Publications by authors named "Mary M Machulda"

195 Publications

Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease.

Neurobiol Aging 2021 Aug 25;108:90-98. Epub 2021 Aug 25.

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

The apolipoprotein E (APOE) ε4 allele is the most well-established risk factor for Alzheimer's disease (AD), although its relationship to age at onset and clinical phenotype is unclear. We aimed to assess relationships between APOE genotype and age at onset, amyloid-beta (Aβ) deposition and typical versus atypical clinical presentations in AD. Frequency of APOE ε4 carriers by age at onset was assessed in 447 AD patients, 138 atypical AD patients recruited by the Neurodegenerative Research Group at Mayo Clinic, and 309 with typical AD from ADNI. APOE ε4 frequency increased with age at onset in atypical AD but showed a bell-shaped curve in typical AD where highest frequencies were observed between 65 and 70 years. Typical AD showed higher APOE ε4 frequencies than atypical AD only between the ages of 57 and 69 years. Global Aβ standard uptake value ratios did not differ according to APOE e4 status in either group. APOE genotype varies by both age at onset and clinical phenotype in AD, highlighting the heterogeneous nature of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.08.012DOI Listing
August 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

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

A Comparison of Cross-Sectional and Longitudinal Methods of Defining Objective Subtle Cognitive Decline in Preclinical Alzheimer's Disease Based on Cogstate One Card Learning Accuracy Performance.

J Alzheimers Dis 2021 ;83(2):861-877

Division of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.

Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer's disease continuum.

Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (ΔOBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer's disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance.

Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50 + with amyloid and tau PET scans (n = 311) comprised the biomarker-defined sample. A case-control sample of participants aged 65 + remaining cognitively unimpaired for at least 30 months included 64 who subsequently developed MCI (incident MCI cases) and 184 controls, risk-set matched by age, sex, education, and visit number. sOBJ was assessed by OCL z-scores. ΔOBJ was assessed using within subjects' standard deviation and annualized change from linear regression or linear mixed effects (LME) models. Concordance measures Area Under the ROC Curve (AUC) or C-statistic and odds ratios (OR) from conditional logistic regression models were derived. sOBJ and ΔOBJ were modeled jointly to compare methods.

Results: sOBJ and ΔOBJ-LME methods differentiated A+T+ from A-T- (AUC = 0.64, 0.69) and controls from incident MCI (C-statistic = 0.59, 0.69) better than chance; other ΔOBJ methods did not. ΔOBJ-LME improved prediction of future MCI over baseline sOBJ (p = 0.003) but not over 30-month sOBJ (p = 0.09).

Conclusion: Longitudinal decline did not offer substantial benefit over cross-sectional assessment in detecting preclinical Alzheimer's disease or incident MCI.
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http://dx.doi.org/10.3233/JAD-210251DOI Listing
January 2021

Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Eli Lilly and Company, Indianapolis, Indiana, USA.

Introduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood.

Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging.

Results: CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle.

Discussion: There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers.
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http://dx.doi.org/10.1002/alz.12415DOI Listing
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

Diffusion models reveal white matter microstructural changes with ageing, pathology and cognition.

Brain Commun 2021 19;3(2):fcab106. Epub 2021 May 19.

