Publications by authors named "Matthew L Senjem"

200 Publications

Posterior cortical atrophy phenotypic heterogeneity revealed by decoding F-FDG-PET.

Brain Commun 2021 19;3(4):fcab182. Epub 2021 Aug 19.

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

Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer's disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45-72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values ('eigenbrains' or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.
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http://dx.doi.org/10.1093/braincomms/fcab182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600283PMC
August 2021

Longitudinally Increasing Elevated Asymmetric Flortaucipir Binding in a Cognitively Unimpaired Amyloid-Negative Older Individual.

J Alzheimers Dis 2021 Nov 7. Epub 2021 Nov 7.

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

We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.
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http://dx.doi.org/10.3233/JAD-215052DOI Listing
November 2021

Neuroimaging correlates of gait abnormalities in progressive supranuclear palsy.

Neuroimage Clin 2021 Oct 12;32:102850. Epub 2021 Oct 12.

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

Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.
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http://dx.doi.org/10.1016/j.nicl.2021.102850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527041PMC
October 2021

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

Neurobiol Aging 2021 Dec 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616794PMC
December 2021

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

Mov Disord 2021 Nov 23;36(11):2669-2675. Epub 2021 Aug 23.

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

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

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

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

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

Conclusions: Differential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595517PMC
November 2021

Relationships between β-amyloid and tau in an elderly population: An accelerated failure time model.

Neuroimage 2021 11 29;242:118440. Epub 2021 Jul 29.

Department of Radiology, Mayo Clinic 200 1st St. SW, Rochester, MN 55905.

Using positron emission tomography (PET)-derived amyloid and tau measurements from 1,495 participants, we explore the evolution of these values over time via an accelerated failure time (AFT) model. The AFT model assumes a shared pattern of progression, but one which is shifted earlier or later in time for each individual; an individual's time shift for amyloid and for tau are assumed to be linked. The resulting pattern for each outcome consists of an earlier indolent phase followed by sharp progression of the accumulation rate. APOE ε4 shifts the amyloid curve leftward (earlier) by 6.1 years, and the tau curve leftward by 2.6 years. Female sex shifts the amyloid curve leftward by 2.4 years and the tau curve leftward by 2.6 years. Per-person shifts (i.e., the individual's deviation from the population mean) for the onset of amyloid accumulation ranged from 13 years earlier to 13 years later (10th to 90th percentile) than average and 11 years earlier to 14 years later for tau, with an estimated correlation of 0.49. The average delay between amyloid increase and tau increase was 13.3 years.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499700PMC
November 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

FDG PET metabolic signatures distinguishing prodromal DLB and prodromal AD.

Neuroimage Clin 2021 4;31:102754. Epub 2021 Jul 4.

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

Background And Purpose: Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto-occipital cortex and the cingulate island sign (CIS) on F-fluorodeoxyglucose (FDG) PET. Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer's disease (AD) dementia and clinically unimpaired (CU) controls.

Methods: Patients with MCI from the Mayo Clinic Alzheimer's Disease Research Center who underwent FDG PET at baseline and progressed to either probable DLB (MCI-DLB; n = 17) or AD dementia (MCI-AD; n = 41) during follow-up, and a comparison cohort of CU controls (n = 100) were included.

Results: Patients with MCI-DLB had hypometabolism in the parieto-occipital cortex extending into temporal lobes, substantia nigra and thalamus. When compared to MCI-AD, medial temporal and posterior cingulate metabolism were preserved in patients with MCI-DLB, accompanied by greater hypometabolism in the substantia nigra in MCI-DLB compared to MCI-AD. In distinguishing MCI-DLB from MCI-AD at the maximum value of Youden's index, CIS ratio was highly specific (90%) but not sensitive (59%), but a higher medial temporal to substantia nigra ratio was both sensitive (94%) and specific (83%).

Conclusion: FDG PET is a potential biomarker for the prodromal stage of DLB. A higher medial temporal metabolism and CIS ratio, and lower substantia nigra metabolism have additive value in distinguishing prodromal DLB and AD.
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http://dx.doi.org/10.1016/j.nicl.2021.102754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278422PMC
September 2021

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

Neurobiol Aging 2021 09 14;105:252-261. Epub 2021 May 14.

