression models assessed relationships between swallowing metrics and regional gray matter volumes and white matter fractional anisotropy and mean diffusivity.

Results: Oral phase impairments were associated with reduced superior parietal volumes and abnormal diffusivity in parietal and sensorimotor white matter, posterior limb of the internal capsule, and superior longitudinal fasciculus. Pharyngeal phase impairments were associated with disruption to medial frontal lobe, corticospinal tract, and cerebral peduncle. No regions were predictive of airway incursion.

Conclusions: Differential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28731DOI Listing
August 2021

Sleep disturbances in the speech-language variant of progressive supranuclear palsy.

Parkinsonism Relat Disord 2021 Aug 18;91:9-12. Epub 2021 Aug 18.

Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Introduction: Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL.

Methods: Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients.

Results: At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being "unable to fall or stay asleep". Prob. PSP-RS showed higher frequency of "screaming or talking in sleep", "acting out dreams", and "unable to fall or stay asleep" compared to both PSP-SL groups, but did not differ from possible PSP-SL in "excessive daytime sleepiness".

Conclusion: Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.
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http://dx.doi.org/10.1016/j.parkreldis.2021.08.009DOI Listing
August 2021

Neurodegeneration of the visual word form area in a patient with word form alexia.

Neurol Clin Neurosci 2021 Jul 24;9(4):359-360. Epub 2021 May 24.

Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1111/ncn3.12516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349473PMC
July 2021

Neuropsychological Profiles of Patients with Progressive Apraxia of Speech and Aphasia.

J Int Neuropsychol Soc 2021 Jul 22:1-11. Epub 2021 Jul 22.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Objective: To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA).

Method: Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale - Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy).

Results: The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains.

Conclusion: The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.
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http://dx.doi.org/10.1017/S1355617721000692DOI Listing
July 2021

Phonological Errors in Posterior Cortical Atrophy.

Dement Geriatr Cogn Disord 2021 16;50(2):195-203. Epub 2021 Jul 16.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Posterior cortical atrophy (PCA) is an atypical variant of Alzheimer's disease (AD) that presents with visuospatial/perceptual deficits. PCA is characterized by atrophy in posterior brain regions, which overlaps with atrophy occurring in logopenic variant of primary progressive aphasia (lvPPA), another atypical AD variant characterized by language difficulties, including phonological errors. Language abnormalities have been observed in PCA, although the prevalence of phonological errors is unknown. We aimed to compare the frequency and severity of phonological errors in PCA and lvPPA and determine the neuroanatomical correlates of phonological errors and language abnormalities in PCA.

Methods: The presence and number of phonological errors were recorded during the Boston Naming Test and Western Aphasia Battery repetition subtest in 27 PCA patients and 27 age- and disease duration-matched lvPPA patients. Number of phonological errors and scores from language tests were correlated with regional gray matter volumes using Spearman correlations.

Results: Phonological errors were evident in 55% of PCA patients and 70% of lvPPA patients, with lvPPA having higher average number of errors. Phonological errors in PCA correlated with decreased left inferior parietal and lateral temporal volume. Naming and fluency were also associated with decreased left lateral temporal lobe volume.

Conclusions: Phonological errors are common in PCA, although they are not as prevalent or severe as in lvPPA, and they are related to involvement of left temporoparietal cortex. This highlights the broad spectrum of clinical symptoms associated with AD and overlap between PCA and lvPPA.
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http://dx.doi.org/10.1159/000516481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376759PMC
July 2021

Primary Progressive Apraxia of Speech: From Recognition to Diagnosis and Care.

Aphasiology 2021 7;35(4):560-591. Epub 2020 Jul 7.

Departments of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Apraxia of speech (AOS) can be caused by neurodegenerative disease and sometimes is its presenting sign (i.e., primary progressive apraxia of speech, PPAOS). During the last several decades our understanding of PPAOS has evolved from clinical recognition to a fuller understanding of its core and associated clinical features, its distinction from but relationship with primary progressive aphasia, its temporal course and eventual progression to include other neurological deficits, and its neuroimaging correlates and underlying pathology.

Aims: This paper provides a comprehensive summary of the literature that has built the current knowledge base about PPAOS and progressive AOS as it co-occurs with progressive aphasia. It reviews the history of its emergence as a recognized syndrome; its relationship with the agrammatic/nonfluent variant of primary progressive aphasia; its salient perceptual features and subtypes; the acoustic and structural/physiological imaging measures that index its presence, severity, and distinction from aphasia; and principles and available data regarding its management and care.

