Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. METHODS: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). RESULTS: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (ß = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; ß = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; ß = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; ß = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (ß = -0.005, 95% CI -0.032 to 0.021, p = 0.69). DISCUSSION: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

Cardiovascular Risk Factors and Risk of Alzheimer Disease and Mortality: A Latent Class Approach.

Background Cardiovascular risk factors co-occur with one another, and little is known about the extent of their clustering and risk of Alzheimer disease (AD). We identify groups of cardiovascular risk factors in cognitively normal individuals and investigate between-group differences in incident AD and death. Methods and Results Cognitively normal individuals were recruited from the National Alzheimer's Coordinator Center. A latent class analysis was conducted with hypertension, hypercholesterolemia, heart condition, stroke, smoking history, diabetes, and high body mass index. Between-group differences in the incidence of AD, mortality, and mortality-adjusted AD were investigated. This study included 12 412 cognitively normal individuals (average follow-up, 65 months). Three groups were identified: (1) low probabilities of cardiovascular risk factors (reference; N=5398 [43%]), (2) hypertension and hypercholesterolemia (vascular-dominant; N=5721 [46%]), and (3) hypertension, hypercholesterolemia, diabetes, and high body mass index (vascular-metabolic; N=1293 [10%]). Both vascular groups were significantly older, had more men, were slightly less educated, and were slightly more cognitively impaired than the reference group (all P<0.05). However, only the vascular-metabolic group had a significantly younger age of death compared with the reference group (84.3 versus 88.7 years, P<0.001). Only the vascular-dominant group had a greater incidence of AD (odds ratio [OR], 1.30; P<0.001) compared with the reference group. Mortality was greater in the vascular-dominant (OR, 3.26; P<0.001) and vascular-metabolic groups (OR, 1.84; P=0.02). Mortality-adjusted AD was greater in the vascular-dominant (OR, 1.54; P=0.02) and vascular-metabolic groups (OR, 1.46; P=0.04). Conclusions Three distinct cardiovascular risk factor groups were identified in cognitively normal elderly individuals. Only the vascular-dominant group was associated with a greater incidence of AD. Selective mortality may contribute to the attenuated association between the vascular-metabolic group and incident AD.

Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease.

BACKGROUND: This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. BODY: Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program. CONCLUSION: The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.

Altered central and blood glutathione in Alzheimer's disease and mild cognitive impairment: a meta-analysis.

BACKGROUND: Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease. AIM: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. METHOD: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger's test were used to assess heterogeneity and risk of publication bias, respectively. RESULTS: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-0.87 [-1. 30, -0.44], z=3.96, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger's test indicated risk of publication bias. CONCLUSION: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.

Automated generation of cerebral blood flow and arterial transit time maps from multiple delay arterial spin-labeled MRI.

PURPOSE: Develop and evaluate a deep learning approach to estimate cerebral blood flow (CBF) and arterial transit time (ATT) from multiple post-labeling delay (PLD) ASL MRI. METHODS: ASL MRI were acquired with 6 PLDs on a 1.5T or 3T GE system in adults with and without cognitive impairment (N = 99). Voxel-level CBF and ATT maps were quantified by training models with distinct convolutional neural network architectures: (1) convolutional neural network (CNN) and (2) U-Net. Models were trained and compared via 5-fold cross validation. Performance was evaluated using mean absolute error (MAE). Model outputs were trained on and compared against a reference ASL model fitting after data cleaning. Minimally processed ASL data served as another benchmark. Model output uncertainty was estimated using Monte Carlo dropout. The better-performing neural network was subsequently re-trained on inputs with missing PLDs to investigate generalizability to different PLD schedules. RESULTS: Relative to the CNN, the U-Net yielded lower MAE on training data. On test data, the U-Net MAE was 8.4 ± 1.4 mL/100 g/min for CBF and 0.22 ± 0.09 s for ATT. A significant association was observed between MAE and Monte Carlo dropout-based uncertainty estimates. Neural network performance remained stable despite systematically reducing the number of input images (i.e., up to 3 missing PLD images). Mean processing time was 10.77 s for the U-Net neural network compared to 10 min 41 s for the reference pipeline. CONCLUSION: It is feasible to generate CBF and ATT maps from 1.5T and 3T multi-PLD ASL MRI with a fast deep learning image-generation approach.

