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To synthesize quantitatively the mild cognitive impairment (MCI) literature with respect to the relationship between cognitive reserve and neuropsychological and functional outcomes.Participants with a diagnosis of MCI (total n = 7,871; 53% female) were included in this random-effects meta-analysis. Neuropsychological measures were combined into composite scores (e.g., overall cognitive functioning, screening measures, memory, language, visuospatial, attention/processing speed/working memory, executive functioning, and motor functioning). Measures assessing real-world abilities were combined into an activities of daily living (ADL) composite.Nearly all neuropsychological composite values were significantly correlated with education, with effect sizes ranging from small to moderate. The effect between overall neuropsychological functioning and occupation was weak and varied by cognitive domain. For cognitively stimulating leisure activity, only overall neuropsychological functioning demonstrated a significant relationship, with a weak effect size (r = .16). In contrast, ADLs were most strongly associated with leisure experience (r = .27), with a negligible relationship with education (r = 0.08) and occupation (r = 0.09).Of the cognitive reserve proxies examined in this study, participation in leisure activity had the largest magnitude of effect size with ADL functioning. This was in stark contrast to the negligible relationship found for education and occupation. Although education has been widely considered the most important cognitive reserve proxy with respect to cognition, this work questions whether other lifestyle factors may play a more important role in preserving real world functioning.

Background: The detailed extent of neuroinvasion or deleterious brain changes resulting from COVID-19 and their time courses remain to be determined in relation to “long-haul” COVID-19 symptoms. Our objective is to determine whether there are alterations in functional brain imaging measures among people with COVID-19 after hospital discharge or self-isolation. Methods: This paper describes a protocol for NeuroCOVID-19, a longitudinal observational study of adults aged 20–75 years at Sunnybrook Health Sciences Centre in Toronto, Ontario, that began in April 2020. We aim to recruit 240 adults, 60 per group: people who contracted COVID-19 and were admitted to hospital (group 1), people who contracted COVID-19 and self-isolated (group 2), people who experienced influenza-like symptoms at acute presentation but tested negative for COVID-19 and self-isolated (group 3, control) and healthy people (group 4, control). Participants are excluded based on premorbid neurologic or severe psychiatric illness, unstable cardiovascular disease, and magnetic resonance imaging (MRI) contraindications. Initial and 3-month follow-up assessments include multiparametric brain MRI and electroencephalography. Sensation and cognition are assessed alongside neuropsychiatric assessments and symptom self-reports. We will test the data from the initial and follow-up assessments for group differences based on 3 outcome measures: MRI cerebral blood flow, MRI resting state fractional amplitude of low-frequency fluctuation and electroencephalography spectral power. Interpretation: If neurophysiologic alterations are detected in the COVID-19 groups in our NeuroCOVID-19 study, this information could inform future research regarding interventions for long-haul COVID-19. The study results will be disseminated to scientists, clinicians and COVID-19 survivors, as well as the public and private sectors to provide context on how brain measures relate to lingering symptoms.

Background Remote health monitoring with wearable sensor technology may positively impact patient self-management and clinical care. In individuals with complex health conditions, multi-sensor wear may yield meaningful information about health-related behaviors. Despite available technology, feasibility of device-wearing in daily life has received little attention in persons with physical or cognitive limitations. This mixed methods study assessed the feasibility of continuous, multi-sensor wear in persons with cerebrovascular (CVD) or neurodegenerative disease (NDD). Methods Thirty-nine participants with CVD, Alzheimer’s disease/amnestic mild cognitive impairment, frontotemporal dementia, Parkinson’s disease, or amyotrophic lateral sclerosis (median age 68 (45–83) years, 36% female) wore five devices (bilateral ankles and wrists, chest) continuously for a 7-day period. Adherence to device wearing was quantified by examining volume and pattern of device removal (non-wear). A thematic analysis of semi-structured de-brief interviews with participants and study partners was used to examine user acceptance. Results Adherence to multi-sensor wear, defined as a minimum of three devices worn concurrently, was high (median 98.2% of the study period). Non-wear rates were low across all sensor locations (median 17–22 min/day), with significant differences between some locations (p = 0.006). Multi-sensor non-wear was higher for daytime versus nighttime wear (p

Author(s): Pilotto, Andrea; Romagnolo, Alberto; Scalvini, Andrea; Masellis, Mario; Shimo, Yasushi; Bonanni, Laura; Camicioli, Richard; Wang, Lily L; Dwivedi, Alok K; Longardner, Katherine; Rodriguez-Porcel, Federico; DiFrancesco, Mark; Vizcarra, Joaquin A; Montanaro, Elisa; Maule, Simona; Lupini, Alessandro; Ojeda-Lopez, Carmen; Black, Sandra E; Delli Pizzi, Stefano; Gee, Myrlene; Tanaka, Ryota; Yamashiro, Kazuo; Hatano, Taku; Borroni, Barbara; Gasparotti, Roberto; Rizzetti, Maria C; Hattori, Nobutaka; Lopiano, Leonardo; Litvan, Irene; Espay, Alberto J; Padovani, Alessandro; Merola, Aristide | Abstract: ObjectiveTo evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).MethodsSupine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.ResultsA total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72).ConclusionsOH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.

