Machulda, Mary M.

Objective: Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome characterized by impaired motor speech planning and programming, whereas behavioral variant frontotemporal dementia (bvFTD) is characterized by deviant behavioral (e.g., personality and social) features. Clinical and anatomic characteristics of bvFTD in the context of PAOS are understudied. Methods: We identified 12 participants with PAOS and features that were consistent with bvFTD at baseline or follow-up. Eleven completed a head MRI scan. We compared clinical features and anatomical patterns of atrophy in these 11 PAOS-bvFTD participants to 11 matched PAOS participants without bvFTD and 22 age- and sex-matched healthy controls. Statistical Parametric Mapping (SPM) was applied to visualize gray matter volume across both groups compared to controls and each other. Medians and 25th and 75th percentiles were assessed in patients and across groups; Fisher’s Exact Test and Mann–Whitney U tests were applied using BlueSky software, version 10.3.1-Pro. Results: As expected, PAOS-bvFTD participants performed worse on the Frontal Behavioral Inventory (median: 33/72 vs. 10/72), 20-item behavioral assessment scale (4.5/20 vs. 1.0/20), and the Neuropsychiatry inventory (4/36 vs. 1.5/36) compared to the PAOS group (p < 0.01 for all), with no differences in other demographic, neurological, or language tests. Seven of the eleven PAOS-bvFTD participants had bvFTD features develop within three years of symptom onset. The PAOS-bvFTD and PAOS groups showed volume loss in frontal lobe regions compared to controls, with PAOS-bvFTD participants having more prefrontal volume loss than PAOS participants. Conclusions: Behavioral features consistent with bvFTD can co-occur in patients with PAOS and are related to greater atrophy of the prefrontal cortex.

ABSTRACTBackgroundPrimary progressive apraxia of speech is a neurodegenerative disorder characterized by early, isolated speech impairment due to impairment of motor speech planning and programming. Patients with PPAOS have varying disease durations from the estimated onset of the first symptom to death. Clinicopathological and neuroimaging features related to disease duration are unknown for PPAOS. We determine whether clinical, neuroimaging, or pathological features are associated with disease duration in primary progressive apraxia of speech (PPAOS).MethodsWe analyzed data from 41 PPAOS participants who were enrolled and longitudinally followed to death in NIH‐funded studies over 15 years. Demographic, clinical, and genetic features were abstracted. Brain volumes of cortical, subcortical, and brainstem regions were calculated. Regional tau lesion count (burden) was assessed histologically. Spearman rank correlations were performed between disease duration and variables of interest, followed by multiple regression analyses.ResultsDisease duration did not correlate with any baseline demographic, clinical, or pathologic features. Shorter disease duration correlated with a faster rate of behavioral change and of apraxia of speech severity over time, smaller baseline volumes of the superior frontal lobe and supplementary motor cortex, and higher tau burden in the locus ceruleus (ρ = −0.5, p = 0.03). Multiple regression analysis identified rate of behavioral change and volume loss in the superior frontal lobe as key clinical and neuroimaging variables, respectively.ConclusionIn patients with PPAOS, we found shorter disease duration to be related to behavioral dyscontrol and involvement of the frontal lobe, as well as a higher burden of 4‐repeat tau lesions in the locus ceruleus.

Abstract INTRODUCTION Research is limited regarding meaningful change thresholds for individual patients on clinical outcome assessments (COAs) frequently used in clinical trials for Alzheimer's disease and related dementias (ADRD), particularly in population‐based studies early in the disease course. METHODS There were 646 study participants in the population‐based Mayo Clinic Study of Aging (MCSA), 54–99 years old (47% females), who developed the clinical syndromes of mild cognitive impairment (MCI) with complete data to establish clinically meaningful within‐patient change thresholds in cognitive and functional COAs. RESULTS Using the diagnosis of incident MCI as the anchor, mean (95% confidence interval [CI]) annualized estimates of change were: Clinical Dementia Rating (CDR) scale Sum of Boxes (SB) 0.49 (0.43, 0.55), Mini‐Mental State Examination (MMSE) −1.01 (−1.12, −0.91), and Functional Activities Questionnaire (FAQ) score 1.04 (0.82, 1.26). DISCUSSION This study provides within‐patient estimates of clinically meaningful change early in disease progression in a community‐based sample. Highlights We studied incident mild cognitive impairment (MCI) participants from a population‐based study. Within‐patient change thresholds were estimated for clinical outcome assessments (COAs) used in clinical trials for Alzheimer's disease and related dementia (ADRD). These estimates may be used to plan and evaluate clinical trials involving disease‐modifying therapies (DMTs).

