Knopman, David S.

Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

Abstract Introduction We evaluated whether incident mild cognitive impairment (MCI) subtypes could be empirically derived in the Mayo Clinic Study of Aging. Methods We performed cluster analysis on neuropsychological data from 506 participants with incident MCI. Results The 3‐cluster solution resulted in (1) amnestic, (2) dysexecutive, (3) dysnomic subtypes. The 4‐cluster solution produced these same three groups and a fourth group with subtle cognitive impairment (SCI). The SCI cluster was a subset of the amnestic cluster and distinct from well‐matched cognitively unimpaired participants based on memory and global z‐score area under the receiver operating characteristic curve analyses and probability of progression to MCI/dementia. Discussion We empirically identified three neuropsychological subtypes of MCI that share some features with MCI subtypes identified in the Alzheimer's Disease Neuroimaging Initiative. The fourth subtype with SCI in the Mayo Clinic Study of Aging differed from the fourth cluster‐derived normal group in Alzheimer's Disease Neuroimaging Initiative and could represent a group to target with early interventions.

Objectives: Patients requiring admission to an ICU may subsequently experience cognitive decline. Our objective was to investigate longitudinal cognitive trajectories in older adults hospitalized in ICUs. We hypothesized that individuals hospitalized for critical illness develop greater cognitive decline compared with those who do not require ICU admission. Design: A retrospective cohort study using prospectively collected cognitive scores of participants enrolled in the Mayo Clinic Study of Aging and ICU admissions retrospectively ascertained from electronic medical records. A covariate-adjusted linear mixed effects model with random intercepts and slopes assessed the relationship between ICU admissions and the slope of global cognitive z scores and domains scores (memory, attention/executive, visuospatial, and language). Setting: ICU admissions and cognitive scores in the Mayo Clinic Study of Aging from October 1, 2004, to September 11, 2017. Patients: Nondemented participants age 50 through 91 at enrollment in the Mayo Clinic Study of Aging with an initial cognitive assessment and at least one follow-up visit. Interventions: None. Measurements and Main Results: Of 3,673 participants, 372 had at least one ICU admission with median (25–75th percentile) follow-up after first ICU admission of 2.5 years (1.2–4.4 yr). For global cognitive z score, admission to an ICU was associated with greater decline in scores over time compared with participants not requiring ICU admission (difference in annual slope = –0.028; 95% CI, –0.044 to –0.012; p < 0.001). ICU admission was associated with greater declines in memory (–0.029; 95% CI, –0.047 to –0.011; p = 0.002), attention/executive (–0.020; 95% CI, –0.037 to –0.004; p = 0.016), and visuospatial (–0.013; 95% CI, –0.026 to –0.001; p = 0.041) domains. ICU admissions with delirium were associated with greater declines in memory (interaction p = 0.006) and language (interaction p = 0.002) domains than ICU admissions without delirium. Conclusions: In older adults, ICU admission was associated with greater long-term cognitive decline compared with patients without ICU admission. These findings were more pronounced in those who develop delirium while in the ICU.

Abstract Agrammatic aphasia affects grammatical language production and can result from a neurodegenerative disease. Although it typically presents with concomitant apraxia of speech, this is not always the case. Little is known about the clinical course and imaging features of patients that present with agrammatism in the absence of apraxia of speech, which we will refer to as progressive agrammatic aphasia. We aimed to make a detailed description of the longitudinal clinical, linguistic, and neuroimaging features of a cohort of 11 patients with progressive agrammatic aphasia to provide a complete picture of this syndrome. All patients underwent detailed speech and language, neurological and neuropsychological assessments, 3 T structural and diffusion tensor imaging MRI, 18F-fluorodeoxyglucose and Pittsburgh compound B PET. The 11 patients were matched by age and gender to 22 patients who had mixed apraxia of speech and agrammatism. The progressive agrammatic aphasia patients performed abnormally on tests of language, general cognition, executive function, and functional ability at baseline and declined in these measures over time. Only two patients eventually developed apraxia of speech, while parkinsonism was absent-to-mild throughout all visits for all patients. When compared to the patients with mixed apraxia of speech and agrammatism, the patients with progressive agrammatic aphasia performed better on tests of motor speech and parkinsonism but more poorly, and declined faster over time, on tests of general aphasia severity, agrammatism, and naming. The patients with progressive agrammatic aphasia also showed different neuroimaging abnormalities, with greater atrophy, hypometabolism and white matter tract degeneration in the prefrontal and anterior temporal lobes compared to patients with mixed apraxia of speech and agrammatism. These differences were more pronounced as the disease progressed. These results demonstrate that progressive agrammatic aphasia has a different clinical disease course and different underlying neuroanatomical abnormalities than patients with the more common syndrome of mixed agrammatism and apraxia of speech. This supports the distinction of progressive agrammatic aphasia and has implications for the classification of patients with agrammatic aphasia.