Rationale We evaluated K-means clustering to classify amyloid brain PETs as positive or negative. Patients and methods Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data. Results Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%. Conclusions K-means clustering may be a powerful algorithm for classifying amyloid brain PET.

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by 18F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer’s disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E e4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer’s disease prevention and treatment.

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.

Obstructive sleep apnea (OSA) increases the risk of developing dementia. Home sleep apnea testing (HSAT) is a convenient and validated method to screen for OSA among cognitively well individuals; however, it is unknown if it is a clinically feasible and practical approach in clinic patients with cognitive impairment. We evaluated if HSAT was a feasible and practical approach to screen for OSA in clinic patients with cognitive impairment.Patients with cognitive impairment due to neurodegenerative and/or vascular etiologies completed OSA screening using HSAT. HSAT was considered a feasible technique if ≥ 80% of those who attempted HSAT obtained analyzable data (ie, ≥ 4 hours of flow, effort, and oxygen evaluation), and a practical technique if ≥ 50% of all patients approached for study inclusion obtained analyzable data.Of the 119 patients who were approached for participation, 83 were enrolled and offered HSAT; 5 did not complete HSAT screening, and the remaining 78 patients attempted HSAT; mean age (± standard deviation) of 72.86 (± 9.89) years and 46% were male. In those that attempted HSAT, 85.9% (67/78) obtained analyzable data and 56.3% (67/119) of eligible patients approached for study inclusion obtained analyzable data.HSAT is a feasible and practical technique in a clinic population with cognitive impairment. As OSA is a modifiable risk factor for patients with dementia, HSAT has the potential to lead to expedited treatment for OSA, which may potentially improve health-related outcomes such as cognition.

Background and Purpose: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression. Methods: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003–2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke. Results: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X 2 =5.4; P =0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHR Depression =1.57 [1.24–1.98]) and incident dementia (aHR Depression =1.85 [1.40–2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHR Diabetes =1.20 [1.12–1.29]; aHR Depression =1.19 [1.04–1.37]), incident dementia (aHR Diabetes =1.14 [1.06–1.23]; aHR Depression =1.27 [1.08–1.49]), stroke/transient ischemic attack readmission (aHR Diabetes =1.18 [1.10–1.26]; aHR Depression =1.24 [1.07–1.42]), and all-cause mortality (aHR Diabetes =1.29 [1.23–1.36]; aHR Depression =1.16 [1.05–1.29]). Conclusions: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

We have provided an overview on the profound impact of COVID‐19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health‐care settings, including hospital, out‐patient, care homes, and the community during the COVID‐19 pandemic. We have also proposed a conceptual framework and practical suggestions for health‐care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health‐care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD‐19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

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.

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) 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 Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aβ 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 Aβ 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 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.

Introduction Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. Methods Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised–Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed‐effects models with inverse probability treatment weights. Results In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase‐4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. Discussion Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Background and Purpose:Large prospective observational studies have cast doubt on the common assumption that endovascular thrombectomy (EVT) is superior to intravenous thrombolysis for patients with acute basilar artery occlusion (BAO). The purpose of this study was to retrospectively review our experience for patients with BAO undergoing EVT with modern endovascular devices.Methods:All consecutive patients undergoing EVT with either a second-generation stent retriever or direct aspiration thrombectomy for BAO at our regional stroke center from January 1, 2013 to March 1, 2019 were included. The primary outcome measure was functional outcome at 1 month using the modified Rankin Scale (mRS) score. Multivariable logistic regression was used to assess the association between patient characteristics and dichotomized mRS.Results:A total of 43 consecutive patients underwent EVT for BAO. The average age was 67 years with 61% male patients. Overall, 37% (16/43) of patients achieved good functional outcome. Successful reperfusion was achieved in 72% (31/43) of cases. The median (interquartile range) stroke onset to treatment time was 420 (270–639) minutes (7 hours) for all patients. The procedure-related complication rate was 9% (4/43). On multivariate analysis, posterior circulation Alberta stroke program early computed tomography score and Basilar Artery on Computed Tomography Angiography score were associated with improved functional outcome.Conclusion:EVT appears to be safe and feasible in patients with BAO. Our finding that time to treatment and successful reperfusion were not associated with improved outcome is likely due to including patients with established infarcts. Given the variability of collaterals in the posterior circulation, the paradigm of utilizing a tissue window may assist in patient selection for EVT. Magnetic resonance imaging may be a reasonable option to determine the extent of ischemia in certain situations.