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

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338792PMC
September 2021

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

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

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

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

Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease (AD) pathology in the form of β-amyloid plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of AD co-pathology on functional network changes within the default mode network (DMN) in DLB. Secondly, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 AD, and 99 cognitively unimpaired (CU) participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), β-amyloid-PET with Pittsburgh compound-B (PiB), and resting state (rs)-fMRI scans. The rs-fMRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir-PET and PiB-PET standardized uptake value ratio (SUVr). The strength of inter-regional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot- and coldspots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r=-0.39, p = 0.04) and amyloid-PET uptake (r=-0.41, p = 0.03) in the DLB group, i.e. DLB patients with more concurrent AD pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of AD co-pathology in DLB patients is associated with more AD-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology which has recently been described in AD. We show that this relationship also exists in DLB patients, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.
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http://dx.doi.org/10.1093/brain/awab218DOI 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 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

MRI quantitative susceptibility mapping of the substantia nigra as an early biomarker for Lewy body disease.

J Neuroimaging 2021 09 25;31(5):1020-1027. Epub 2021 May 25.

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

Background And Purpose: Neurodegeneration of the substantia nigra in Lewy body disease is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. Our objective was to measure iron deposition in the substantia nigra in patients with probable dementia with Lewy bodies (pDLB) and patients who are at risk for pDLB by quantitative susceptibility mapping (QSM).

Methods: Participants included pDLB (n = 36), mild cognitive impairment with at least one core feature of DLB (MCI-LB; n = 15), idiopathic rapid eye movement sleep behavior disorder (iRBD; n = 11), and an age-and gender-matched clinically unimpaired control group (n = 102). QSM was derived from multi-echo 3D gradient recalled echo MRI at 3T, and groups were compared on mean susceptibility values of the substantia nigra and its relation to parkinsonism severity.

Results: Patients with pDLB had higher susceptibility in the substantia nigra compared to controls (p< 0.001) and MCI-LB (p = 0.043). The susceptibility of substantia nigra showed an increasing trend from controls to iRBD and MCI-LB, and to pDLB (p< 0.001). Parkinsonism severity was not associated with the mean susceptibility in the substantia nigra in the patient groups.

Conclusions: Our data suggested that QSM is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in pDLB. The trend of increasing susceptibility from controls to iRBD and MCI-LB, and to pDLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity.
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http://dx.doi.org/10.1111/jon.12878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440493PMC
September 2021

CSF dynamics as a predictor of cognitive progression.

Neuroimage 2021 05 23;232:117899. Epub 2021 Feb 23.

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

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237937PMC
May 2021

Sleep quality and cortical amyloid-β deposition in postmenopausal women of the Kronos early estrogen prevention study.

Neuroreport 2021 03;32(4):326-331

Department of Radiology.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17β-estradiol may reduce the accumulation of cortical amyloid-β. However, how menopausal hormone therapies modify the associations of amyloid-β accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-β deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17β-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-β deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-β accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-β accumulation.
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http://dx.doi.org/10.1097/WNR.0000000000001592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878341PMC
March 2021

β-Amyloid PET and I-FP-CIT SPECT in Mild Cognitive Impairment at Risk for Lewy Body Dementia.

Neurology 2021 Jan 6. Epub 2021 Jan 6.

Department of Radiology, Mayo Clinic, Rochester, Minnesota

Objective: To determine the clinical phenotypes associated with the amyloid-β PET and dopamine transporter imaging (I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB).

Methods: Patients with MCI who had at least one core clinical feature of DLB (n=34) were grouped into β-amyloid A+ or A- and I-FP-CIT SPECT D+ or D- groups based on previously established abnormality cut points for A+ with Pittsburgh compound-B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z-score with DATQUANT < -0.82 on I-FP-CIT SPECT. Individual MCI-LB patients fell into one of four groups: A+D+, A+D-, A-D+, or A-D-. Log transformed PiB SUVR and putamen z-score were tested for associations with patient characteristics.