Artificial intelligence for molecular neuroimaging.

In recent years, artificial intelligence (AI) or the study of how computers and machines can gain intelligence, has been increasingly applied to problems in medical imaging, and in particular to molecular imaging of the central nervous system. Many AI innovations in medical imaging include improving image quality, segmentation, and automating classification of disease. These advances have led to an increased availability of supportive AI tools to assist physicians in interpreting images and making decisions affecting patient care. This review focuses on the role of AI in molecular neuroimaging, primarily applied to positron emission tomography (PET) and single photon emission computed tomography (SPECT). We emphasize technical innovations such as AI in computed tomography (CT) generation for the purposes of attenuation correction and disease localization, as well as applications in neuro-oncology and neurodegenerative diseases. Limitations and future prospects for AI in molecular brain imaging are also discussed. Just as new equipment such as SPECT and PET revolutionized the field of medical imaging a few decades ago, AI and its related technologies are now poised to bring on further disruptive changes. An understanding of these new technologies and how they work will help physicians adapt their practices and succeed with these new tools.

Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study.

BACKGROUND: In 2015, a patient in hospice with Alzheimer's disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD. OBJECTIVE: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given. METHODS: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments. RESULTS: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change. CONCLUSION: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.

Physical activity perceptions, experiences, and beliefs of older adults with mild cognitive impairment or Alzheimer's disease and their care partners.

Physical activity (PA) participation provides functional and social benefits for persons with mild cognitive impairment (MCI) and Alzheimer's disease (AD), but PA participation in these populations is low. To support health promotion initiatives for cognitively impaired older adults, this study explored the perceptions, experiences, and beliefs of older adults with cognitive impairment and their caregivers concerning PA. Ten care dyads (community-dwelling adult aged ≥65 years diagnosed with MCI or mild-to-moderate AD and their care partner) participated in semi-structured interviews informed by the Theoretical Domains Framework about their PA perceptions, experiences, and beliefs. Interpretive phenomenological analysis of interview transcripts yielded 4 emergent themes: (1) PA as a meaningful activity, (2) experience versus evidence as motivating, (3) participation is possible despite dementia, and (4) care partners as enablers. Findings from this study address a research gap concerning the PA perceptions, experiences, and beliefs of cognitively impaired older adults and their care partners. Novelty Older adults with MCI/AD want to and are capable of engaging in PA. Care partners are critical supporters of PA participation in MCI/AD. Adapted health promotion strategies could enhance PA in MCI/AD.

Amyloid-beta burden predicts prospective decline in body mass index in clinically normal adults.

In the present study, we tested the hypothesis that higher amyloid-beta (Aß) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aß positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aß burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aß burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer's disease.

BACKGROUND: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. METHODS: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1ß), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. RESULTS: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1ß (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (ß = - 0.152, p = 0.015) but not memory (ß = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis.

Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

Special topic section: linkages among cerebrovascular, cardiovascular, and cognitive disorders: Preventing dementia by preventing stroke: The Berlin Manifesto.

The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer's Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.

Preventing dementia by preventing stroke: The Berlin Manifesto.

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.

Development of cognitive screening test for the severely hearing impaired: Hearing-impaired MoCA.

