Mielke, Michelle M.

AbstractIntroductionThis study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use.MethodsWomen enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e‐mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in‐person neuropsychological tests (n = 96, ages 55–79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer's disease (n = 47).ResultsSLS performance significantly correlated with the Auditory Verbal Learning Test and measures of neurodegeneration (temporal meta‐regions of interest and entorhinal cortical thickness, adjusting for age and education). Test–retest reliabilities across two sessions were 0.71–0.76 (two‐way mixed intraclass correlation coefficients).DiscussionThe SLS is a valid and reliable self‐administered memory test that shows promise for remote assessment of aging and neurodegenerative disorders.

Abstract Introduction : Plasma glial fibrillary acidic protein (GFAP) may be associated with amyloid burden, neurodegeneration, and stroke but its specificity for Alzheimer's disease (AD) in the general population is unclear. We examined associations of plasma GFAP with amyloid and tau positron emission tomography (PET), cortical thickness, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Methods : The study included 200 individuals from the Mayo Clinic Study of Aging who underwent amyloid and tau PET and magnetic resonance imaging and had plasma GFAP concurrently assayed; multiple linear regression and hurdle model analyses were used to investigate associations controlling for age and sex. Results : GFAP was associated with amyloid and tau PET in multivariable models. After adjusting for amyloid, the association with tau PET was no longer significant. GFAP was associated with cortical thickness, WMH, and lobar CMBs only among those who were amyloid‐positive. Discussion : This cross‐sectional analysis demonstrates the utility of GFAP as a plasma biomarker for AD‐related pathologies.

BACKGROUND: Parkinson’s disease (PD)-associated psychosis is a well-known non-motor complication, occurring years after diagnosis of PD. Incidence data vary across different studies highlighting a need for long-term observation and clinical definition. OBJECTIVE: To determine the incidence of psychosis in patients with PD and to investigate their survival in an incident cohort study from 1991–2010 in Olmsted County, MN. METHODS: We used the Rochester Epidemiology Project to define an incident-cohort study of parkinsonism (1991–2010) in Olmsted County, MN. A movement-disorder specialist reviewed the electronic medical records and applied diagnosis criteria to PD. Psychosis was diagnosed using of NINDS/NIMH unified criteria. RESULTS: We identified 669 cases of parkinsonism; 297 patients were clinically diagnosed with PD. 114/297 (38.4%) patients had evidence of psychosis (60% male); the median onset age of psychosis was 79.4 years. The incidence of Parkinson’s disease psychosis (PDP) was 4.28/100 person-years. PDP patients had a 71% increased risk of death compared to PD patients. In PD patients without psychosis, men had 73.4% increased risk of death compared to women, whereas no significant sex difference was observed among PDP men vs. women. Of 114 patients diagnosed with psychosis, 59 were treated with antipsychotics. There was no significant difference in survival between treated and untreated patients. CONCLUSION: PDP increased the odds of death compared to PD patients. Men with PD without psychosis had greater odds of death compared to women; however, in PD with psychosis the odds of death were comparable among sexes. Lastly, treatment with anti-psychotics did not significantly affect survival.

Abstract Introduction In this longitudinal study, we aimed to examine if slowing gait speed preceded cognitive decline and correlated with brain amyloidosis. Methods The sample (n = 287) was derived from the Gothenburg H70 Birth Cohort Studies, with follow‐ups between 2000 and 2015. Gait speed was measured by indoor walk, and cognition using the Clinical Dementia Rating (CDR) score. All participants had CDR = 0 at baseline. Some participants had data on cerebrospinal fluid (CSF) amyloid beta (Aβ) 1‐42 concentrations at the 2009 examination. Results Gait speed for participants who worsened in CDR score during follow‐up was slower at most examinations. Baseline gait speed could significantly predict CDR change from baseline to follow‐up. Subjects with pathological CSF Aβ 1‐ 42 concentrations at the 2009 visit had lost more gait speed compared to previous examinations. Discussion Our results indicate that gait speed decline precedes cognitive decline, is linked to Alzheimer's pathology, and might be used for early detection of increased risk for dementia development.

AbstractBackgroundSummarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both pathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and post‐mortem CVD evaluation. We used (1) Strozyk scale (Strozyk et. al. NBA 2010) which is based on presence and number of three macroscopic lesions (large infarctions, lacunar infarctions, and leukoencephalopathy) and (2) Kalaria scale (Deramecourt et. al. Neurology 2012) which summarizes detailed evaluation of vessel wall modifications (arteriolosclerosis, amyloid angiopathy), perivascular spaces, myelin loss, microinfarctions, and large infarctions.MethodWe identified n=51 individuals in Mayo Clinic Study of Aging (mean age of 83.8 years, 37% female) with MRI scans within 5 years of death. We computed CVD measures from DTI (fractional anisotropy of the genu of the corpus callosum [FAGCC] and fractional anisotropy of cingulum adjoining the hippocampus [FACGH]), FLAIR (white matter hyperintensities [WMH] and total number of infarctions), and T2* GRE (total number of microbleeds). We also computed our recently developed imaging CVD composite score which summarizes the variability in all individual CVD imaging measures described above. We computed the Strozyk and Kalaria scales on postmortem tissue. We used weighted linear regression models with adjustments for MRI scan time to death to evaluate the associations between the antemortem neuroimaging measures and pathology scales in those who had scans within 3 years of death (N=31) and 5 years of death (N=51) (tables 1 and 2).ResultOf all the neuroimaging measures, DTI measures were the best predictors of the Strozyk and Kalaria Scales (p<0.05). In sensitivity analyses of data in Table 1, FAGCC explained 44% and FACGH predicted only 5.5% variability in white matter sub‐component of the Strozyk scale. The CVD composite score was a poor surrogate of the composite pathological scales.ConclusionMicrostructural white matter injury measurement using DTI may be a good surrogate of pathological CVD scales and possibly captures diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions.

AbstractBackgroundProton MR Spectroscopy (1H MRS) provides non‐invasive measurements of alterations in brain biochemistry associated with neuronal and glial abnormalities in neurodegeneration. 1H MRS with along with automated voxel placement (AVP) improves the precision of 1H MRS metabolite measurements. Our objective was to investigate the association of 1H MRS metabolites obtained by the advanced sLASER single voxel 1H MRS protocol with early tau deposition as measured by AV‐1451 PET and Aβ deposition as measured by 11C‐Pittsburgh compound B (PiB) PET in cognitively unimpaired older adults.MethodCognitively unimpaired adults with median (range) age of 77 (66, 94) from the population‐based Mayo Clinic Study of Aging (MCSA) participated in the single‐voxel 1H MRS study (n=40). All participants had an MRI, 11C‐PiB and AV‐1451 PET examinations. The posterior cingulate cortex (PCC) and the left hippocampus (LHC) were chosen for the 1H MRS voxel locations because of their vulnerability to early AD pathology. Right hippocampus was not studied due to time constraints of the MR examination. 1H MRS was performed at 3T (Siemens) using an optimized sLASER protocol with AVP. Standardized uptake value ratios (SUVR) were calculated for global cortical and regional (PCC, LHC) PiB and AV‐1451. Associations between log transformed SUVRs and the concentration of MRS‐measured metabolites (µmol/g) were assessed using age‐adjusted Pearson correlations.ResultThe median (range) global PiB SUVR was 1.42 (1.20‐2.81) and AV‐1451 SUVR was 1.20 (0.94, 1.46). In the PCC, higher AV‐1451 SUVR was associated with lower N‐acetylaspartate (NAA) (r=‐0.375; p=0.019) and glutamate (r=‐0.354; p=0.027) concentrations. Higher global PIB SUVR was associated with higher myo‐inositol in the LHC (r=0.361; p=0.039).ConclusionLower levels of NAA, a marker of neuronal health, and the neurotransmitter glutamate are associated with local tau pathology in the PCC, suggesting early neuronal dysfunction in relation to tau accumulation. The association of hippocampal myo‐inositol, a putative glial marker, with the global cortical Aβ pathology suggests that myo‐inositol elevation may be an indicator of neuroinflammatory response to Aβ related pathology.