Abstract INTRODUCTION Plasma biomarkers’ utility for predicting incident mild cognitive impairment (MCI) remains unclear. We evaluated associations of plasma Alzheimer's disease (AD) biomarkers and amyloid positron emission tomography (PET) with transitions from cognitively unimpaired (CU) to MCI in the Mayo Clinic Study of Aging (MCSA) and BioFINDER‐2 studies. METHODS Associations of continuous baseline plasma biomarker levels and amyloid PET Centiloid with progression to MCI, adjusting for age, sex, and education, were evaluated with Cox proportional hazards models. RESULTS The study included 381 MCSA and 584 BioFINDER‐2 participants. Amyloid PET and percent phosphorylated to non‐phosphorylated tau217 (%p‐tau217) were strong predictors of progression to MCI in both cohorts: hazard ratios of 1.49 and 1.23 in the MCSA and 1.72 and 1.65 in BioFINDER, respectively. Amyloid beta 42/40 was a significant predictor in BioFINDER‐2 only (hazard ratio 2.20). DISCUSSION Plasma %p‐tau217 was associated with progression from CU to MCI in both cohorts, although differences in biomarker associations may be related to differences in the two cohorts. Highlights Mass‐spectrometry‐based plasma phosphorylated tau217 was associated with cognitively unimpaired to mild cognitive impairment (MCI) progression. Plasma amyloid beta 42/40 was a significant predictor in BioFINDER but not the Mayo Clinic Study of Aging (MCSA). Amyloid positron emission tomography (PET) was the strongest predictor of progression to MCI in the MCSA. Plasma had added value to amyloid PET in BioFINDER but not the MCSA. Biomarker performance may vary with cohort and biomarker measurement differences.

Abstract Objective: We investigated differences in cognition between variants of progressive supranuclear palsy (PSP) including PSP-Richardson (PSP-RS) and subcortical and cortical variants using updated diagnostic criteria and comprehensive neuropsychological assessment. Method: We recruited 140 participants with PSP (age = 71.3 ± 6.9 years; education = 15.0 ± 2.8 years; 49.3% female) who completed neurological and neuropsychological assessment. Participants received diagnoses of PSP clinical variants at their evaluation (or retrospectively if evaluated before 2017) according to the Movement Disorder Society PSP criteria. We grouped variants as PSP-RS (62 participants), PSP-Cortical (25 with PSP-speech/language and 9 with PSP-corticobasal syndrome), and PSP-Subcortical (27 with PSP-parkinsonism, 11 with PSP-progressive gait freezing, and 6 with PSP-postural instability). Analysis of covariance adjusted for age assessed for differences in neuropsychological performance between variants across cognitive domains. Results: PSP-Cortical participants performed worst on measures of visual attention/working memory (Spatial Span Forward/Backward/Total), executive function (Frontal Assessment Battery), and language (Letter Fluency). PSP-RS participants performed worst on verbal memory (Camden Words). There were no significant group differences for the MoCA or indices of visuospatial function. There were no sex or education differences between PSP groups; however, there were differences in age at visit and disease duration. Conclusions: In a large sample of participants with PSP, there were differences in cognition across PSP-RS, PSP-Subcortical, and PSP-Cortical variants, with PSP-Cortical and, to a lesser extent, PSP-RS, performing worse on tests of attention and executive function. These findings suggest cognitive distinctions among PSP clinical variants and highlight the value of neuropsychological assessment in differential diagnosis of PSP subtypes for more accurate and timely clinical classification.

Abstract INTRODUCTION When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid‐beta‐peptide (Aβ) related pathology are discordant, therapeutic decision‐making becomes uncertain. METHODS Using data from patients with mild cognitive impairment ( n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints. RESULTS Discordant groups for brain Aβ status (CSF+/PET− and CSF−/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF−/PET− group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures. DISCUSSION In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET− or CSF−/PET+ brain amyloid patterns did not exhibit incipient decline. Highlights Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF‐PET discrepant persons with MCI tend to have less abnormal values initially. CSF‐PET discrepant persons with MCI have a benign prognosis at 4 years.

ABSTRACT Background and Purpose Diffusion tensor imaging (DTI) is commonly used to assess the integrity of gray and white matter (WM) structures in progressive supranuclear palsy (PSP). Beyond DTI, nontraditional diffusion techniques such as diffusion kurtosis imaging (DKI) have been shown to characterize brain tissue further. In this work, we aim to determine the utility of DKI in the differential diagnosis of PSP—Richardson syndrome (PSP‐RS) and PSP with predominant parkinsonism (PSP‐P) from Parkinson's disease (PD) and controls. Methods A multishell diffusion‐weighted sequence was acquired at 3 Tesla on a Siemens system in 22 patients with PSP‐RS, 23 with PSP‐P, 19 with PD, and 19 controls. Fractional anisotropy, mean diffusivity, kurtosis fractional anisotropy (KFA), and mean kurtosis (Kmean) were calculated for nine deep gray matter regions and six different WM tracts. Results DKI identified differences (not found by DTI) between control and PSP groups in the globus pallidum externus, subthalamic region, and putamen, with Kmean in the putamen able to differentiate PSP‐RS and PD. DKI WM measurements in the body of the corpus callosum and dentatorubrothalamic tract differentiated PSP‐RS from PD, and the corticostriatal tract differentiated PSP‐P from PD. KFA in the body of the corpus callosum identified worse microstructural anomalies in PSP‐RS compared to PSP‐P. DKI metrics correlated with the severity of ocular motor impairment and parkinsonism scores. Conclusions DKI measurements could differentiate PSP‐RS, PSP‐P, and PD and, hence, may be a promising imaging tool for studying structural neuropathological changes in PSP.