We assessed visuospatial abilities in PCA. Sequential display of two simple geometric figures enhanced detection and discrimination relative to simultaneous display (Exps 1 2). Comparing edges of a single object enhanced discrimination relative to comparing edges of two separate objects, consistent with object-based attention (Exp. 3). Recognition of complex line drawings was spared for a single object but disrupted by an attention-grabbing small circle (Exp. 4). A covert orienting task showed difficulty disengaging from previous locations and attentional bias toward the right visual field (Exp. 5). These findings shed light on the role of visual attention in perceptual awareness.

Background: Differential cognitive trajectories in Alzheimer’s disease (AD) may be predicted by biomarkers from multiple domains. Objective: In a longitudinal sample of AD and AD-related dementias patients (n = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE] ɛ4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern. Methods: We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive function [EF]/attention). We then tested these associations as stratified by APOE (ɛ4–/ɛ4+), PP (low/high), and APOE+ PP (low/intermediate/high) risk. Results: First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOE ɛ4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE+ PP risk group both concurrently and longitudinally. Conclusion: As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE+ PP risk does not produce further cognitive decline.

Background The incidence of ischemic stroke has increased among adults aged 18 to 64 years, yet little is known about relationships between specific risk factors and outcomes. This study investigates in‐hospital and long‐term outcomes in patients with stroke aged Methods and Results Consecutive patients aged Conclusions Focused secondary prevention and risk factor management may be needed to address poor long‐term outcomes for patients with stroke aged

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.

Objective To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD). Design This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases. Setting Patients were recruited from a long-term care facility and geriatric psychiatry clinics. Participants Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3). Intervention Nabilone (target 1–2 mg) versus placebo. Measurements The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events. Results Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = −4.0 [−6.5 to −1.5], t(30.2) = −3.3, p = 0.003), NPI-NH total (b = −4.6 [−7.5 to −1.6], t(32.9) = −3.1, p = 0.004), NPI-NH caregiver distress (b = −1.7 [−3.4 to −0.07, t(33.7) = −2.1, p = 0.041), and sMMSE (b = 1.1 [0.1–2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = −4.6 [−7.3 to −1.8], t(20.7) = −4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22). Conclusions Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored.

It is currently unclear whether the glymphatic system, a brain-wide interstitial fluid-cerebrospinal fluid exchange described in rodents, exists in humans. Focal blood-brain barrier disruption using magnetic resonance-guided focused ultrasound allows parenchymal penetration of gadobutrol contrast, creating an opportunity to study glymphatics in vivo noninvasively. We describe patterns of contrast distribution in the perivascular space, subarachnoid space, and space surrounding large veins draining toward the dural sinuses on fluid-attenuated inversion recovery in subjects with Alzheimer disease and amyotrophic lateral sclerosis. This is the first evidence suggesting glymphatic efflux persists in humans. It's relevance to proteinopathies and drug delivery is discussed. ANN NEUROL 2019;86:975-980.

Hippocampal volumetry is a critical biomarker of aging and dementia, and it is widely used as a predictor of cognitive performance; however, automated hippocampal segmentation methods are limited because the algorithms are (a) not publicly available, (b) subject to error with significant brain atrophy, cerebrovascular disease and lesions, and/or (c) computationally expensive or require parameter tuning. In this study, we trained a 3D convolutional neural network using 259 bilateral manually delineated segmentations collected from three studies, acquired at multiple sites on different scanners with variable protocols. Our training dataset consisted of elderly cases difficult to segment due to extensive atrophy, vascular disease, and lesions. Our algorithm, (HippMapp3r), was validated against four other publicly available state‐of‐the‐art techniques (HippoDeep, FreeSurfer, SBHV, volBrain, and FIRST). HippMapp3r outperformed the other techniques on all three metrics, generating an average Dice of 0.89 and a correlation coefficient of 0.95. It was two orders of magnitude faster than some of the tested techniques. Further validation was performed on 200 subjects from two other disease populations (frontotemporal dementia and vascular cognitive impairment), highlighting our method's low outlier rate. We finally tested the methods on real and simulated “clinical adversarial” cases to study their robustness to corrupt, low‐quality scans. The pipeline and models are available at: https://hippmapp3r.readthedocs.ioto facilitate the study of the hippocampus in large multisite studies.