Results: The A-D+ biomarker profile was most common (38.2%) followed by A+D+ (26.5%) and A-D- (26.5%). Least common was A+D- biomarker profile (8.8 %). The A+ group was older, had a higher frequency of ε4 carriers, and a lower MMSE score than the A- group. The D+ group was more likely to have probable rapid eye movement sleep behavior disorder. Lower putamen DATQUANT z-scores and lower PiB SUVRs were independently associated with higher Unified Parkinson Disease Rating Scale (UPDRS)-III scores.

Conclusions: A majority of MCI-LB patients are characterized by low amyloid-β deposition and reduced dopaminergic activity. Amyloid-β PET and I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.
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http://dx.doi.org/10.1212/WNL.0000000000011454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055344PMC
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

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

Predicting future rates of tau accumulation on PET.

Brain 2020 10;143(10):3136-3150

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

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.
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http://dx.doi.org/10.1093/brain/awaa248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586089PMC
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

Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers.

Neuroimage 2021 01 6;224:117433. Epub 2020 Oct 6.

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

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860631PMC
January 2021

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

β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies.

Neurology 2020 12 28;95(24):e3257-e3268. Epub 2020 Sep 28.

From the Division of Clinical Geriatrics (D.F., S.G.-P., E.W.), Center for Alzheimer's Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Departments of Radiology (D.F., Z.N., C.G.S., M.L.S., V.J.L., C.R.J., K.K.), Health Sciences (S.A.P., T.G.L.), Neurology (J.G.-R., D.S.K., R.S., R.C.P., B.F.B.), Information Technology (M.L.S.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center (A.W.L.), VU University Medical Center, Amsterdam, the Netherlands; Clinical Memory Research Unit (E.L.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Day Hospital of Geriatrics (F.B.), Memory Resource and Research Centre (CM2R) of Strasbourg; Department of Geriatrics (F.B.), Hopitaux Universitaires de Strasbourg; University of Strasbourg and French National Centre for Scientific Research (CNRS) (F.B.), ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, Strasbourg, France; Department of Neurology (Z.N., J.H.), Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic; Departments of Psychiatry and Psychology (T.J.F.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Paracelsus-Elena-Klinik (B.M.), Kassel; and University Medical Center (B.M.), Department of Neurosurgery and Institute of Neuropathology, Göttingen, Germany; Fundació ACE (C.A.), Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona, Spain; International Clinical Research Center (J.H.), St. Anne's University Hospital Brno, Czech Republic; Department of Neuroscience Imaging and Clinical Sciences and CESI (L.B.), University G d'Annunzio of Chieti-Pescara, Chieti, Italy; Centre for Age-Related Medicine (K.O., D.A.), Stavanger University Hospital; Stavanger Medical Imaging Laboratory (SMIL) (K.O.), Department of Radiology, Stavanger University Hospital; Department of Electrical Engineering and Computer Science (K.O.), University of Stavanger, Norway; Department of Neurology (M.G.K.), University Medical Centre Ljubljana, Medical Faculty, University of Ljubljana, Slovenia; Institute of Psychiatry, Psychology and Neuroscience (D.A.) and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Objective: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.

Methods: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+.

Results: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.

Conclusions: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Classification Of Evidence: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
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http://dx.doi.org/10.1212/WNL.0000000000010943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836666PMC
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

Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes.

Brain Commun 2020 27;2(1):fcaa068. Epub 2020 May 27.

Department of Neurology Mayo Clinic, Rochester, MN 55902, USA.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer's pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer's disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with F-fluorodeoxyglucose-positron emission tomography and Alzheimer's disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as 'memory problems' but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one ε allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer's disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic ( = 110), visual ( = 18) and language ( = 7) predominate clinical phenotypes of Alzheimer's disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer's disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.
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http://dx.doi.org/10.1093/braincomms/fcaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325839PMC
May 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

F-fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies.

Brain Commun 2020 8;2(1):fcaa040. Epub 2020 Apr 8.

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

Among individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer's pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer's pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease ( = 34) and a clinically diagnosed group of dementia with Lewy bodies ( = 87). A subset of the clinically diagnosed group was followed longitudinally ( = 51). We evaluated whether F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.
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http://dx.doi.org/10.1093/braincomms/fcaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293797PMC
April 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
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