Mary M. Machulda

YNICL Journal 2025 Journal Article

Functional connectivity abnormalities in clinical variants of progressive supranuclear palsy

• Irene Sintini
• Farwa Ali
• Yehkyoung Stephens
• Heather M. Clark
• Julie A. Stierwalt
• Mary M. Machulda
• Ryota Satoh
• Keith A. Josephs

Progressive supranuclear palsy (PSP) can present with different clinical variants which show distinct, but partially overlapping, patterns of neurodegeneration and tau deposition in a network of regions including cerebellar dentate, superior cerebellar peduncle, midbrain, thalamus, basal ganglia, and frontal lobe. We sought to determine whether disruptions in functional connectivity within this PSP network measured using resting-state functional MRI (rs-fMRI) differed between PSP-Richardson's syndrome (PSP-RS) and the cortical and subcortical clinical variants of PSP. Structural MRI and rs-fMRI scans were collected for 36 PSP-RS, 25 PSP-cortical and 34 PSP-subcortical participants who met the Movement Disorder Society PSP clinical criteria. Ninety participants underwent flortaucipir-PET scans. MRIs were processed using CONN Toolbox. Functional connectivity between regions of the PSP network was compared between each PSP group and 83 healthy controls, and between the PSP groups, covarying for age. The effect of flortaucipir uptake and clinical scores on connectivity was assessed. Connectivity was reduced in PSP-RS compared to controls throughout the network, involving cerebellar dentate, midbrain, basal ganglia, thalamus, and frontal regions. Frontal regions showed reduced connectivity to other regions in the network in PSP-cortical, particularly the thalamus, caudate and substantia nigra. Disruptions in connectivity in PSP-subcortical were less pronounced, with the strongest disruption between the pallidum and striatum. There was moderate evidence that elevated subcortical flortaucipir uptake correlated with both increased and reduced connectivity between regions of the PSP network. Lower connectivity within the PSP network correlated with worse performance on clinical tests, including PSP rating scale. Patterns of disrupted functional connectivity revealed both variant-specific and shared disease pathways within the PSP network among PSP clinical variants, providing insight into disease heterogeneity.

YNIMG Journal 2024 Journal Article

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies

• Neha Atulkumar Singh
• Austin W. Goodrich
• Jonathan Graff-Radford
• Mary M. Machulda
• Irene Sintini
• Arenn F. Carlos
• Carling G. Robinson
• Robert I. Reid

F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

YNICL Journal 2024 Journal Article

Assessing network degeneration and phenotypic heterogeneity in genetic frontotemporal lobar degeneration by decoding FDG-PET

• Nick Corriveau-Lecavalier
• Leland R. Barnard
• Scott A. Przybelski
• Venkatsampath Gogineni
• Hugo Botha
• Jonathan Graff-Radford
• Vijay K. Ramanan
• Leah K. Forsberg

Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing.

YNICL Journal 2024 Journal Article

Complex relationships of socioeconomic status with vascular and Alzheimer’s pathways on cognition

• Dror Shir
• Jonathan Graff-Radford
• Angela J. Fought
• Timothy G. Lesnick
• Scott A. Przybelski
• Maria Vassilaki
• Val J. Lowe
• David S. Knopman

INTRODUCTION: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function. METHODS: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired). RESULTS: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition. DISCUSSION: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation.

YNICL Journal 2024 Journal Article

Speech-language within and between network disruptions in primary progressive aphasia variants

• Neha Singh-Reilly
• Hugo Botha
• Joseph R. Duffy
• Heather M. Clark
• Rene L. Utianski
• Mary M. Machulda
• Jonathan Graff-Radford
• Christopher G. Schwarz

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

YNICL Journal 2023 Journal Article

Spatial patterns of elevated magnetic susceptibility in progressive apraxia of speech

• Ryota Satoh
• Arvin Arani
• Matthew L. Senjem
• Joseph R. Duffy
• Heather M. Clark
• Rene L. Utianski
• Hugo Botha
• Mary M. Machulda