Background Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1. Objective To assess whether 24S-OHC was associated with agitation severity and response to nabilone. Methods 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression). Results 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03). Conclusion 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone.

To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification.The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB.A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees).Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Purpose/background Loss of gray matter after stroke has been associated with cognitive impairment. This pilot study aimed to investigate the therapeutic potential of lithium, a putative neurotrophic agent, in the stroke recovery process within a year of stroke occurrence. Methods Twelve stroke patients (mean ± SD age, 71.1 ± 11.9 years) were recruited to the study, and eligible participants were prescribed open-label lithium for 60 days. Magnetic resonance imaging was used to assess global gray matter at baseline and end of treatment; global cognition was assessed using the standardized Mini-Mental State Examination and Montreal Cognitive Assessment, and verbal memory was evaluated using the Hopkins Verbal Learning Test-Revised. Findings/results There was no difference in global gray matter volume between baseline and follow-up (t = 1.977, P = 0.074). There was a significant interaction between higher lithium dose and increased global gray matter volume (F = 14.25, P = 0.004) and a correlation between higher lithium dose and improved verbal memory (r = 0.576, P = 0.05). Implications/conclusions Lithium pharmacotherapy may be associated with gray matter volume change and verbal memory improvement in stroke patients, providing a rationale for future trials assessing therapeutic potential of lithium in a poststroke population.

Background In the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies. Methods Between 2013 and 2019, 8252 participants (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported. Results Severe structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy. Conclusion The management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies. Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02220582.

Background Diabetes is a risk factor for cerebrovascular disease and cognitive impairment. The anatomical basis for this is uncertain. Methods The Canadian Alliance for Healthy Hearts and Minds collected brain and carotid magnetic resonance imaging (MRI) and 2 cognitive tests (the Digit Symbol Substitution Test and the Montreal Cognitive Assessment test) in a cross-sectional sample of men and women. Brain MRIs identified brain infarcts (BI), lacunar BI, high white matter hyperintensity (WMH), vascular brain injury (VBI; BI or high WMH), and small vessel VBI (lacunar BI or high WMH). Carotid MRIs estimated carotid wall volume, a measure of subclinical atherosclerosis. Cognitive scores were standardized to each site’s mean score, and cognitive impairment was identified by 1 or both test scores ≤1 standard deviation below the site’s mean score on that test. Results The 7733 participants included 495 participants (6.4%) with diabetes, of whom 388 were taking diabetes drugs. After age and sex adjustment, diabetes was independently associated with BI (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.05, 2.24), VBI (OR 1.64, 95% CI 1.26, 2.13), small vessel VBI (OR 1.67, 95% CI 1.28, 2.19), and cognitive impairment (OR 1.47, 95% CI 1.20, 1.80). The association between diabetes and small vessel VBI persisted after adjustment for cerebrovascular disease risk factors and nonlacunar infarcts (OR 1.52, 95% CI 1.15, 2.01), and the association with cognitive impairment persisted after adjustment for small vessel VBI (OR 1.27, 95% CI 1.03, 1.56). Conclusion Small vessel disease characterizes much of the relationship between diabetes and VBI. However, additional factors are required to disentangle the relationship between diabetes and cognitive impairment.

Perturbations in fatty acid (FA) metabolism as well as thinning of the cerebral cortex have been associated with cognitive decline in the elderly. Predominant FAs in the brain are docosahexaenoic acid (DHA) and arachidonic acid (ARA). Approximately 2–8% of esterified DHA and 3–5% of esterified ARA in the brain are replaced daily. DHA and ARA are derivatives of 18-carbon essential FAs, α-linolenic acid and linoleic acid, that must be imported into the brain from the circulation. In blood, FAs are primarily transported in triacylglycerols (TAGs) from which they can be released at the blood–brain-barrier and transported inside the brain. We show that circulating levels of TAGs carrying 18-carbon FAs are positively associated with cortical thickness in middle-aged adults. These associations are stronger in cortical regions with higher expression of genes regulating long-chain FA metabolism and cellular membranes, and cortical thickness in the same regions may be related to cognitive performance., Eeva Sliz et al. show an association between triacylglycerols species carrying 18-carbon unsaturated fatty acids and cortical thickness by combining serum lipidomics and brain imaging data. This association is more pronounced in cortical regions with higher expression of genes regulating fatty acid metabolism and cellular membranes.