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

White matter microstructure undergoes progressive changes during the lifespan, but the neurobiological underpinnings related to ageing and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging, to investigate the microstructural alterations due to demographics, common age-related pathological processes (amyloid, tau and white matter hyperintensities) and cognition. We also compared Neurite Orientation Dispersion and Density Imaging findings to the older Diffusion Tensor Imaging model-based findings. Three hundred and twenty-eight participants (264 cognitively unimpaired, 57 mild cognitive impairment and 7 dementia with a mean age of 68.3 ± 13.1 years) from the Mayo Clinic Study of Aging with multi-shell diffusion imaging, fluid attenuated inversion recovery MRI as well as amyloid and tau PET scans were included in this study. White matter tract level diffusion measures were calculated from Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging. Pearson correlation and multiple linear regression analyses were performed with diffusion measures as the outcome and age, sex, education/occupation, white matter hyperintensities, amyloid and tau as predictors. Analyses were also performed with each diffusion MRI measure as a predictor of cognitive outcomes. Age and white matter hyperintensities were the strongest predictors of all white matter diffusion measures with low associations with amyloid and tau. However, neurite density decrease from Neurite Orientation Dispersion and Density Imaging was observed with amyloidosis specifically in the temporal lobes. White matter integrity (mean diffusivity and free water) in the corpus callosum showed the greatest associations with cognitive measures. All diffusion measures provided information about white matter ageing and white matter changes due to age-related pathological processes and were associated with cognition. Neurite orientation dispersion and density imaging and diffusion tensor imaging are two different diffusion models that provide distinct information about variation in white matter microstructural integrity. Neurite Orientation Dispersion and Density Imaging provides additional information about synaptic density, organization and free water content which may aid in providing mechanistic insights into disease progression.
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http://dx.doi.org/10.1093/braincomms/fcab106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202149PMC
May 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 vs Left Hemisphere-Predominant Logopenic Progressive Aphasia.

Neurology 2021 08 4;97(5):e523-e534. Epub 2021 Jun 4.

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

Objective: To assess and compare demographic, clinical, neuroimaging, and pathologic characteristics of a cohort of patients with right hemisphere-predominant vs 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 [F]-fluorodeoxyglucose (FDG) PET scan. Patients were classified as rLPA if right temporal lobe metabolism was ≥1 SD 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, β-amyloid, and tau-PET), and pathologic characteristics.

Results: Of 103 prospectively recruited patients with LPA, 8 (4 female) were classified as rLPA (7.8%); all patients with rLPA were right-handed. Patients with rLPA had milder aphasia based on the Western Aphasia Battery-Aphasia Quotient ( = 0.04) and less frequent phonologic errors ( = 0.015). Patients with 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, or neurologic or neuropsychological tests. Compared to the 24 frequency-matched patients with typical LPA, patients with rLPA showed greater frontotemporal hypometabolism of the nondominant 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 disease pathologic changes being the most frequent pathology.

Conclusions: rLPA is associated with less severe aphasia but has shorter survival from reported symptom onset than typical LPA, possibly related to greater involvement of the nondominant hemisphere.
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http://dx.doi.org/10.1212/WNL.0000000000012322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356378PMC
August 2021

White matter abnormalities are key components of cerebrovascular disease impacting cognitive decline.

Brain Commun 2021 12;3(2):fcab076. Epub 2021 Apr 12.

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

While cerebrovascular disease can be observed using MRI, the multiplicity and heterogeneity in the mechanisms of cerebrovascular damage impede accounting for these measures in ageing and dementia studies. Our primary goal was to investigate the key sources of variability across MRI markers of cerebrovascular disease and evaluate their impact in comparison to amyloidosis on cognitive decline in a population-based sample. Our secondary goal was to evaluate the prognostic utility of a cerebrovascular summary measure from all markers. We included both visible lesions seen on MRI (white matter hyperintensities, cortical and subcortical infarctions, lobar and deep microbleeds) and early white matter damage due to systemic vascular health using diffusion changes in the genu of the corpus callosum. We identified 1089 individuals aged ≥60 years with concurrent amyloid-PET and MRI scans from the population-based Mayo Clinic Study of Aging. We divided these into discovery and validation datasets. Using the discovery dataset, we conducted principal component analyses and ascertained the main sources of variability in cerebrovascular disease markers. Using linear regression and mixed effect models, we evaluated the utility of these principal components and combinations of these components for the prediction of cognitive performance along with amyloidosis. Our main findings were (i) there were three primary sources of variability among the CVD measures-white matter changes are driven by white matter hyperintensities and diffusion changes; number of microbleeds (lobar and deep); and number of infarctions (cortical and subcortical); (ii) Components of white matter changes and microbleeds but not infarctions significantly predicted cognition trajectories in all domains with greater contributions from white matter; and (iii) The summary vascular score explained 3-5% of variability in baseline global cognition in comparison to 3-6% variability explained by amyloidosis. Across all cognitive domains, the vascular summary score had the least impact on memory performance (∼1%). Though there is mechanistic heterogeneity in the cerebrovascular disease markers measured on MRI, these changes can be grouped into three components and together explain variability in cognitive performance equivalent to the impact of amyloidosis on cognition. White matter changes represent dynamic ongoing damage, predicts future cognitive decline across all domains and diffusion measurements help capture white matter damage due to systemic vascular changes. Therefore, measuring and accounting for white matter changes using diffusion MRI and white matter hyperintensities along with microbleeds will allow us to capture vascular contributions to cognitive impairment and dementia.
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http://dx.doi.org/10.1093/braincomms/fcab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072521PMC
April 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