OBJECTIVES: To develop a version of the Montreal Cognitive Assessment (MoCA) to be administered to the severely hearing impaired (HI-MoCA), and to assess its performance in two groups of cognitively intact adults over the age of 60. STUDY TYPE: Test development followed by prospective subject recruitment. METHODS: The MoCA was converted into a timed PowerPoint (Microsoft Corp., Redmond, WA) presentation, and verbal instructions were converted into visual instructions. Two groups of subjects over the age of 60 were recruited. All subjects passed screening questionnaires to eliminate those with undiagnosed mild cognitive impairment. The first group had normal hearing (group 1). The second group was severely hearing impaired (group 2). Group 1 received either the MoCA or HI-MoCA test (T1). Six months later (T2), subjects were administered the test (MoCA or HI-MoCA) they had not received previously to determine equivalency. Group 2 received the HI-MoCA at T1 and again at T2 to determine test-retest reliability. RESULTS: One hundred and three subjects were recruited into group 1, with a score of 26.66 (HI-MoCA) versus 27.14 (MoCA). This was significant (P < 0.05), but scoring uses whole numerals and the 0.48 difference was found not clinically significant using post hoc sensitivity analyses. Forty-nine subjects were recruited into group 2. They scored 26.18 and 26.49 (HI-MoCA at T1 and T2). No significance was noted (P > 0.05), with a test-retest coefficient of 0.66. CONCLUSION: The HI-MoCA is easy to administer and reliable for screening cognitive impairment in the severely hearing impaired. No conversion factor is required in our prospectively tested cohort of cognitively intact subjects. LEVEL OF EVIDENCE: 1b. Laryngoscope, 127:S4-S11, 2017.

Peripheral inflammatory markers indicate microstructural damage within periventricular white matter hyperintensities in Alzheimer's disease: A preliminary report.

INTRODUCTION: White matter hyperintensities (WMH) presumed to reflect cerebral small vessel disease and increased peripheral inflammatory markers are found commonly in Alzheimer's disease (AD), but their interrelationships remain unclear. METHODS: Inflammatory markers were assayed in 54 elderly participants (n = 16 with AD). Periventricular WMH were delineated from T1, T2/proton density, and fluid-attenuated magnetic resonance imaging using semiautomated fuzzy lesion extraction and coregistered with maps of fractional anisotropy (FA), a measure of microstructural integrity assessed using diffusion tensor imaging. RESULTS: Mean FA within periventricular WMH was associated with an inflammatory factor consisting of interleukin (IL)-1ß, tumor necrosis factor, IL-10, IL-21, and IL-23 in patients with AD (ρ = -0.703, P = .002) but not in healthy elderly (ρ = 0.217, P = .190). Inflammation was associated with greater FA in deep WMH in healthy elderly (ρ = 0.425, P = .008) but not in patients with AD (ρ = 0.174, P = .520). DISCUSSION: Peripheral inflammatory markers may be differentially related to microstructural characteristics within the white matter affected by cerebral small vessel disease in elders with and without AD.

Identifying obstructive sleep apnea after stroke/TIA: evaluating four simple screening tools.

OBJECTIVE: Despite its high prevalence and unfavorable clinical consequences, obstructive sleep apnea (OSA) often remains underappreciated after cerebrovascular events. The purpose of our study was to evaluate the clinical utility of four simple paper-based screening tools for excluding OSA after stroke or transient ischemic attack (TIA). PATIENTS/METHODS: Sixty-nine inpatients and outpatients with stroke or TIA during the past 180 days completed the 4-Variable screening tool (4V), STOP-BAG questionnaire (ie, STOP-BANG questionnaire without the neck circumference measurement), Berlin questionnaire, and the Sleep Obstructive apnea score optimized for Stroke (SOS). They subsequently underwent objective testing using a portable sleep monitoring device. Cutoffs were selected to maximize sensitivity and exclude OSA (AHI ≥ 10) in ≥10% of the cohort. RESULTS: The mean age was 68.3 ± 14.2 years and 47.8% were male. Thirty-two patients (46.4%) were found to have OSA. Male sex, body mass index (BMI), and atrial fibrillation were independent predictors of OSA. Among the screening tools, the 4V had the greatest area under the curve (AUC) of 0.688 (p = 0.007); the sensitivity was 96.9% for a cutoff of <6. The STOP-BAG also significantly detected OSA with an AUC of 0.677 (p = 0.012); the sensitivity was 93.8% for a cutoff of <2. Scores on the 4V and STOP-BAG were significantly correlated with the AHI. CONCLUSIONS: The 4V and STOP-BAG questionnaire may aid clinicians with ruling out OSA within 180 days of stroke/TIA. Due to the atypical presentation of poststroke/TIA OSA, these tools are only moderately predictive; objective testing should still be used for OSA diagnosis in this population.