Main Contribution: A broad summary of what is known about AOS as a manifestation of neurodegenerative disease.

Conclusions: Primary progressive apraxia of speech is a recognizable syndrome that can be distinguished from other neurodegenerative conditions that affect speech and language.
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http://dx.doi.org/10.1080/02687038.2020.1787732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247786PMC
July 2020

Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation.

Neuroimage 2021 09 9;238:118259. Epub 2021 Jun 9.

Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester 55905, MN, USA.

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model. Our comparisons used MRI and Flortaucipir scans of 97 Mayo Clinic study participants who clinically either: a) were cognitively unimpaired, or b) had cognitive impairments that were consistent with Alzheimer's disease pathology. Tested methods included cross-sectional and longitudinal variants of two overarching pipelines (FreeSurfer 6.0, and an in-house pipeline based on SPM12), three choices of target region (entorhinal, inferior temporal, and a temporal lobe meta-ROI), five types of partial volume correction (PVC) (none, two-compartment, three-compartment, geometric transfer matrix (GTM), and a tau-specific GTM variant), seven choices of reference region (cerebellar crus, cerebellar gray matter, whole cerebellum, pons, supratentorial white matter, eroded supratentorial WM, and a composite of eroded supratentorial WM, pons, and whole cerebellum), two choices of region masking (GM or GM and WM), and two choices of statistic (voxel-wise mean vs. median). Our strongest findings were: 1) larger temporal-lobe target regions greatly outperformed entorhinal cortex (median sample size estimates based on a hypothetical clinical trial were 520-526 vs. 1740); 2) longitudinal processing pipelines outperformed cross-sectional pipelines (median sample size estimates were 483 vs. 572); and 3) reference regions including supratentorial WM outperformed traditional cerebellar and pontine options (median sample size estimates were 370 vs. 559). Altogether, our results favored longitudinally SUVR methods and a temporal-lobe meta-ROI that includes adjacent (juxtacortical) WM, a composite reference region (eroded supratentorial WM + pons + whole cerebellum), 2-class voxel-based PVC, and median statistics.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407434PMC
September 2021

A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech.

Nat Commun 2021 06 8;12(1):3452. Epub 2021 Jun 8.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.
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http://dx.doi.org/10.1038/s41467-021-23687-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187627PMC
June 2021

Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition.

Neuropathol Appl Neurobiol 2021 May 9. Epub 2021 May 9.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Aims: To assess the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP).

Methods: The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n = 15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n = 10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n = 10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology.

Results: Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups.

Conclusions: In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.
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http://dx.doi.org/10.1111/nan.12727DOI Listing
May 2021

In Vivo Imaging and Autoradiography in a Case of Autopsy-Confirmed Pick Disease.

Neurol Clin Pract 2021 Feb;11(1):e11-e14

Department of Neurology (RLU, KAJ) and Department of Radiology (CGS, NES, VJL, JLW), Mayo Clinic, Rochester, MN; and Department of Neuroscience (MEM), Mayo Clinic, Jacksonville, FL.

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http://dx.doi.org/10.1212/CPJ.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101319PMC
February 2021

Progressive apraxia of speech: delays to diagnosis and rates of alternative diagnoses.

J Neurol 2021 May 4. Epub 2021 May 4.

Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder of speech programming distinct from aphasia and dysarthria, most commonly associated with a 4-repeat tauopathy. Our objective was to better understand the reasons for possible delays or diagnostic errors for patients with PAOS.

Methods: Seventy-seven consecutive PAOS research participants from the Neurodegenerative Research Group were included in this study. The medical records for these patients were reviewed in detail. For each speech-related visit, data such as the chief complaint, clinical findings, and neuroimaging findings were recorded.

Results: Apraxia of speech was the initial diagnosis in 20.1% of participants at first evaluation noted in the historical record. Other common diagnoses included primary progressive aphasia (PPA) (20.1%), dysarthria (18.18%), MCI/Dementia (6.5%), and motor neuron disease (3.9%). It took a median of 2.02 (range: 0.16-8.18) years from symptoms onset for participants to receive an initial diagnosis and 3.00 (range: 0.49-9.42) years to receive a correct diagnosis. Those who were seen by a speech-language pathologist (SLP) during their first documented encounter were more likely to be correctly diagnosed with PAOS (37/48) after SLP consultation than those who were not seen by an SLP on initial encounter (5/29) (p < 0.001).