NIA-AA Alzheimer's Disease Framework: Clinical Characterization of Stages.

Ann Neurol 2021 06 6;89(6):1145-1156. Epub 2021 Apr 6.

Department of Radiology, Mayo Clinic, Rochester, MN.

Background: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid.

Methods: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.

Results: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).

Interpretation: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145-1156.
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http://dx.doi.org/10.1002/ana.26071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131266PMC
June 2021

Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology.

Acta Neuropathol Commun 2021 03 23;9(1):48. Epub 2021 Mar 23.

Department of Radiology, Mayo Clinic-Minnesota, 200 First Street SW, Rochester, MN, 55905, USA.

Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
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http://dx.doi.org/10.1186/s40478-021-01154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986461PMC
March 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

Neuropsychiatric symptoms and the outcome of cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging.

Int J Geriatr Psychiatry 2021 09 24;36(9):1362-1369. Epub 2021 Mar 24.

Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.

Objective: Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain-specific cognitive trajectories.

Methods: In this longitudinal study conducted in the setting of the population-based Mayo Clinic Study of Aging, 5081 community-dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI-Q), and Beck Depression and Anxiety Inventories (BDI-II, BAI). Global and domain-specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z-scores were calculated using linear mixed-effect models.

Results: Cognition declined regardless of NPS status over the median follow-up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z-scores for participants with NPS compared to without NPS ranged from -0.018 (95% CI -0.032, -0.004; p = 0.011) for irritability to -0.159 (-0.254, -0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI-Q-assessed NPS and clinical depression (BDI-II≥13). Participants with NPI-Q-assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain-specific z-scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills.

Conclusion: NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals.
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http://dx.doi.org/10.1002/gps.5528DOI Listing
September 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

Diagnostic accuracy of the Cogstate Brief Battery for prevalent MCI and prodromal AD (MCI A T ) in a population-based sample.

Alzheimers Dement 2021 04 1;17(4):584-594. Epub 2021 Mar 1.

Division of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: This study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population-based sample.

Methods: Participants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A-T-) or had prodromal AD (A+T+).

Results: Diagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A-T- and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut-offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%).

Discussion: Clinical utility of the CBB for detecting MCI in a population-based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.
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http://dx.doi.org/10.1002/alz.12219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371696PMC
April 2021

Longitudinal deterioration of white-matter integrity: heterogeneity in the ageing population.

Brain Commun 2021 22;3(1):fcaa238. Epub 2021 Jan 22.

Department of Radiology, Mayo Clinic, Rochester, MN 559 05, USA.

Deterioration in white-matter health plays a role in cognitive ageing. Our goal was to discern heterogeneity of white-matter tract vulnerability in ageing using longitudinal imaging data (two to five imaging and cognitive assessments per participant) from a population-based sample of 553 elderly participants (age ≥60 years). We found that different clusters (healthy white matter, fast white-matter decliners and intermediate white-matter group) were heterogeneous in the spatial distribution of white-matter integrity, systemic health and cognitive trajectories. White-matter health of specific tracts (genu of corpus callosum, posterior corona radiata and anterior internal capsule) informed about cluster assignments. Not surprisingly, brain amyloidosis was not significantly different between clusters. Clusters had differential white-matter tract vulnerability to ageing (commissural fibres > association/brainstem fibres). Identification of vulnerable white-matter tracts is a valuable approach to assessing risk for cognitive decline.
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http://dx.doi.org/10.1093/braincomms/fcaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884606PMC
January 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

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

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging.