Purpose The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score. Materials and methods Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB. Results F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score. Conclusions Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.

Background and Purpose— Little is known about the association between covert vascular brain injury and cognitive impairment in middle-aged populations. We investigated if scores on a cognitive screen were lower in individuals with higher cardiovascular risk, and those with covert vascular brain injury. Methods— Seven thousand five hundred forty-seven adults, aged 35 to 69 years, free of cardiovascular disease underwent a cognitive assessment using the Digital Symbol Substitution test and Montreal Cognitive Assessment, and magnetic resonance imaging (MRI) to detect covert vascular brain injury (high white matter hyperintensities, lacunar, and nonlacunar brain infarctions). Cardiovascular risk factors were quantified using the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction) risk score. Multivariable mixed models tested for independent determinants of reduced cognitive scores. The population attributable risk of risk factors and MRI vascular brain injury on low cognitive scores was calculated. Results— The mean age of participants was 58 (SD, 9) years; 55% were women. Montreal Cognitive Assessment and Digital Symbol Substitution test scores decreased significantly with increasing age ( P P Conclusions— Among a middle-aged community-dwelling population, scores on a cognitive screen were lower in individuals with higher cardiovascular risk factors or MRI vascular brain injury. Much of the population attributable risk of low cognitive scores can be attributed to lower educational attainment, higher cardiovascular risk factors, and MRI vascular brain injury.

Background and Purpose— Compared with other causes of ischemic stroke, the mechanism of action of embolic stroke of undetermined source (ESUS) remains unclear, with previous literature suggesting that ESUS may be due to an undetected cardioembolic source. This study aimed to improve our understanding of the pathophysiology of ESUS through current knowledge of sleep disorders. Methods— Patients were included in this study if they sustained an ischemic stroke and completed either polysomnography or a home sleep apnea test. Strokes were classified into 1 of 6 mechanisms and were compared with the presence of sleep disorders (ie, obstructive sleep apnea, periodic limb movements, and abnormalities in sleep architecture). Results— There was a significant relationship between obstructive sleep apnea and cardioembolic stroke mechanism compared with the other stroke mechanisms ( P =0.018). There was no significant relationship between obstructive sleep apnea and ESUS ( P =0.585). Patients with ESUS were significantly more likely to have an elevated periodic limb movement index ( P =0.037) and prolonged sleep onset latency ( P =0.0166) compared with patients with other causes of stroke. Conclusions— ESUS was not associated with markers of cardioembolic stroke such as obstructive sleep apnea. There was a significant relationship between ESUS and elevated periodic limb movements and impaired sleep architecture, which suggests that ESUS may have a multifactorial underlying pathophysiology.

Background:Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer’s disease (AD) and may underpin part of the disease’s neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD.Methods:Thirty-three subjects (age range: 52–83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite.Results:Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction.Conclusion:The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.

White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (β = - 0.473, p = 0.001, adjusted r2 = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = - 0.50, 95% bootstrap confidence interval [- 0.99, - 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter.

Background Interindividual differences in cognitive reserve (CR) are associated with complex and dynamic clinical phenotypes observed in cognitive impairment and dementia. We tested whether (1) CR early in life (E-CR; measured by education and IQ), (2) CR later in life (L-CR; measured by occupation), and (3) CR panel (CR-P) with the additive effects of E-CR and L-CR, act as moderating factors between baseline ventricular size and clinical dementia severity at baseline and across 2 years. We further examined whether this moderation is differentially represented by sex. Methods We examined a longitudinal model using patients (N = 723; mean age = 70.8 ± 9.4 years; age range = 38–90 years; females = 374) from the Sunnybrook Dementia Study. The patients represented Alzheimer’s disease (n = 439), mild cognitive impairment (n = 77), vascular cognitive impairment (n = 52), Lewy body disease (n = 30), and frontotemporal dementia (n = 125). Statistical analyses included (1) latent growth modeling to determine how clinical dementia severity changes over 2 years (measured by performance on the Dementia Rating Scale), (2) confirmatory factor analysis to establish a baseline E-CR factor, and (3) path analysis to predict dementia severity. Baseline age (continuous) and Apolipoprotein E status (ɛ4−/ɛ4+) were included as covariates. Results The association between higher baseline ventricular size and dementia severity was moderated by (1) E-CR and L-CR and (2) CR-P. This association was differentially represented in men and women. Specifically, men in only the low CR-P had higher baseline clinical dementia severity with larger baseline ventricular size. However, women in the low CR-P showed the (1) highest baseline dementia severity and (2) fastest 2-year decline with larger baseline ventricular size. Conclusions Clinical dementia severity associated with ventricular size may be (1) selectively moderated by complex and additive CR networks and (2) differentially represented by sex. Trials registration ClinicalTrials.gov, NCT01800214. Registered on 27 February 2013. Electronic supplementary material The online version of this article (10.1186/s13195-018-0419-2) contains supplementary material, which is available to authorized users.