Conclusion: Approximately 80% of patients with PAOS were imprecisely diagnosed at their first visit, with it taking a median of 3 years from symptom onset to receiving a diagnosis of PAOS. Being seen by a speech-language pathologist during the initial evaluation increased the likelihood of a correct apraxia of speech diagnosis.
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http://dx.doi.org/10.1007/s00415-021-10585-8DOI Listing
May 2021

Underlying pathology identified after 20 years of disease course in two cases of slowly progressive frontotemporal dementia syndromes.

Neurocase 2021 04 27;27(2):212-222. Epub 2021 Apr 27.

Departments of Neurology, Mayo Clinic Rochester, Minnesota, USA.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.
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http://dx.doi.org/10.1080/13554794.2021.1918723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189252PMC
April 2021

Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases.

Brain 2021 05;144(4):1082-1088

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10-4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10- 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
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http://dx.doi.org/10.1093/brain/awab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105038PMC
May 2021

A Cognitive Psychometric Investigation of Word Production and Phonological Error Rates in Logopenic Progressive Aphasia.

Am J Speech Lang Pathol 2021 05 19;30(3):1194-1202. Epub 2021 Apr 19.

Department of Neurology, Mayo Clinic, Rochester, MN.

Purpose This study investigated the relationship between word production rates (WPRs) and phonological error rates (PERs) in generative and responsive tasks in logopenic progressive aphasia (lvPPA). We examined whether a portion of the reduced WPR during generative tasks related directly to phonological impairments affecting PER on all tasks, irrespective of other task differences that contributed to WPR. Method Two cognitive psychometric models were hypothesized and fit to the total number of words produced and the number of phonological errors produced by 22 participants on 10 tasks. Bayesian inference was used to construct posterior distributions of participant ability and task difficulty parameters. Model fit statistics were compared. Association strengths for average generative WPR and average responsive PER were also evaluated with linear least-squares regression. Results Average generative WPR and average responsive PER were significantly associated ( = -.77, = .00002). A cognitive psychometric model that assumed reduced WPR on generative tasks reflects a portion of general phonological impairment yielded better fit than a model that ignored performance differences between generative and responsive tasks. Generative fluency tasks that elicited few phonological errors still reflected phonological impairment, via suppression. Individual participants were estimated to suppress between 62% and 93% of phonological errors on generative tasks that would have emerged on responsive tasks. Conclusions Suppression of phonological errors may present as decreased WPR on generative tasks in lvPPA. Failure to account for this suppression tendency may lead to overestimation of phonological ability. The findings indicate the need to account for task demands in assessing lvPPA.
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http://dx.doi.org/10.1044/2021_AJSLP-20-00221DOI Listing
May 2021

Neurobehavioral Characteristics of FDG-PET Defined Right-Dominant Semantic Dementia: A Longitudinal Study.

Dement Geriatr Cogn Disord 2021 23;50(1):17-28. Epub 2021 Mar 23.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA,

Introduction: Semantic dementia (SD) is characterized by fluent speech, anomia, and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG)-PET. We assessed neurobehavioral features in SD patients across 3 FDG-PET-defined metabolic patterns and investigated progression over time.

Methods: Thirty-four patients with SD who completed FDG-PET were classified into a left- and right-dominant group based on the degree of hypometabolism in each temporal lobe. The left-dominant group was further subdivided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 patients with longitudinal follow-up.

Results: The right-dominant group performed worse on the NPI-Q and had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ patients but appeared to improve in the 2 right-dominant patients with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, the degree of temporal lobe asymmetry remained relatively constant over time.

Conclusion: In SD, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in patients that present with left-dominant patterns of hypometabolism.
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http://dx.doi.org/10.1159/000513979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243786PMC
March 2021

Motor Speech Disorders and Communication Limitations in Progressive Supranuclear Palsy.

Am J Speech Lang Pathol 2021 06 9;30(3S):1361-1372. Epub 2021 Mar 9.

Department of Neurology, Mayo Clinic, Rochester, MN.