J Alzheimers Dis 2021 ;79(1):377-388

Biodesign Institute, Arizona State University, Tempe, AZ, USA.

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults.

Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status.

Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores.

Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition.

Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.
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http://dx.doi.org/10.3233/JAD-200959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839815PMC
January 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

Association of Cortical and Subcortical β-Amyloid With Standardized Measures of Depressive and Anxiety Symptoms in Adults Without Dementia.

J Neuropsychiatry Clin Neurosci 2021 22;33(1):64-71. Epub 2020 Oct 22.

Departments of Health Sciences Research (Krell-Roesch, Syrjanen, Rakusa, Kremers, Mielke, Vassilaki), Radiology (Vemuri, Lowe, Jack), Psychiatry and Psychology (Machulda), and Neurology (Mielke, Knopman, Petersen), Mayo Clinic, Rochester, Minn.; Institute of Sports and Sports Science, Karlsruhe Institute of Technology, Karlsruhe, Germany (Krell-Roesch); Department of Neurology, University Medical Center, Maribor, Slovenia (Rakusa); International Clinical Research Center, St. Anne Hospital, Brno, Czech Republic (Stokin); and Department of Neurology, Barrow Neurological Institute, Phoenix (Geda).

Objective: The purpose of this study was to test the hypothesis that subcortical β-amyloid (Aβ) deposition was associated with elevated scores on standardized measures of depressive and anxiety symptoms when compared with cortical (Aβ) deposition in persons without dementia.

Methods: The authors performed a cross-sectional study, derived from the population-based Mayo Clinic Study of Aging, comprising participants aged ≥70 years (N=1,022; 55% males; 28% apolipoprotein E [APOE] ε4 carriers; without cognitive impairment, N=842; mild cognitive impairment; N=180). To assess Aβ deposition in cortical and subcortical (the amygdala, striatum, and thalamus) regions, participants underwent Pittsburgh Compound B positron emission tomography (PiB-PET) and completed the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). The investigators ran linear regression models to examine the association between PiB-PET standardized uptake value ratios (SUVRs) in the neocortex and subcortical regions and depressive and anxiety symptoms (BDI-II and BAI total scores). Models were adjusted for age, sex, education level, and APOE ε4 carrier status and stratified by cognitive status (without cognitive impairment, mild cognitive impairment).

Results: Cortical PiB-PET SUVRs were associated with depressive symptoms (β=0.57 [SE=0.13], p<0.001) and anxiety symptoms (β=0.34 [SE=0.13], p=0.011). PiB-PET SUVRs in the amygdala were associated only with depressive symptoms (β=0.80 [SE=0.26], p=0.002). PiB-PET SUVRs in the striatum and thalamus were associated with depressive symptoms (striatum: β=0.69 [SE=0.18], p<0.001; thalamus: β=0.61 [SE=0.24], p=0.011) and anxiety symptoms (striatum: β=0.56 [SE=0.18], p=0.002; thalamus: β=0.65 [SE=0.24], p=0.008). In the mild cognitive impairment subsample, Aβ deposition, regardless of neuroanatomic location, was associated with depressive symptoms but not anxiety symptoms.

Conclusions: Elevated amyloid deposition in cortical and subcortical brain regions was associated with higher depressive and anxiety symptoms, although these findings did not significantly differ by cortical versus subcortical Aβ deposition. This cross-sectional observation needs to be confirmed by a longitudinal study.
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http://dx.doi.org/10.1176/appi.neuropsych.20050103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856245PMC
October 2020

Association of Initial β-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment.

JAMA Neurol 2021 Feb;78(2):217-228

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Importance: Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum.