Background A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. Methods We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. Results The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. Conclusions The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.

The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD.

Introduction Although the apolipoprotein E e4-allele (APOE-e4) is a susceptibility factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored. Methods We studied 298 patients (AD = 250, DLB = 48; 38 autopsy-confirmed; NCT01800214 ) using neuropsychological testing, volumetric magnetic resonance imaging, and APOE genotyping to investigate the association of APOE-e4 with hippocampal volume and learning/memory phenotypes, irrespective of diagnosis. Results Across the AD/DLB spectrum: (1) hippocampal volumes were smaller with increasing APOE-e4 dosage (no genotype × diagnosis interaction observed), (2) learning performance as assessed by total recall scores was associated with hippocampal volumes only among APOE-e4 carriers, and (3) APOE-e4 carriers performed worse on long-delay free word recall. Discussion These findings provide evidence that APOE-e4 is linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum, which could be useful as biomarkers of disease progression in therapeutic trials of mixed disease.

ObjectiveTo determine the relationship between white matter hyperintensities (WMH) presumed to indicate disease of the cerebral small vessels, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease (AD) and other dementias.MethodsWe recruited groups of participants with and without AD, including strata with extensive WMH and minimal WMH, into a cross-sectional proof-of-principle study (n = 118). A consecutive case series from a memory clinic was used as an independent validation sample (n = 702; Sunnybrook Dementia Study; NCT01800214). We assessed WMH volume and left temporal lobe atrophy (measured as the brain parenchymal fraction) using structural MRI and verbal memory using the California Verbal Learning Test. Using path modeling with an inferential bootstrapping procedure, we tested an indirect effect of WMH on verbal recall that depends sequentially on temporal lobe atrophy and verbal learning.ResultsIn both samples, WMH predicted poorer verbal recall, specifically due to temporal lobe atrophy and poorer verbal learning (proof-of-principle −1.53, 95% bootstrap confidence interval [CI] −2.45 to −0.88; and confirmation −0.66, 95% CI [−0.95 to −0.41] words). This pathway was significant in subgroups with (−0.20, 95% CI [−0.38 to −0.07] words, n = 363) and without (−0.71, 95% CI [−1.12 to −0.37] words, n = 339) AD. Via the identical pathway, WMH contributed to deficits in recognition memory (−1.82%, 95% CI [−2.64% to −1.11%]), a sensitive and specific sign of AD.ConclusionsAcross dementia syndromes, WMH contribute indirectly to verbal memory deficits considered pathognomonic of Alzheimer disease, specifically by contributing to temporal lobe atrophy.

Background The Montreal Cognitive Assessment (MoCA) is psychometrically superior over the Mini-mental State Examination (MMSE) for cognitive screening in stroke or transient ischemic attack (TIA). It is free for clinical and research use. The objective of this study is to convert scores from the MMSE to MoCA and MoCA-5-minute protocol (MoCA-5 min) and to examine the ability of the converted scores in detecting cognitive impairment after stroke or TIA. Methods A total of 904 patients were randomly divided into training (n = 623) and validation (n = 281) samples matched for demography and cognition. MMSE scores were converted to MoCA and MoCA-5 min using (1) equipercentile method with log-linear smoothing and (2) Poisson regression adjusting for age and education. Receiver operating characteristics curve analysis was used to examine the ability of the converted scores in differentiating patients with cognitive impairment. Results The mean education was 5.8 (SD = 4.6; ranged 0-20) years. The entire spectrum of MMSE scores was converted to MoCA and MoCA-5 min using equipercentile method. Relationship between MMSE and MoCA scores was confounded by age and education, and a conversion equation with adjustment for age and education was derived. In the validation sample, the converted scores differentiated cognitively impaired patients with area under receiver operating characteristics curve 0.826 to 0.859. Conclusion We provided 2 methods to convert scores from the MMSE to MoCA and MoCA-5 min based on a large sample of patients with stroke or TIA having a wide range of education and cognitive levels. The converted scores differentiated patients with cognitive impairment after stroke or TIA with high accuracy.