Purpose This study describes motor speech disorders and associated communication limitations in six variants of progressive supranuclear palsy (PSP). Method The presence, nature, and severity of dysarthria and apraxia of speech (AOS) were documented, along with scores on the Apraxia of Speech Rating Scale-Version 3 (ASRS-3) for 77 (40 male and 37 female) patients with PSP. Clinician-estimated and patient-estimated communication limitations were rated using the Motor Speech Disorders Severity Rating (MSDSR) Scale and the Communicative Effectiveness Survey (CES), respectively. Descriptive statistics were calculated for each of these dependent variables. One-tailed tests were conducted to test mean differences in ASRS-3 and CES between participants with and without AOS and between participants with and without dysarthria. Spearman rank correlations were calculated between ASRS-3 scores and clinical judgments of AOS and dysarthria severity and between MSDSR and CES ratings. Results Nine participants (12%) had normal speech. Eighty-seven percent exhibited dysarthria; hypokinetic and mixed hypokinetic-spastic dysarthria were observed most frequently. AOS was observed in 19.5% of participants across all variants, but in only 10% exclusive of the PSP speech and language variant. Nearly half presented with AOS in which neither phonetic nor prosodic features clearly predominated. The mean ASRS-3 score for participants with AOS was significantly higher than for those without and correlated strongly with clinician judgment of AOS severity. Mean ASRS-3 was higher for participants with dysarthria than for those without but correlated weakly with dysarthria severity. Mean MSDSR and CES ratings were lower in participants with AOS compared to those without and moderately correlated with each other. Conclusions Motor speech disorders that negatively impact communicative effectiveness are common in PSP and occur in many variants. This is the first description of motor speech disorders across PSP variants, setting the stage for future research characterizing neuroanatomical correlates, progression of motor speech disorders, and benefits of targeted interventions. Supplemental Material https://doi.org/10.23641/asha.14111837.
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http://dx.doi.org/10.1044/2020_AJSLP-20-00126DOI Listing
June 2021

Diffusion tensor imaging analysis in three progressive supranuclear palsy variants.

J Neurol 2021 Sep 12;268(9):3409-3420. Epub 2021 Mar 12.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Clinical variants of progressive supranuclear palsy (PSP) include the classic Richardson's syndrome (PSP-RS), as well as cortical presentations such as PSP-speech/language (PSP-SL) and subcortical presentations such as PSP-parkinsonism (PSP-P). Patterns of white matter tract degeneration underlying these variants, and the degree to which white matter patterns could differentiate these variants, is unclear.

Methods: Forty-nine PSP patients (28 PSP-RS, 12 PSP-P, and 9 PSP-SL) were recruited by the Neurodegenerative Research Group and underwent diffusion tensor imaging. Regional diffusion tensor imaging metrics were compared across PSP variants using Bayesian linear mixed-effects models, with inter-variant differentiation assessed using the area under the receiver operator characteristic curve (AUROC).

Results: All three variants showed degeneration of the body of the corpus callosum, posterior thalamic radiation, superior cerebellar peduncle, internal and external capsule, and superior fronto-occipital fasciculus. PSP-RS showed greater degeneration of superior cerebellar peduncle compared to PSP-P and PSP-SL, whereas PSP-SL showed greater degeneration of body and genu of the corpus callosum, internal capsule, external capsule, and superior longitudinal fasciculus compared to the other variants. Fractional anisotropy in body of the corpus callosum provided excellent differentiation of PSP-SL from both PSP-P and PSP-RS (AUROC = 0.91 and 0.92, respectively). Moderate differentiation of PSP-RS and PSP-P was achieved with fractional anisotropy in superior fronto-occipital fasciculus (AUROC = 0.68) and mean diffusivity in the superior cerebellar peduncle (AUROC = 0.65).

Conclusion: In this pilot study, patterns of white matter tract degeneration differed across PSP-RS, PSP-SL, and PSP-P, with the body of the corpus callosum showing some utility in the differentiation of PSP-SL from the other two variants.
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http://dx.doi.org/10.1007/s00415-020-10360-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363518PMC
September 2021

Natural History of "Pure" Primary Lateral Sclerosis.

Neurology 2021 04 26;96(17):e2231-e2238. Epub 2021 Feb 26.

From the Department of Neurology (A.H., K.A.J., E.J.S., J.E.A.), Mayo Clinic, Rochester, MN; Department of Neurology (S.O.M.), Cleveland Clinic Abu Dhabi, United Arab Emirates; and Department of Neurology (W.T.H.), Emory University, Atlanta, GA.

Objective: To assess whether primary lateral sclerosis (PLS), classified as pure when the EMG is normal, converts to amyotrophic lateral sclerosis (ALS) after longitudinal follow-up.