PURPOSE: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder affecting the planning or programming of speech. Little is known about its magnetic susceptibility profiles indicative of biological processes such as iron deposition and demyelination. This study aims to clarify (1) the pattern of susceptibility in PAOS patients, (2) the susceptibility differences between the phonetic (characterized by predominance of distorted sound substitutions and additions) and prosodic (characterized by predominance of slow speech rate and segmentation) subtypes of PAOS, and (3) the relationships between susceptibility and symptom severity. METHODS: Twenty patients with PAOS (nine phonetic and eleven prosodic subtypes) were prospectively recruited and underwent a 3 Tesla MRI scan. They also underwent detailed speech, language, and neurological evaluations. Quantitative susceptibility maps (QSM) were reconstructed from multi-echo gradient echo MRI images. Region of interest analysis was conducted to estimate susceptibility coefficients in several subcortical and frontal regions. We compared susceptibility values between PAOS and an age-matched control group and performed a correlation analysis between susceptibilities and an apraxia of speech rating scale (ASRS) phonetic and prosodic feature ratings. RESULTS: The magnetic susceptibility of PAOS was statistically greater than that of controls in subcortical regions (left putamen, left red nucleus, and right dentate nucleus) (p < 0.01, also survived FDR correction) and in the left white-matter precentral gyrus (p < 0.05, but not survived FDR correction). The prosodic patients showed greater susceptibilities than controls in these subcortical and precentral regions. The susceptibility in the left red nucleus and in the left precentral gyrus correlated with the prosodic sub-score of the ASRS. CONCLUSION: Magnetic susceptibility in PAOS patients was greater than controls mainly in the subcortical regions. While larger samples are needed before QSM is considered ready for clinical differential diagnosis, the present study contributes to our understanding of magnetic susceptibility changes and the pathophysiology of PAOS.

YNIMG Journal 2022 Journal Article

Deep learning identifies brain structures that predict cognition and explain heterogeneity in cognitive aging

• Krishnakant V. Saboo
• Chang Hu
• Yogatheesan Varatharajah
• Scott A. Przybelski
• Robert I. Reid
• Christopher G. Schwarz
• Jonathan Graff-Radford
• David S. Knopman

Specific brain structures (gray matter regions and white matter tracts) play a dominant role in determining cognitive decline and explain the heterogeneity in cognitive aging. Identification of these structures is crucial for screening of older adults at risk of cognitive decline. Using deep learning models augmented with a model-interpretation technique on data from 1432 Mayo Clinic Study of Aging participants, we identified a subset of brain structures that were most predictive of individualized cognitive trajectories and indicative of cognitively resilient vs. vulnerable individuals. Specifically, these structures explained why some participants were resilient to the deleterious effects of elevated brain amyloid and poor vascular health. Of these, medial temporal lobe and fornix, reflective of age and pathology-related degeneration, and corpus callosum, reflective of inter-hemispheric disconnection, accounted for 60% of the heterogeneity explained by the most predictive structures. Our results are valuable for identifying cognitively vulnerable individuals and for developing interventions for cognitive decline.

YNICL Journal 2022 Journal Article

Diffusion tractography of superior cerebellar peduncle and dentatorubrothalamic tracts in two autopsy confirmed progressive supranuclear palsy variants: Richardson syndrome and the speech-language variant

• Rodolfo G. Gatto
• Peter R. Martin
• Farwa Ali
• Heather M. Clark
• Joseph R. Duffy
• Rene L. Utianski
• Hugo Botha
• Mary M. Machulda

BACKGROUND: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP. OBJECTIVES: To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson's syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL). METHODS: We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer's disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups. RESULTS: The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson's Disease Rating Scale correlated with the DRTT (p = 0.014). CONCLUSIONS: Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL.