Objective: To investigate the association of β-amyloid (Aβ) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aβ and tau accumulation and inform clinical trial design.

Design, Setting, And Participants: This cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aβ) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020.

Exposures: Participants were stratified by index Aβ levels on PET into low Aβ (≤8 centiloid [CL]), subthreshold Aβ (9-21 CL), suprathreshold Aβ (22-67 CL), and high Aβ (≥68 CL).

Main Outcomes And Measures: Changes over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI).

Results: A total of 167 people were included (mean age, 74 [range, 65-85] years; 75 women [44.9%]); 101 individuals were excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64 women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aβ group were greater than the suprathreshold, subthreshold, and low Aβ groups in the entorhinal ROI (suprathreshold, 0.025 [95% CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95% CI, 0.014-0.037] SUVR units; low Aβ, 0.034 [95% CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold, 0.025 [95% CI, 0.014-0.035] SUVR units; subthreshold, 0.027 [95% CI, 0.017-0.037] SUVR units; low Aβ, 0.035 [95% CI, 0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold, 0.023 [95% CI, 0.013-0.032] SUVR units; subthreshold, 0.025 [95% CI, 0.016-0.034] SUVR units; low Aβ, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P < .001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aβ groups in temporal regions were nonsignificantly elevated compared with the low Aβ group. In the ADNI cohort, the variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were CU per group with PET Aβ of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with 80% power.

Conclusions And Relevance: Substantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aβ PET levels, compared with those with lower Aβ levels. Recruiting persons who were CU and exhibiting Aβ of 68 CL or more on an index Aβ PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure.
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http://dx.doi.org/10.1001/jamaneurol.2020.3921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573795PMC
February 2021

Association Between Neuropsychiatric Symptoms and Functional Change in Older Non-Demented Adults: Mayo Clinic Study of Aging.

J Alzheimers Dis 2020 ;78(3):911-917

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.

We examined the associations between baseline neuropsychiatric symptoms (NPS) and longitudinal changes in functional performance among 5,394 non-demented individuals aged ≥50 years (2,729 males; median age 74.2 years; 4,716 cognitively unimpaired, 678 mild cognitive impairment). After adjusting for age, sex, education, and medical comorbidities, NPS assessed by the Neuropsychiatric Inventory Questionnaire, clinical depression (Beck Depression Inventory score ≥13) and anxiety (Beck Anxiety Inventory score ≥10) were significantly associated with an increase in the Functional Activities Questionnaire score, indicating functional decline over time. This association may vary depending on the degree of cognitive impairment at baseline.
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http://dx.doi.org/10.3233/JAD-200764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794056PMC
January 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

Reduced fractional anisotropy of the genu of the corpus callosum as a cerebrovascular disease marker and predictor of longitudinal cognition in MCI.

Neurobiol Aging 2020 12 8;96:176-183. Epub 2020 Sep 8.

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

Our goal was to evaluate the utility of diffusion tensor imaging (DTI) for predicting future cognitive decline in mild cognitive impairment (MCI) in conjunction with Alzheimer's disease (AD) biomarkers (amyloid positron emission tomography and AD signature neurodegeneration) in 132 MCI individuals ≥60 year old with structural magnetic resonance imaging, DTI, amyloid positron emission tomography, and at least one clinical follow-up. We used mixed-effect models to evaluate the prognostic ability of fractional anisotropy of the genu of the corpus callosum (FA-Genu), as a cerebrovascular disease marker, for predicting cognitive decline along with AD biomarkers. We contrasted the value of white matter hyperintensities, a traditional cerebrovascular disease marker as well as FA in the hippocampal cingulum bundle with the FA-Genu models. FA-Genu significantly predicted cognitive decline even after accounting for AD biomarkers. WMH was not associated with cognitive decline in the model with both WMH and FA-Genu. DTI specifically FA-Genu provides unique complementary information to AD biomarkers and has significant utility for prediction of cognitive decline in MCI.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722208PMC
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
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