Healthy(?), wealthy, and wise: Birth order and adult health.

While recent research has found that birth order affects outcomes such as education and earnings, the evidence for effects on health is more limited. This paper uses a large Norwegian dataset to focus on the relationship between birth order and a range of health and health-related behaviors, outcomes not previously available in datasets of this magnitude. Interestingly, we find complicated effects of birth order. First-borns are more likely to be overweight, to be obese, and to have high blood pressure and high triglycerides. For example, compared to fifth-borns, first-borns are about 5% points more likely to be obese and 7% points more likely to have high blood pressure. So, unlike education or earnings, there is no clear first-born advantage in health. However, first-borns are about 13% points less likely to smoke daily than fifth-borns and are more likely to report good physical and mental health. Later-borns also score lower on well-being with fifth-borns being about 9% points less likely than first-borns to report that they are happy. Our findings are generally monotonic with middle-borns having outcomes that are intermediate between first- and fifth-borns. We find that these effects are largely unaffected by conditioning on education and earnings, suggesting that these are not the only important pathways to health differentials by birth order. When we explore possible mechanisms, we find that early maternal investment may play a role in birth order effects on health.

A short-term scan-rescan reliability test measuring brain tissue and subcortical hyperintensity volumetrics obtained using the lesion explorer structural MRI processing pipeline.

Lesion Explorer (LE) is a reliable and comprehensive MRI-derived tissue segmentation and brain region parcellation processing pipeline for obtaining intracranial tissue and subcortical hyperintensity (SH) volumetrics. The processing pipeline segments: gray (GM) and white matter (WM); sulcal (sCSF) and ventricular cerebrospinal fluid (vCSF); periventricular (pvSH) and deep white subcortical hyperintensities (dwSH); and cystic fluid filled lacunar-like infarcts (Lacunar); into 26 regions of interest. A short-term scan-rescan reliability test was performed on 20 healthy volunteers: 10 older (mean = 77.7 years, SD = 11.1) and 10 younger (mean = 29.4 years, SD = 7.1). Each participant was scanned twice with an average interscan interval of 15.4 days (range: 29 min-50 days). Results suggest low technique-related error as indicated by excellent intraclass correlation coefficient (ICC) results, with ICCs above 0.90 (p < 0.05) for GM, WM, and CSF, in all 26 regions of interest (13 per hemisphere). Ventricular and lesion sub-type (pvSH, dwSH, and Lacunar) volumes also showed high scan-rescan reliability (dwSH = 0.9998, pvSH = 0.9998, Lacunar = 0.9859, p < 0.01). As indicated by the results of this short-term scan-rescan study, the LE structural MRI processing pipeline can be applied for longitudinal volumetric analyses with confidence.

Terminal, but not concurrent prism exposure produces perceptual aftereffects in healthy young adults.

A short period of prism adaptation (PA) has been shown to reduce spatial neglect symptoms. Recent evidence suggests that the positive effects of PA might be restricted to visually guided actions, with PA having little effect on perception. However, the majority of studies have adopted a concurrent exposure technique that fosters the development of a change in felt arm position (proprioceptive straight ahead, PSA). Few studies have used terminal exposure that promotes a change in the perceived visual direction (visual straight ahead, VSA). The positive effects of PA might appear to be primarily action based because studies have adopted an exposure technique that promotes a change in proprioception. Here, we compare the effects of the two exposure types on a perceptual and a manual line bisection task in healthy young adults. Before and after seven minutes of exposure to leftward displacing prisms we measured performance on two line bisection tasks (manual and perceptual) and perceived straight ahead (PSA and VSA). During the exposure period participants made pointing movements while the view of their pointing arm was either (i) restricted to the second half of the pointing movement (concurrent exposure) or (ii) restricted to the final part of the pointing movement (terminal exposure). In line with the previous research, concurrent exposure produced a large shift in PSA and a shift on the manual line bisection task. Interestingly, terminal exposure produced a large shift in VSA and a shift in performance on the perceptual line bisection task. Our results shed light on the underlying mechanisms of prism-induced neglect recovery and help to address an apparent discrepancy within the literature.