Publications by authors named "Jennifer L Whitwell"

216 Publications

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 Jul 16:1-9. 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
July 2021

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

Neuroimage 2021 Jun 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
June 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

Clinical, Imaging, and Pathologic Characteristics of Patients With Right Versus Left Hemisphere-Predominant Logopenic Progressive Aphasia.

Neurology 2021 Jun 4. Epub 2021 Jun 4.

Department of Neurology, Rochester, MN, USA

Objective: To assess and compare demographic, clinical, neuroimaging and pathologic characteristics of a cohort of patients with right versus left hemisphere-predominant logopenic progressive aphasia (LPA).

Methods: This is a case-control study of patients with LPA who were prospectively followed at Mayo Clinic and underwent an [F]-fluorodeoxyglucose (FDG)-PET scan. Patients were classified as rLPA if right temporal lobe metabolism was ≥1 standard deviation lower than left temporal lobe metabolism. Patients with rLPA were frequency-matched 3:1 to typical left-predominant LPA based on degree of asymmetry and severity of temporal lobe metabolism. Patients were compared on clinical, imaging (MRI, FDG-PET, amyloid-beta- and tau-PET) and pathologic characteristics.

Results: Of 103 prospectively recruited LPA patients 8 (4 females) were classified as rLPA (7.8%); all rLPA cases were right-handed. rLPA patients had milder aphasia based on the Western Aphasia Battery-Aphasia Quotient (=0.04) and less frequent phonologic errors (=0.015). rLPA had shorter survival compared to typical LPA: hazard ratio 4.0(1.2- 12.9), =0.02. There were no other differences in demographics, handedness, genetics, neurological or neuropsychological tests. Compared to the 24 frequency-matched typical LPA patients, rLPA showed greater frontotemporal hypometabolism of the non-dominant hemisphere on FDG-PET and less atrophy in amygdala and hippocampus of the dominant hemisphere. Autopsy evaluation revealed a similar distribution of pathologic findings in both groups, with Alzheimer's disease pathologic changes being the most frequent pathology.

Conclusions: Right LPA is associated with less severe aphasia but has shorter survival from reported symptom onset than typical LPA, possibly related to greater involvement of the non-dominant hemisphere.
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http://dx.doi.org/10.1212/WNL.0000000000012322DOI Listing
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

Update on neuroimaging in Alzheimer's disease.

Curr Opin Neurol 2021 Aug;34(4):525-531

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

Purpose Of Review: The purpose of this review was to discuss the contribution of the most recent neuroimaging studies to our understanding of the mechanisms underlying Alzheimer's disease.

Recent Findings: Studies have applied cross-sectional and longitudinal positron emission tomography (PET), structural and resting-state functional magnetic resonance imaging to primarily investigate (1) how Alzheimer's disease pathological hallmarks like tau and amyloid-beta build up and spread across the brain at different disease stage and in different disease phenotypes and (2) how the spreading of these proteins is related to atrophy, to neuronal network disruption and to neuroinflammation.

Summary: The findings of these studies offer insight on the mechanisms that drive the pathological and clinical progression of Alzheimer's disease, highlighting their multifactorial nature, which is a crucial aspect for the development of disease-modifying therapeutics and can be captured with multimodal imaging approaches.
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http://dx.doi.org/10.1097/WCO.0000000000000947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263471PMC
August 2021

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

Neurocase 2021 Apr 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

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 Mar 12. 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
March 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
January 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

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

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

Cereb Cortex 2021 Feb;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

Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes.

Neurology 2020 12 28;95(24):e3190-e3202. Epub 2020 Sep 28.

From the Departments of Radiology (J.L.W., C.C.S., M.L.S., A.J.S., V.J.L., C.R.J.), Health Sciences Research (N.T.), Neurology (J.R.D., J.G.-R., B.F.B., D.S.K., R.C.P., K.A.J.), Psychiatry and Psychology (M.M.M.), and Neuropathology (J.E.P.), Mayo Clinic, Rochester, MN; and Department of Neuropathology (D.W.D.), Mayo Clinic, Jacksonville, FL.

Objective: To characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome.

Methods: Seventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine β-amyloid positivity.

Results: The bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was β-amyloid-positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter.

Conclusion: Patterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.
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http://dx.doi.org/10.1212/WNL.0000000000010948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836669PMC
December 2020

Sensitivity-Specificity of Tau and Amyloid β Positron Emission Tomography in Frontotemporal Lobar Degeneration.

Ann Neurol 2020 11 12;88(5):1009-1022. Epub 2020 Sep 12.

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

Objective: To examine associations between tau and amyloid β (Aβ) molecular positron emission tomography (PET) and both Alzheimer-related pathology and 4-repeat tau pathology in autopsy-confirmed frontotemporal lobar degeneration (FTLD).

Methods: Twenty-four patients had [ F]-flortaucipir-PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD-TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)-PET. Braak staging, Aβ plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta-ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden.

