Weigand, Stephen D.

AbstractBackgroundDysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death.ObjectiveThe aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity.MethodsThirty‐eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging. Penalized linear regression models assessed relationships between swallowing metrics and regional gray matter volumes and white matter fractional anisotropy and mean diffusivity.ResultsOral phase impairments were associated with reduced superior parietal volumes and abnormal diffusivity in parietal and sensorimotor white matter, posterior limb of the internal capsule, and superior longitudinal fasciculus. Pharyngeal phase impairments were associated with disruption to medial frontal lobe, corticospinal tract, and cerebral peduncle. No regions were predictive of airway incursion.ConclusionsDifferential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society

Abstract Introduction We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. Methods Cut points for Elecsys amyloid beta 42 (Aβ42), total tau (t‐tau), hyperphosphorylated tau (p‐tau), and t‐tau/Aβ42 and p‐tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants. Results The t‐tau/Aβ42 and p‐tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)‐based cut points were 0.26 (0.24–0.27) for t‐tau/Aβ42 and 0.023 (0.020–0.025) for p‐tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA). Conclusion CSF t‐tau/Aβ42 and p‐tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.

ObjectiveHistology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T‐cell‐ and macrophage‐associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers.MethodsWe evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow‐up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112).ResultsA strong association of a ringlike enhancement and a hypointense T2‐weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients.InterpretationWe provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440–454

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS). Objectives: To describe long-term clinical–radiographic–cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS. Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery. Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm 3 ). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes. Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.

BackgroundTo operationalize the National Institute on Aging – Alzheimer's Association (NIA‐AA) Research Framework for Alzheimer's Disease 6‐stage continuum of clinical progression for persons with abnormal amyloid.MethodsThe Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross‐sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.ResultsAmong 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44–59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short‐term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).InterpretationThe frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145–1156

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

AbstractBackgroundDisproportionately enlarged subarachnoid‐space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. Although this imaging phenotype was originally described in normal pressure hydrocephalus (NPH), it has since been more widely recognized in the aging population with a prevalence of 6‐7% in the Mayo Clinic Study of Aging (MCSA) 1. The clinical significance of DESH with regards to cognitive decline outside of NPH is not yet well‐defined. The goal of this work is to determine if DESH is associated with risk of cognitive impairment.MethodParticipants in the population‐based MCSA who met the following criteria were included: age ≥ 65 years, 3T MRI, cognitively unimpaired at enrollment, and at least one follow‐up visit. A support vector machine based method to detect the DESH imaging features on T1‐weighted MRI was used to calculate “computational DESH” or CDESH scores2 (Figure 1). Cox proportional hazard models were fit with events defined as progression from cognitively unimpaired to mild cognitive impairment or dementia. Time was defined as years from MCSA enrollment to the first visit with cognitive impairment with censoring at last follow‐up. CDESH was modelled as a spline to allow for non‐linear effects. Covariates included age, sex, education, APOE status, cortical thickness, white matter hyperintensity (WMH) volume, and total intracranial volume.ResultParticipant demographics are summarized in Table 1. The model including the above co‐variates showed a significant CDESH effect (p=0.02) with an approximately 20% greater hazard of progression for a CDESH score of +1 versus −1 (HR 1.2, 95% CI 1.0‐1.4) (Figure 2).ConclusionImaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well‐known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically and also used as a selection stratification variable for clinical trials. References: (1) Graff‐Radford et al doi:10.1212/WNL.0000000000008616; (2) N. Gunter et al doi:10.1016/j.nicl.2018.11.015.

AbstractBackgroundThe Network Failure Quotient (NFQ) metric summarizes functional MRI network integrity. We wanted to investigate the stability of the NFQ results across time, hardware, software and protocol changes during the last decade in ADNI Resting State (RS‐) fMRI.MethodIn ADNI‐2 (2009‐2016) RS‐fMRI was acquired on Philips scanners. In ADNI‐3 (2017‐present) RS‐fMRI is acquired on GE, Philips, and Siemens systems with “Basic” and “Advanced” variants based on the availability of simultaneous multi‐slice (SMS, multi‐band) imaging. (Table 1.) Resting state images were preprocessed by performing slice timing correction, trimming volumes from the first 10 seconds of acquired data, despiking and within‐series alignment. Simultaneous bandpass and regression was performed using spatial registration parameters and their first temporal derivatives, mean WM signal, mean CSF signal and global signal. Dual regression via GIFT was applied creating regional time courses. The NFQ is calculated as NFQ=(pDMN_to_vDMN + pDMN_to_adDMN) / (pDMN +vDMN) where pDMN_to_vDMN and pDMN_to_adDMN are correlations between time courses in the posterior DMN, ventral DMN and anterior‐dorsal DMN. pDMN and vDMN are the within‐region correlations. NFQ values from 1447 scans of 739 individual study participants (Table 1) were analyzed using linear mixed effects models to account for age, clinical diagnosis, vendor, and time trends.ResultBox plots of NFQ values by diagnosis within ADNI‐phase and protocol are shown in Figure 2 and suggest important differences among clinical diagnoses and between ADNI‐2 and ADNI‐3. The mixed model analysis indicates that a 10‐year increase in age is associated with a 0.05±0.01 (mean±SD) increase in NFQ; individuals with MCI average roughly 0.05±0.01 higher than unimpaired and individuals with dementia average 0.14±0.02 higher. Differences by vendor for ADNI‐2 and ADNI‐3 are summarized in Figures 2 and 3 with effect sizes on par with these clinical factors. Mean NFQ for Phillips ADNI‐2 were highest (0.54±0.02); somewhat lower were Philips ADNI‐3 (0.51±0.02) and Siemens ADNI‐3 advanced (0.49±0.03); Siemens ADNI‐3 basic (0.40±0.02) and GE ADNI‐3 were the lowest (0.38±0.02).ConclusionNFQ values consistently increase with impairment. Vendor‐specific differences are observed and vendor changes over the life of a study introduce variability on the scale of disease‐related changes in NFQ.

ObjectiveMultiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.MethodsWe used synchrotron X‐ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.ResultsImmunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17–127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = −40 to −14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X‐ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron.InterpretationIron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron‐sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498–510