Movement is traditionally viewed as a process that involves motor brain regions. However, movement also implicates non-motor regions such as prefrontal and parietal cortex, regions whose integrity may thus be important for motor recovery after stroke. Importantly, focal brain damage can affect neural functioning within and between distinct brain networks implicated in the damage. The aim of this study is to investigate how resting state connectivity (rs-connectivity) within and between motor and frontoparietal networks are affected post-stroke in correlation with motor outcome. Twenty-seven participants with chronic stroke with unilateral upper limb deficits underwent motor assessments and magnetic resonance imaging. Participants completed the Chedoke-McMaster Stroke Assessment as a measure of arm (CMSA-Arm) and hand (CMSA-Hand) impairment and the Action Research Arm Test (ARAT) as a measure of motor function. We used a seed-based rs-connectivity approach defining the motor (seed = contralesional primary motor cortex (M1)) and frontoparietal (seed = contralesional dorsolateral prefrontal cortex (DLPFC)) networks. We analyzed the rs-connectivity within each network (intra-network connectivity) and between both networks (inter-network connectivity), and performed correlations between: a) intra-network connectivity and motor assessment scores; b) inter-network connectivity and motor assessment scores. We found: a) Participants with high rs-connectivity within the motor network (between M1 and supplementary motor area) have higher CMSA-Hand stage (z = 3.62, p = 0.003) and higher ARAT score (z = 3.41, p = 0.02). Rs-connectivity within the motor network was not significantly correlated with CMSA-Arm stage (z = 1.83, p > 0.05); b) Participants with high rs-connectivity within the frontoparietal network (between DLPFC and mid-ventrolateral prefrontal cortex) have higher CMSA-Hand stage (z = 3.64, p = 0.01). Rs-connectivity within the frontoparietal network was not significantly correlated with CMSA-Arm stage (z = 0.93, p = 0.03) or ARAT score (z = 2.53, p = 0.05); and c) Participants with high rs-connectivity between motor and frontoparietal networks have higher CMSA-Hand stage (rs = 0.54, p = 0.01) and higher ARAT score (rs = 0.54, p = 0.009). Rs-connectivity between the motor and frontoparietal networks was not significantly correlated with CMSA-Arm stage (rs = 0.34, p = 0.13). Taken together, the connectivity within and between the motor and frontoparietal networks correlate with motor outcome post-stroke. The integrity of these regions may be important for an individual's motor outcome. Motor-frontoparietal connectivity may be a potential biomarker of motor recovery post-stroke.

For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers’ cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology.

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis.

Background Restless legs syndrome (RLS) is a movement disorder that is associated with poor quality of life and depressive symptoms in the general population. Emerging evidence suggests that RLS is closely associated with cerebrovascular disease. We assessed the effect of RLS on quality of life after stroke and transient ischemic attack (TIA). Methods In this single-center prospective study, we recruited patients within 14 days of high-risk TIA or minor stroke. Patients were diagnosed with RLS using a questionnaire based on the 2003 International RLS Study Group criteria, and diagnoses were confirmed by a sleep neurologist. Follow-up assessments were conducted within 2–6 months of recruitment. The outcome of quality of life was measured using the Stroke-specific Quality of Life (SS-QoL). Results Of the 94 patients recruited into the study, 23 (24.4%) were diagnosed with RLS: 11 were newly diagnosed with RLS and 12 had RLS preceding the index stroke/TIA. There were no significant differences in baseline characteristics between those with or without RLS. Median SS-QoL in patients with RLS was lower at baseline (p = 0.008) and at follow-up (p = 0.002). RLS patients had more depressive symptoms at follow-up (p = 0.007). Ordinal logistic regression demonstrated that RLS was negatively associated with quality of life at baseline (OR = 0.28; p = 0.010) and at follow-up (OR = 0.14; p = 0.029), independent of functional outcome and depressive symptoms. Conclusions RLS is common after stroke or TIA and negatively affects the quality of life. Screening for RLS after cerebrovascular events may be warranted, and future research should assess whether treatment of RLS can improve post-stroke quality of life.