Results: Nine cases (37.5%) had Aβ plaques. Global PiB SUVR correlated with Aβ plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty-one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta-ROI SUVRs were not elevated in Braak IV or primary age-related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions.

Interpretation: Molecular PET shows expected correlations with Alzheimer-related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009-1022.
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http://dx.doi.org/10.1002/ana.25893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861121PMC
November 2020

Communication Limitations in Patients With Progressive Apraxia of Speech and Aphasia.

Am J Speech Lang Pathol 2020 11 5;29(4):1976-1986. Epub 2020 Aug 5.

Department of Neurology, Mayo Clinic, Rochester, MN.

Purpose Individuals with primary progressive apraxia of speech (AOS) have AOS in which disruptions in articulation and prosody predominate the speech pattern. Many develop aphasia and/or dysarthria later in the disease course. The aim of this study was to describe the communication limitations in these patients, as 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) Functional Communication Measures (FCMs) and an adapted motor speech disorder (MSD) severity rating. Method Speech and language evaluations were completed for 24 patients with progressive AOS ( = 7 with isolated AOS; = 17 with a combination of AOS and aphasia). Descriptive comparisons were utilized to evaluate differences in communication measures among patients with various combinations of MSDs and aphasia. Differences associated with phonetic predominant or prosodic predominant AOS were also examined. Across the entire cohort, correlations were calculated between the participation ratings and other clinical assessment measures. Results The CPIB reflected greater limitations for those with aphasia and AOS compared to isolated AOS, but was not notably different when dysarthria occurred with AOS ( = 9/24). Across the cohort, there were statistically significant correlations between the CPIB and ASHA FCM-Motor Speech and Language Expression ratings and the MSD severity rating. The CPIB did not correlate with the ASHA FCM-Language Comprehension or other speech-language measures. Conclusions Patients with neurodegenerative AOS experience reduced participation in communication that is further exacerbated by co-occurring language deficits. The study suggests measures of severity cannot be assumed to correlate with measures of participation restrictions and offers a foundation for further research examining the day-to-day sequela of progressive speech and language disorders. Supplemental Material https://doi.org/10.23641/asha.12743252.
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http://dx.doi.org/10.1044/2020_AJSLP-20-00012DOI Listing
November 2020

Dementia with Lewy bodies presenting as Logopenic variant primary progressive Aphasia.

Neurocase 2020 10 16;26(5):259-263. Epub 2020 Jul 16.

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

We report a patient presenting with clinical features of logopenic variant primary progressive aphasia (lvPPA) who was later diagnosed with probable dementia with Lewy bodies. LvPPA is a neurodegenerative disease that is characterized by anomia, word-finding difficulty, impaired comprehension, and phonological errors. The most common underlying pathology for lvPPA is Alzheimer's disease. However, our patient with clinical features of logopenic progressive aphasia was later diagnosed with probable dementia with Lewy bodies. This case demonstrates that lvPPA can also be an initial manifestation of a phenotype of dementia with Lewy bodies.
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http://dx.doi.org/10.1080/13554794.2020.1795204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530001PMC
October 2020

Longitudinal neuroimaging biomarkers differ across Alzheimer's disease phenotypes.

Brain 2020 07;143(7):2281-2294

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

Alzheimer's disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer's disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer's disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer's disease (18 with typical amnestic Alzheimer's disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer's disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer's disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer's disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer's disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363492PMC
July 2020

Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy.

Neurology 2020 07 9;95(1):e23-e34. Epub 2020 Jun 9.

From the Departments of Neurology (M.B., H.B., D.T.J., D.S.K., B.F.B., R.C.P., K.A.J.), Radiology (C.G.S., M.L.S., C.R.J., V.L., J.L.W.), and Laboratory Medicine and Pathology (J.E.P.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (M.E.M., L.P., D.W.D.), Mayo Clinic, Jacksonville, FL.

Objective: To evaluate FDG-PET as an antemortem diagnostic tool for Alzheimer-related TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy.

Methods: We conducted a cross-sectional neuroimaging-histologic analysis of patients with antemortem FDG-PET and postmortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center and Study of Aging with Alzheimer spectrum pathology. TDP-43-positive status was assigned when TDP-43-immunoreactive inclusions were identified in the amygdala. Statistical parametric mapping (SPM) analyses compared TDP-43-positive (TDP-43[+]) with TDP-43-negative cases (TDP-43[-]), correcting for field strength, sex, Braak neurofibrillary tangle, and neuritic plaque stages. Cross-validated logistic regression analyses were used to determine whether regional FDG-PET values predict TDP-43 status. We also assessed the ratio of inferior temporal to medial temporal (IMT) metabolism as this was proposed as a biomarker of hippocampal sclerosis.

Results: Of 73 cases, 27 (37%) were TDP-43(+), of which 6 (8%) had hippocampal sclerosis. SPM analysis showed TDP-43(+) cases having greater hypometabolism of medial temporal, frontal superior medial, and frontal supraorbital (FSO) regions ( < 0.001). Logistic regression analysis showed only FSO and IMT to be associated with TDP-43(+) status, identifying up to 81% of TDP-43(+) cases ( < 0.001). An IMT/FSO ratio was superior to the IMT in discriminating TDP-43(+) cases: 78% vs 48%, respectively.

