Machulda, Mary M.

AbstractIntroductionLittle is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD).MethodsRegional tau and β‐amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model.ResultsAge was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β‐amyloid differed little by age. Age showed a stronger association with tau than volume and β‐amyloid in all cortical regions. Age was not associated with cognitive performance.DiscussionAge is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.

There has been no comparison of excessive daytime sleepiness (EDS) in patients with Alzheimer’s disease dementia (AD), dementia with Lewy bodies (DLB), and behavioral variant frontotemporal dementia (bvFTD). We identified patients with mild dementia who met criteria for these disorders who also had the Epworth Sleepiness Scale (ESS) completed. The sample included 17 bvFTD, 111 AD, and 31 DLB. An ESS score ≥10 was considered abnormal and consistent with EDS. Analyses with age and sex as covariates revealed higher mean ESS scores for DLB compared to the other groups (DLB 13.9 [5], bvFTD 9.6 [8], AD 8.8 [5], P < .05). An ESS score ≥10 was significantly more likely to occur in DLB compared to bvFTD or AD (DLB 81% vs bvFTD 47% vs AD 45%, P < .01). In patients with mild dementia, EDS is greatest in DLB and comparably lower in bvFTD and AD.

AbstractAs more biomarkers for Alzheimer’s disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-β levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

This study examined the rate of producing alternating motion rates, sequential motion rates (SMRs), and repeated words in 27 individuals with the semantic variant of Primary Progressive Aphasia (svPPA). Only the rate of producing SMRs was significantly elevated in svPPA compared to controls. This may be associated with concomitant neuropsychiatric symptoms in svPPA, as correlation analysis showed a relationship between increased SMR rate and the Neuropsychiatric Inventory Questionnaire, which documented anxiety and disinhibition. Future studies will assess these findings in a larger cohort and work to better understand if this phenomenon is a manifestation of behavioral and/or motor changes.

AbstractAlzheimer's disease (AD) can present with atypical clinical forms where the prominent domain of deficit is not memory, that is, atypical AD. Atypical AD patients show cortical atrophy on MRI, hypometabolism on [18F]fluorodeoxyglucose (FDG) PET, tau uptake on [18F]AV‐1451 PET, and white matter tract degeneration on diffusion tensor imaging (DTI). How these disease processes relate to each other locally and distantly remains unclear. We aimed to examine multimodal neuroimaging relationships in individuals with atypical AD, using univariate and multivariate techniques at region‐ and voxel‐level. Forty atypical AD patients underwent MRI, FDG‐PET, tau‐PET, beta‐amyloid PET, and DTI. Patients were all beta‐amyloid positive. Partial Pearson's correlations were performed between tau and FDG standardized uptake value ratios, gray matter MRI‐volumes and white matter tract fractional anisotropy. Sparse canonical correlation analysis was applied to identify multivariate relationships between the same quantities. Voxel‐level associations across modalities were also assessed. Tau showed strong local negative correlations with FDG metabolism in the occipital and frontal lobes. Tau in frontal and parietal regions was negatively associated with temporoparietal gray matter MRI‐volume. Fractional anisotropy in a set of posterior white matter tracts, including the splenium of the corpus callosum, cingulum, and posterior thalamic radiation, was negatively correlated with parietal and occipital tau, atrophy and, predominantly, with hypometabolism. These results support the view that tau is the driving force behind neurodegeneration in atypical AD, and that a breakdown in structural connectivity is related to cortical neurodegeneration, particularly hypometabolism.

Despite much attention to the use of biomarkers for predicting Alzheimer disease, little information is available at the individual level. We used the population‐based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75‐year‐old with abnormal amyloid and cortical thinning biomarkers has about a 20% chance of cognitive impairment by age 80 years, whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. ANN NEUROL 2019;85:155–160.

Purpose This case series details the clinical progression of patients with primary progressive apraxia of speech (PPAOS) to illustrate, using several methods and supplemental material examples, the changes that occur in speech and language functioning in this patient population. Method Four patients who presented with PPAOS were followed between 5 and 6 years. Two patients had predominant articulatory abnormalities (termed phonetic PPAOS ), 1 had predominant prosodic abnormalities (prosodic PPAOS), and 1 had relatively equal articulatory and prosodic abnormalities (mixed PPAOS). Detailed speech (including acoustics), language, neurologic, and neuropsychological data were collected. Results At initial exam, the patients ranged from 60 to 77 years old, with presenting disease duration of 1.5–10 years. Although all patients presented with an isolated apraxia of speech, all developed varying degrees of aphasia and dysarthria. Patients with phonetic PPAOS developed relatively more severe aphasia than the other 2 patients. All patients eventually had severe functional communication limitations and required alternative or augmentative means of communication, although at varying times postonset of their initial speech problem. Two patients developed dysphagia, 3 showed mild–moderate Parkinsonism, and 2 developed depression. For all patients, simple temporal acoustic measurements documented slowed speech rate over time. Conclusions This case series demonstrates that patients who initially present with PPAOS may develop aphasia and dysarthria, cognitive and behavioral changes, and other neurologic signs. Whether these changes can be predicted by the perceptual characteristics of the apraxia of speech is yet to be determined. The detailed longitudinal profiles provide valuable clinical insight into the progression of disease in people with PPAOS. Supplemental Material https://doi.org/10.23641/asha.7051616

Objectives To examine the cross‐sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI)). Design Cross‐sectional. Setting Olmsted County, Minnesota. Participants Population‐based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C‐Pittsburgh compound B ( 11 C‐PiB) positron emission tomography (PET) (N=1,782). Measurements We defined an abnormal (high) 11 C‐PiB‐PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A–) and neurodegeneration (N+/N–). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ). Results Participants with a CDR‐SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77–8.67, adjusting for age, sex, education, global cognitive z‐score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04–2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A–N + in CU participants. Conclusion The findings of this cross‐sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274–2281, 2018 .