Methods: Retrospective chart review was performed of patients with pure PLS at Mayo Clinic in Rochester, MN (1990-2016). Inclusion criteria required a normal EMG during the first 4 years of symptoms.

Results: Forty-three patients had pure PLS (25 female, 58%) with a median onset age of 50 years (range 38-78 years) and median follow-up at 9 years' disease duration (range 4-36 years). The ascending paraparesis phenotype (n = 30, 70%) was most common, followed by hemiparetic onset (n = 9, 21%) and bulbar onset (n = 4, 9%). Among the 30 paraparetic-onset cases, bladder symptoms (n = 18, 60%) and dysarthria (n = 15, 50%) were more common than pseudobulbar affect (n = 9, 30%) and dysphagia (n = 8, 27%). By the last follow-up, 17 of 30 (56%) used a cane and 6 (20%) required a wheelchair. The paraparetic variant, compared with hemiparetic and bulbar onset, had the youngest onset (48 vs 56 vs 60 years, respectively; = 0.02). Five patients died; 1 patient required a feeding tube; and none required permanent noninvasive ventilation. Two patients developed an idiopathic multisystem neurodegenerative disorder, which surfaced after 19 and 20 years. Two patients developed minor EMG abnormalities. The remainder 39 had persistently normal EMGs.

Conclusions: Pure PLS did not convert to ALS after a median of 9 years' disease duration follow-up in our study population. The ascending paraparetic phenotype was most common, with earlier onset and frequent bladder involvement. After years of pure PLS, <5% develop a more pervasive neurodegenerative disorder.
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http://dx.doi.org/10.1212/WNL.0000000000011771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166429PMC
April 2021

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

J Alzheimers Dis 2021 ;80(2):683-693

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.

Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.

Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.

Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.

Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.
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http://dx.doi.org/10.3233/JAD-201166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020877PMC
September 2021

A Longitudinal Evaluation of Speech Rate in Primary Progressive Apraxia of Speech.

J Speech Lang Hear Res 2021 02 21;64(2):392-404. Epub 2021 Jan 21.

Department of Neurology, Mayo Clinic, Rochester, MN.

Purpose Individuals with primary progressive apraxia of speech (PPAOS) have apraxia of speech (AOS) in which disruptions in articulation or prosody predominate the speech pattern, referred to, respectively, as phonetic or prosodic subtypes. Many develop aphasia and/or dysarthria. Past research has demonstrated that simple temporal acoustic measures are sensitive to the presence of AOS. The aim of this study was to describe the change in temporal acoustic measures over time and assess if specific patterns of AOS or co-occurring aphasia or dysarthria impact the rate of change over time. Method Durations for multiple productions of the words , , , and , in an imitative speech task, were recorded for 73 patients, with two to six visits each. A linear mixed-effects model was used to assess the cross-sectional differences and longitudinal influence of AOS subtype and presence of aphasia/dysarthria on speech rate. Pearson correlations were calculated between rate measures and performance on other clinical measures. Results Cross-sectionally, patients with prosodic-predominant PPAOS produced words more slowly than those with phonetic-predominant PPAOS. Patients with either aphasia or dysarthria produced words more slowly than those without. Longitudinally, the speech rate of patients with phonetic-predominant PPAOS had a reduction of 0.5 syllables per second per year. Patients with prosodic-predominant AOS changed less quickly, as did those who developed aphasia. Dysarthria did not impact rate of change. There were strong associations between speech rate measures and other clinical indices of speech and language functioning. Conclusion Simple temporal acoustic measures may reflect the subtype of AOS (phonetic or prosodic predominant), serve as an index of progression of AOS, and inform prognostication relative to the presenting combination of speech and language features. Supplemental Material https://doi.org/10.23641/asha.13564724.
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http://dx.doi.org/10.1044/2020_JSLHR-20-00253DOI Listing
February 2021

Progressive Supranuclear Palsy and Corticobasal Degeneration.

Adv Exp Med Biol 2021 ;1281:151-176

UC San Diego Department of Neurosciences, La Jolla, CA, USA.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.
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http://dx.doi.org/10.1007/978-3-030-51140-1_11DOI Listing
February 2021

Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype.

Ann Neurol 2021 03 17;89(3):520-533. Epub 2020 Dec 17.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: The objective of this study was to describe clinical features, [ F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).

Methods: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD).

Results: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD.

Interpretation: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.
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http://dx.doi.org/10.1002/ana.25979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040336PMC
March 2021

Timeline of Rapid Eye Movement Sleep Behavior Disorder in Overt Alpha-Synucleinopathies.