Conclusions: Alzheimer-related TDP-43 proteinopathy is associated with hypometabolism in the medial temporal and frontal regions. Combining FDG-PET measures from these regions may be useful for antemortem prediction of Alzheimer-related TDP-43 proteinopathy.

Classification Of Evidence: This study provides Class II evidence that hypometabolism in the medial temporal and frontal regions on FDG-PET is associated with Alzheimer-related TDP-43 proteinopathy.
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http://dx.doi.org/10.1212/WNL.0000000000009722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371379PMC
July 2020

Longitudinal flortaucipir ([F]AV-1451) PET uptake in semantic dementia.

Neurobiol Aging 2020 08 18;92:135-140. Epub 2020 Apr 18.

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

To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365267PMC
August 2020

Association between transactive response DNA-binding protein of 43 kDa type and cognitive resilience to Alzheimer's disease: a case-control study.

Neurobiol Aging 2020 08 15;92:92-97. Epub 2020 Apr 15.

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

Association between the transactive response DNA-binding protein of 43 kDa (TDP-43), its newly described types (type α/type β), and resilience to Alzheimer's disease neuropathological change (ADNC) defined as preservation of normal cognitive functioning despite advanced ADNC has been evaluated in this case-control study of 63 older adults. Twenty-one resilient to ADNC individuals were matched 1:2 to nonresilient (Alzheimer's dementia) using propensity scores, accounting for age at death, neuritic plaque density, and neurofibrillary tangle stage. Resilient and matched nonresilient participants were similar in terms of gender, apolipoprotein E ε4 carriership, education, occupation, AD, and other pathologies. Resilient participants had lower frequency of TDP-43 co-pathology compared to nonresilient (19% vs. 62%, p = 0.002). Among TDP-43-positive cases, TDP-43 type α inclusions were absent in resilient to ADNC participants and were dominant in matched nonresilient cases (65%, p = 0.03). TDP-43 and TDP-43 types appear to be one of the key pathological determinants of loss of cognitive resilience to ADNC and hence are important in the understanding of the clinical expression of ADNC.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682814PMC
August 2020

Ioflupane 123I (DAT scan) SPECT identifies dopamine receptor dysfunction early in the disease course in progressive apraxia of speech.

J Neurol 2020 Sep 9;267(9):2603-2611. Epub 2020 May 9.

Department of Neurology, Mayo Clinic College of Medicine and Science, 200 1st Street S.W., Rochester, MN, 55905, USA.

Objective: To describe I-FP-CIT (DAT scan) SPECT findings in progressive apraxia of speech (PAOS) patients and to compare those findings with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

Background: PAOS is a neurodegenerative syndrome in which patients present with apraxia of speech, a motor speech disorder affecting programming and planning of speech. Patients with PAOS predictably develop Parkinsonism. DAT scan is a neuroimaging tool that assesses the integrity of presynaptic dopamine transporters in striatum and is usually abnormal in PSP and CBS.

Methods: As part of an NIH-funded grant, we performed a DAT scan on 17 PAOS patients early in the disease course. DaTQUANT software was used to quantify uptake in the left and right caudate and anterior/posterior putamen, with striatum to background ratios (SBRs). The PAOS cohort was compared to 15 PSP and 8 CBS patients.

Results: Five PAOS patients (29%) showed abnormalities in at least one striatal region on DAT scan. When the five PAOS patients with abnormal DAT were compared to the PSP and CBS patients, the only difference observed was lower uptake in the posterior putamen in PSP (p = 0.03). There were no differences is putamen/caudate ratio or in symmetry of uptake, across all groups. There was also no difference in MDS-UPDRS-III scores between PAOS patients with and without abnormal DAT scans (p = 0.56).

Conclusions: Abnormal DAT scan is observed early in the disease course in approximately 30% of PAOS patients, with striatal abnormalities similar to those in PSP and CBS.
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http://dx.doi.org/10.1007/s00415-020-09883-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426240PMC
September 2020

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous.

Ann Clin Transl Neurol 2020 05 15;7(5):707-721. Epub 2020 Apr 15.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Objective: To assess the relationships between MRI volumetry and [ F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by decade).

Methods: Five-hundred and sixty-four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer's dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and C-PiB; all 166 Alzheimer's participants were beta-amyloid positive and all controls were beta-amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal-to-neocortical and entorhinal-to-neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50-59, 60-69, and 70+). Voxel-level analyses were also performed.

Results: For 50-59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel-level analysis. For 60-69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60-69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes.

Interpretation: MRI volumetry versus flortaucipir PET relationships differ across Alzheimer's clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta-amyloid and tau-positive biomarker defined Alzheimer's disease.
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http://dx.doi.org/10.1002/acn3.51038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261766PMC
May 2020