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

Hui Guo,1,2 William Siu,1,3 Ryan CN D’Arcy,1,4 Sandra E Black,5,6 Lukas A Grajauskas,1,4 Sonia Singh,7,8 Yunting Zhang,2 Kenneth Rockwood,9,10 Xiaowei Song1,4,9 On behalf of The Alzheimer’s Disease Neuroimaging Initiative and the National Alzheimer’s Coordinating Center 1Health Sciences and Innovation, ImageTech Laboratory, Fraser Health Authority, Surrey, BC, Canada; 2Department of Diagnostic Imaging, Tianjin Medical University General Hospital, Tianjin, China; 3Department of Medical Imaging, Fraser Health Authority, Surrey, 4Departments of Applied Sciences and Computing Science, Simon Fraser University, Burnaby, BC, 5Department of Medicine (Neurology), 6LC Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre& University of Toronto, Toronto, ON, 7Department of Family Medicine, University of British Columbia, Vancouver, BC, 8Department of Research and Evaluation, Fraser Health, Surrey, BC, 9Department of Medicine (Geriatric Medicine), Dalhousie University, 10Centre for Healthcare of the Elderly, Nova Scotia Health Authority, Halifax, NS, Canada Purpose: One of the central features of brain aging is the accumulation of multiple age-related structural changes, which occur heterogeneously in individuals and can have immediate or potential clinical consequences. Each of these deficits can coexist and interact, producing both independent and additive impacts on brain health. Many of the changes can be visualized using MRI. To collectively assess whole-brain structural changes, the MRI-based Brain Atrophy and Lesion Index (BALI) has been developed. In this study, we validate this whole-brain health assessment approach using several clinical MRI examinations.Materials and methods: Data came from three independent studies: the Alzheimer’s Disease Neuroimaging Initiative Phase II (n=950; women =47.9%; age =72.7±7.4 years); the National Alzheimer’s Coordinating Center (n=722; women =55.1%; age =72.7±9.9 years); and the Tianjin Medical University General Hospital Research database on older adults (n=170; women =60.0%; age =62.9±9.3 years). The 3.0-Tesla MRI scans were evaluated using the BALI rating scheme on the basis of T1-weighted (T1WI), T2-weighted (T2WI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), and T2*-weighted gradient-recalled echo (T2*GRE) images.Results: Atrophy and lesion changes were commonly seen in each MRI test. The BALI scores based on different sequences were highly correlated (Spearman r2>0.69; P0.29; P26.48, P

Background Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. Objective The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. Methods We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Results Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p Conclusions Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

Background:New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders.Methods:This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD). The concepts of social cognition will be reviewed, including its impairment and neural basis, its clinical assessment, and the different therapeutic interventions available clinically.Results:Socially inappropriate behaviors, such as loss of empathy, inappropriateness of affect, and disinhibition are frequently reported in prodromal bvFTD and in prodromal AD. Lack of self-control, reduced perception of social cues, such as recognition of facial emotions and sarcastic speech, and impaired Theory of Mind all contribute to the neuropsychiatric symptoms and are secondary to neurodegeneration in specific brain regions. In contrasts to bvFTD and AD, deficits in social cognition in IPD occur later in the course of the disease and are often multifactorial in origin.Conclusions:Through various manifestations, social inappropriateness is frequently the first clinical sign of a neurodegenerative process, especially in AD and bvFTD, years before noticeable impairment on classical neuropsychological assessment and brain atrophy on imaging.

BACKGROUND Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer's disease may be explained by gender differences in IADL involvement. OBJECTIVE We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve. METHODS We cross-sectionally examined men (n = 502) and women (n = 340) with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women. RESULTS Gender was associated with total FAQ (p

White matter hyperintensities (WMH) are prevalent. Although arteriolar disease has been implicated in their pathogenesis, venous pathology warrants consideration. We investigated relationships of WMH with histologic venous, arteriolar and white matter abnormalities and correlated findings with premortem neuroimaging. Three regions of periventricular white matter were sampled from archived autopsy brains of 24 pathologically confirmed Alzheimer disease (AD) and 18 age-matched nonAD patients. Using trichrome staining, venous collagenosis (VC) of periventricular veins (150 µm in diameter) was scored for severity of wall thickening and occlusion; percent stenosis by collagenosis of large caliber (200 µm) veins (laVS) was measured. Correlations were made between WMH in premortem neuroimaging and vascular and white matter pathology. We found greater VC (U(114) = 2092.5, p = 0.005 and U(114) = 2121.5, p = 0.002 for small and medium caliber veins, respectively) and greater laVS (t(110) = 3.46, p = 0.001) in patients with higher WMH scores; WMH scores correlated with VC (rs(114) = 0.27, p = 0.004) and laVS (rs(110) = 0.38, p 0.001). By multiple linear regression analysis, the strongest predictor of WMH score was laVS (β = 0.338, p 0.0001). VC was frequent in patients with periventricular infarcts identified on imaging. We conclude that periventricular VC is associated with WMH in both AD and nonAD patients and the potential roles of VC in WMH pathogenesis merit further study.