YNICL Journal 2022 Journal Article

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

• Neha Atulkumar Singh
• Arvin Arani
• Jonathan Graff-Radford
• Matthew L. Senjem
• Peter R. Martin
• Mary M. Machulda
• Christopher G. Schwarz
• Yunhong Shu

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

YNICL Journal 2022 Journal Article

Tractography of supplementary motor area projections in progressive speech apraxia and aphasia

• Adrian Valls Carbo
• Robert I. Reid
• Nirubol Tosakulwong
• Stephen D. Weigand
• Joseph R. Duffy
• Heather M. Clark
• Rene L. Utianski
• Hugo Botha

Progressive apraxia of speech (AOS) is a motor speech disorder affecting the ability to produce phonetically or prosodically normal speech. Progressive AOS can present in isolation or co-occur with agrammatic aphasia and is associated with degeneration of the supplementary motor area. We aimed to assess breakdowns in structural connectivity from the supplementary motor area in patients with any combination of progressive AOS and/or agrammatic aphasia to determine which supplementary motor area tracts are specifically related to these clinical symptoms. Eighty-four patients with progressive AOS or progressive agrammatic aphasia were recruited by the Neurodegenerative Research Group and underwent neurological, speech/language, and neuropsychological testing, as well as 3 T diffusion magnetic resonance imaging. Of the 84 patients, 36 had apraxia of speech in isolation (primary progressive apraxia of speech, PPAOS), 40 had apraxia of speech and agrammatic aphasia (AOS-PAA), and eight had agrammatic aphasia in isolation (progressive agrammatic aphasia, PAA). Tractography was performed to identify 5 distinct tracts connecting to the supplementary motor area. Fractional anisotropy and mean diffusivity were assessed at 10 positions along the length of the tracts to construct tract profiles, and median profiles were calculated for each tract. In a case-control comparison, decreased fractional anisotropy and increased mean diffusivity were observed along the supplementary motor area commissural fibers in all three groups compared to controls. PPAOS also had abnormal diffusion in tracts from the supplementary motor area to the putamen, prefrontal cortex, Broca's area (frontal aslant tract) and motor cortex, with greatest abnormalities observed closest to the supplementary motor area. The AOS-PAA group showed abnormalities in the same set of tracts, but with greater involvement of the supplementary motor area to prefrontal tract compared to PPAOS. PAA showed abnormalities in the left prefrontal and frontal aslant tracts compared to both other groups, with PAA showing greatest abnormalities furthest from the supplementary motor area. Severity of AOS correlated with tract metrics in the supplementary motor area commissural and motor cortex tracts. Severity of aphasia correlated with the frontal aslant and prefrontal tracts. These findings provide insight into how AOS and agrammatism are differentially related to disrupted diffusivity, with progressive AOS associated with abnormalities close to the supplementary motor area, and the frontal aslant and prefrontal tracts being particularly associated with agrammatic aphasia.

YNICL Journal 2019 Journal Article

Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease

• Irene Sintini
• Peter R. Martin
• Jonathan Graff-Radford
• Matthew L. Senjem
• Christopher G. Schwarz
• Mary M. Machulda
• Anthony J. Spychalla
• Daniel A. Drubach

F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration.

YNICL Journal 2018 Journal Article

Disrupted functional connectivity in primary progressive apraxia of speech

• Hugo Botha
• Rene L. Utianski
• Jennifer L. Whitwell
• Joseph R. Duffy
• Heather M. Clark
• Edythe A. Strand
• Mary M. Machulda
• Nirubol Tosakulwong