AbstractBackgroundWhite matter microstructure undergoes progressive changes during the life‐span but the neurobiological underpinnings related to aging and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging (NODDI), to investigate the microstructural alterations due to demographics, common age‐related pathological processes (amyloid, tau, and white matter hyperintensities (WMH)), and cognition. We also compared NODDI findings to the older Diffusion Tensor Imaging (DTI) model based findings.Method328 participants (264 cognitively unimpaired, 57 mild cognitive impairment (MCI), and 7 dementia with a mean age of 68.3 ±13.1 years) from the Mayo Clinic Study of Aging with multi‐shell diffusion imaging, FLAIR‐MRI as well as amyloid and tau PET scans were included in this study. White matter (WM) tract level diffusion measures (Figure 1) were calculated from DTI and NODDI. Pearson correlation and multiple linear regression analyses were performed with diffusion measures as the outcome and age, sex, education/occupation, WMH, amyloid, and tau as predictors. Analyses were also performed with each dMRI measure as a predictor of cognitive outcomes.ResultAge and WMH were the strongest predictors of all WM diffusion measures with low associations with amyloid and tau (Figure 1). However, neurite density decrease from NODDI was observed with amyloidosis specifically in the temporal lobes (Figure 2). WM integrity (mean diffusivity and free water) in the corpus callosum showed the greatest associations with cognitive measures (Table 1). All diffusion measures provided information about WM aging and WM disease processes and were associated with cognition.ConclusionNODDI and DTI are two different biophysical models that provide distinct information about variation in WM microstructural integrity. NODDI provides additional information about synaptic density, organization, and free water content which may aid in providing mechanistic insights into disease progression.

AbstractBackgroundAlzheimer’s disease biomarkers of tau pathology may be assessed by both CSF and PET. Cross‐sectional associations between CSF phosphorylated tau (p‐tau) and tau PET have been studied and regional tau PET SUVR has been shown to have similar diagnostic performance as CSF p‐tau. The association between CSF p‐tau and longitudinal tau PET has not been studied. CSF measures may be thought of as a result of the imbalance of influx vs efflux of soluble tau, whereas, tau PET reflects total tau accumulation into insoluble aggregates to date. We therefore hypothesize that baseline CSF p‐tau may be a leading indicator of future tau PET accumulation.MethodWe identified Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with diagnoses of cognitively unimpaired, mild cognitive impairment, and amnestic dementia who had CSF p‐tau (Elecsys p‐tau [181P]) and subsequent serial tau PET (flortaucipir) exams. The first tau PET scan was within 3 years of the CSF p‐tau collection. A longitudinal pipeline with two‐compartment partial volume correction was used to measure change in tau PET in a temporal‐lobe meta‐ROI (amygdala, fusiform, middle/inferior temporal, entorhinal, and parahippocampal regions) with a composite reference region (eroded supratentorial white matter, pons, and whole cerebellum). Spearman correlation was used to assess the association between CSF p‐tau and annual percent change in tau PET. A linear mixed effects model was fit to assess the association adjusting for age and sex.ResultThe study included 143 participants (76% cognitively unimpaired) (). CSF p‐tau was significantly associated with annual percent change in tau PET overall (Spearman R=0.19, p=0.023) () and after adjusting for age and sex (p<0.001) (). There was nonlinearity in the CSF p‐tau effect, with higher values (>20 pg/mL) having a greater association with annual change in tau PET than lower values.ConclusionIn a group of cognitively unimpaired and impaired participants, CSF p‐tau predicted subsequent tau PET accumulation rate. A threshold effect is suggested with subsequent tau PET accumulation primarily in participants with elevated CSF p‐tau levels near the Mayo threshold of 22 pg/mL.