AbstractIntroductionPrimary age‐related tauopathy (PART) is characterized by the presence of neurofibrillary tangles and absent‐minimal β‐amyloid deposition. Transactive response DNA‐binding protein of 43 kDa (TDP‐43), a third protein, has recently garnished a lot of attention in Alzheimer's disease where it is associated with memory loss and amygdala and hippocampal atrophy. We aimed to determine whether TDP‐43 is associated with brain atrophy in PART.MethodsWe assessed the frequency of TDP‐43 in PART and performed voxel‐level analysis in SPM12, as well as region‐of‐interest analysis using linear regression modeling, controlling for variables of interest, to assess for associations between TDP‐43 and brain atrophy.ResultsOf 116 PART cases, 31 (26.7%) had TDP‐43. The presence of TDP‐43 was associated with significantly greater amygdala, hippocampal, and anterior temporal atrophy in both the region‐of‐interest and the voxel level analyses.DiscussionTDP‐43 is associated with greater brain atrophy in PART.

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. Methods: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. Results: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm3] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm3 [5.5, 18.6], 11.8 cm3 [5.0, 18.6], and 7.3 cm3 [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). Conclusions: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume.

Background: Although associations between hypertension in mid-life and the development of dementia and cognitive decline have been established, the impact of the new 2017 ACC/AHA guidelines on dementia risk at the population level has not been evaluated. Objectives: To assess the association of hypertension categories with the risk of incident dementia and to calculate the population attributable fraction (PAF) for dementia from hypertension categories according to the 2017 ACC/AHA guidelines, and compare these associations with hypertension defined according to JNC7. Methods: We studied dementia-free participants recruited to the Atherosclerosis Risk in Communities (ARIC) cohort in 1987-89. Hypertension was defined by 2003 JNC7 and 2017 ACC/AHA guidelines using blood pressure measured at baseline; participants using antihypertensive medication were included in hypertension stage 2 for both sets of guidelines. Dementia was defined using adjudicated consensus diagnoses at visit 5 (2011-13), informant telephone interviews, and ICD-9 codes from hospitalizations and death certificates through 2013. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) by hypertension categories, adjusting for potential confounders, including sociodemographic, lifestyle and clinical variables. PAF of dementia by hypertension category was calculated using rate ratios from Poisson regression and the prevalence of the risk factor in the population. Results: Among 13,971 participants followed for a median of 23.0 years, 1381 cases of dementia were identified. Prevalence of elevated BP (systolic BP [SBP] 120-129 and diastolic BP [DBP] <80), hypertension stage 1 (SBP 130-139 or DBP 80-89) and hypertension stage 2 (SBP ≥140 or DPB ≥90) according to 2017 ACC/AHA categories was 13%, 15% and 44%, respectively. Corresponding HR (95%CI) compared to normal BP were 1.35 (95%CI 1.12, 1.61), 1.28 (1.07, 1.52) and 1.36 (1.18, 1.57), respectively. PAF (95%CI) of dementia from hypertension categories were 3% (1%, 5%), 3% (1%, 5%) and 9% (4%, 14%). PAF using JNC7 categories were similar to 2017 ACC/AHA: 6% (3%, 9%) for prehypertension (SBP 120-129 or DBP 80-89), 0% (-2%, 2%) for hypertension stage 1 (SBP 140-159 or DBP 90-99), and 9% (5%, 13%) for hypertension stage 2 (SBP ≥160 or DBP ≥100). Conclusions: Risk of dementia was increased across categories defined by the new ACC/AHA hypertension guidelines. However, the population impact on dementia incidence using 2017 ACC/AHA was similar to the impact of JNC7. These results suggest that the new criteria for diagnosis of hypertension will not increase the number of persons in whom hypertension could be reasonably labeled as a risk for dementia.