Ann Neurol 2021 02 20;89(2):293-303. Epub 2020 Nov 20.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Objective: The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age- and sex-matched controls in a population-based incident-cohort study.

Methods: We used a population-based, 1991 to 2010 incident-cohort study of alpha-synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined.

Results: Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0-217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50-4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07-6.62, p < 0.0001), but did not increase mortality risk.

Interpretation: Our cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person-years. With 53 times greater lifetime incidence in alpha-synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2021;89:293-303.
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http://dx.doi.org/10.1002/ana.25952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080353PMC
February 2021

Tau and Amyloid Relationships with Resting-state Functional Connectivity in Atypical Alzheimer's Disease.

Cereb Cortex 2021 02;31(3):1693-1706

Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.

The mechanisms through which tau and amyloid-beta (Aβ) accumulate in the brain of Alzheimer's disease patients may differ but both are related to neuronal networks. We examined such mechanisms on neuroimaging in 58 participants with atypical Alzheimer's disease (posterior cortical atrophy or logopenic progressive aphasia). Participants underwent Aβ-PET, longitudinal tau-PET, structural MRI and resting-state functional MRI, which was analyzed with graph theory. Regions with high levels of Aβ were more likely to be functional hubs, with a high number of functional connections important for resilience to cascading network failures. Regions with high levels of tau were more likely to have low clustering coefficients and degrees, suggesting a lack of trophic support or vulnerability to local network failures. Regions strongly functionally connected to the disease epicenters were more likely to have higher levels of tau and, less strongly, of Aβ. The regional rate of tau accumulation was associated with tau levels in functionally connected regions, in support of tau accumulation in a functional network. This study elucidates the relations of tau and Aβ to functional connectivity metrics in atypical Alzheimer's disease, strengthening the hypothesis that the spread of the 2 proteins is driven by different biological mechanisms related to functional networks.
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http://dx.doi.org/10.1093/cercor/bhaa319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869088PMC
February 2021

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Brain 2020 12;143(11):3463-3476

Department of Radiology (Radiology Research) Mayo Clinic, Rochester, MN, USA.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.
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http://dx.doi.org/10.1093/brain/awaa299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719030PMC
December 2020

Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer's Disease.

J Alzheimers Dis 2020 ;78(3):927-937

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD.

Objective: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD.

Methods: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests.

Results: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA.

Conclusion: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.
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http://dx.doi.org/10.3233/JAD-200625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732352PMC
January 2020

The evolution of parkinsonism in primary progressive apraxia of speech: A 6-year longitudinal study.

Parkinsonism Relat Disord 2020 12 7;81:34-40. Epub 2020 Oct 7.

Department of Neurology, Movement Disorders, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Behavioral Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Introduction: Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome in which patients present with an isolated motor speech disorder. Some PPAOS patients develop parkinsonism and other features of progressive supranuclear palsy (PSP) and/or corticobasal syndrome (CBS) over time. We aimed to assess the evolution of parkinsonian characteristics in PPAOS patients who had been followed yearly for at least six years.

Methods: From a large cohort of 46 PPAOS patients, eight were followed yearly for > 6-years in multiple NIH-funded grants. Parkinsonian and other features, including bradykinesia, tremor, rigidity, postural instability, apraxia, ocular motor function and cognition were assessed at each visit, and research criteria applied for PSP and CBS diagnosis. Neurological, speech-language test scores, and [F]fluorodeoxyglucose PET (FDG-PET) and MRI midbrain volumes were assessed.

Results: A Parkinson's plus syndrome developed in all eight patients (100%). Bradykinesia was the earliest feature, followed by rigidity and postural instability. Tremor was not a significant feature. Parkinsonism, limb apraxia and ocular motor impairment tended to develop four-to-five years after onset with some patients having slight asymmetric parkinsonism. Six patients (75%) met research criteria for probable PSP, although only one for PSP-Richardson's syndrome; three patients met criteria for possible CBS. Slightly asymmetric, left-sided, hypometabolism was observed on FDG-PET, not matching asymmetry of Parkinsonism. Midbrain hypometabolism was absent-minimal. Three patients had progressive midbrain volumes in the PSP-Richardson's syndrome range.

Conclusions: A Parkinson's plus syndrome may inevitably develop in PPAOS supporting PPAOS as an early presentation of a Parkinson's plus disorder.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769910PMC
December 2020
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