Apraxia of speech is a motor speech disorder thought to result from impaired planning or programming of articulatory movements. It can be the initial or only manifestation of a degenerative disease, termed primary progressive apraxia of speech (PPAOS). The aim of this study was to use task-free functional magnetic resonance imaging (fMRI) to assess large-scale brain network pathophysiology in PPAOS. Twenty-two PPAOS participants were identified from a prospective cohort of degenerative speech and language disorders patients. All participants had a comprehensive, standardized evaluation including an evaluation by a speech-language pathologist, examination by a behavioral neurologist and a multimodal imaging protocol which included a task-free fMRI sequence. PPAOS participants were age and sex matched to amyloid-negative, cognitively normal participants with a 1:2 ratio. We chose a set of hypothesis driven, predefined intrinsic connectivity networks (ICNs) from a large, out of sample independent component analysis and then used them to initialize a spatiotemporal dual regression to estimate participant level connectivity within these ICNs. Specifically, we evaluated connectivity within the speech and language, face and hand sensorimotor, left working memory, salience, superior parietal, supramarginal, insular and deep gray ICNs in a multivariate manner. The spatial maps for each ICN were then compared between PPAOS and control participants. We used clinical measures of apraxia of speech severity to assess for clinical-connectivity correlations for regions found to differ between PPAOS and control participants. Compared to controls, PPAOS participants had reduced connectivity of the right supplementary motor area and left posterior temporal gyrus to the rest of the speech and language ICN. The connectivity of the right supplementary motor area correlated negatively with an articulatory error score. PPAOS participants also had reduced connectivity of the left supplementary motor area to the face sensorimotor ICN, between the left lateral prefrontal cortex and the salience ICN and between the left temporal-occipital junction and the left working memory ICN. The latter connectivity correlated with the apraxia of speech severity rating scale, although the finding did not survive correction for multiple comparisons. Increased connectivity was noted in PPAOS participants between the dorsal posterior cingulate and the left working memory ICN. Our results support the importance of the supplementary motor area in the pathophysiology of PPAOS, which appears to be disconnected from speech and language regions. Supplementary motor area connectivity may serve as a biomarker of degenerative apraxia of speech severity.

YNICL Journal 2016 Journal Article

Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech

• Jennifer L. Whitwell
• Stephen D. Weigand
• Joseph R. Duffy
• Edythe A. Strand
• Mary M. Machulda
• Matthew L. Senjem
• Jeffrey L. Gunter
• Val J. Lowe

Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.

YNIMG Journal 2001 Journal Article

fMRI in the diagnosis of early Alzheimer's disease

• Mary M. Machulda
• Heidi A. Ward
• Bret Borowski
• Yue-Cheng Xu
• Clifford R. Jack

YNIMG Journal 2001 Journal Article

Functional Inferences Vary with the Method of Analysis in fMRI

• Mary M. Machulda
• Heidi A. Ward
• Ruth Cha
• Peter O'Brien
• Clifford R. Jack

Neuroanatomic substrates of specific cognitive functions have been inferred from anatomic distributions of activated pixels during fMRI studies. With declarative memory tasks, interest has focused on the extent to which various medial temporal lobe anatomic structures are activated while subjects encode new information. The aim of this project was to examine how commonly used variations in fMRI data processing methods affect the distribution of activation in anatomically defined medial temporal lobe regions of interest (ROIs) during a complex scene-encoding task. ROIs were drawn on an MRI anatomic template formed from 3D SPGR scans of eight subjects combined in Talairach space. Separate ROIs were drawn for the posterior and anterior hippocampal formation, parahippocampal gyrus, and entorhinal cortex. Twelve different activation maps were created for each subject by using four correlation coefficients and three cluster volumes. Friedman's two-way ANOVA by ranks was used to test the hypothesis that the distribution of activated pixels among defined anatomic ROIs varied as a function of the data processing method. By simply varying the combination of correlation coefficient and cluster volume, significantly different distributions of activation within named medial temporal lobe structures were obtained from the same fMRI datasets (P < 0. 015; P < 0. 001). The number of subjects studied (n = 8) is in a range commonly found in the literature yet this clearly resulted in spurious associations between processing parameter variations and activation distribution. Using data processing methods that are independent of the arbitrary selection of cutoff values for thresholding activation maps may reduce the likelihood of obtaining spurious results.

YNIMG Journal 2000 Journal Article

Functional inferences vary with the method of analysis in fMRI

• Mary M. Machulda
• Heidi A. Ward
• Clifford R. Jack