Publications by authors named "Sandra Black"

472 Publications

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

Neurology 2021 Jun 7. Epub 2021 Jun 7.

Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.

Objective: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiological data from a large multicenter consortium of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB).

Methods: Supine and orthostatic blood pressure and structural magnetic resonance imaging data were extracted from PD and DLB patients evaluated at eight tertiary-referral centers in the USA, 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 mmHg with normal sitting blood pressure. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy, as well as WMH were appraised using validated semi-quantitative rating scales.

Results: A 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 medio-temporal (p=0.001) regions, greater in severe vs. non-severe 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).

Conclusions: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH were associated with WMH.
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http://dx.doi.org/10.1212/WNL.0000000000012342DOI Listing
June 2021

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses.

Neurobiol Aging 2021 Apr 24. Epub 2021 Apr 24.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.011DOI Listing
April 2021

nnResting state fMRI scanner instabilities revealed by longitud inal phantom scans in a multi-center study.

Neuroimage 2021 May 21;237:118197. Epub 2021 May 21.

Rotman Research Institute, University of Toronto, Toronto, ON, Canada; Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address:

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118197DOI Listing
May 2021

MRI-visible perivascular space volumes, sleep duration and daytime dysfunction in adults with cerebrovascular disease.

Sleep Med 2021 Jul 19;83:83-88. Epub 2021 Apr 19.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Department of Medicine (Neurology), Sunnybrook Health Sciences Centre and University of Toronto, ON, Canada.

Objectives: Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible PVS volumes, a putative marker of perivascular dysfunction, are associated with compensatory differences in real-world human sleep behavior.

Methods: We analyzed data from 152 cerebrovascular disease patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). PVS volumes were measured using 3T-MRI. Self-reported total sleep time, time in bed, and daytime dysfunction were extracted from the Pittsburgh Sleep Quality Index.

Results: Individuals with greater PVS volumes reported longer time in bed (+0.85 h per log10 proportion of intracranial volume (ICV) occupied by PVS, SE = 0.30, p = 0.006) and longer total sleep times (+0.70 h per log10 proportion of ICV occupied by PVS volume, SE = 0.33, p = 0.04), independent of vascular risk factors, sleep apnea, nocturnal sleep disturbance, depression, and global cognitive status. Further analyses suggested that the positive association between PVS volumes and total sleep time was mediated by greater time in bed. Moreover, despite having on average greater total sleep times, individuals with greater basal ganglia PVS volumes were more likely to report daytime dysfunction (OR 5.63 per log10 proportion of ICV occupied by PVS, 95% CI: 1.38-22.26, p = 0.018).

Conclusions: Individuals with greater PVS volumes spend more time in bed, resulting in greater total sleep time, which may represent a behavioral compensatory response to perivascular space dysfunction.
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http://dx.doi.org/10.1016/j.sleep.2021.03.043DOI Listing
July 2021

Exploratory Assessment of K-means Clustering to Classify 18F-Flutemetamol Brain PET as Positive or Negative.

Clin Nucl Med 2021 Apr 20. Epub 2021 Apr 20.

From the Department of Medicine and Radiology, McMaster University, Hamilton LC Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada Departments of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona Cancer Center, University of Arizona, Tucson, AZ Adult Neurodevelopmental and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, University of Toronto Department of Psychiatry, University of Toronto Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto Krembil Brain Institute, University Health Network Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and the University of Toronto University Health Network Memory Clinic, Toronto Western Hospital, University of Toronto Baycrest Health Sciences Rotman Research Institute of Baycrest Centre Department of Medicine (Neurology), Mt Sinai Hospital Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Ontario, Canada.

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.
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http://dx.doi.org/10.1097/RLU.0000000000003668DOI Listing
April 2021

In vivo detection of beta-amyloid at the nasal cavity and other skull-base sites: a retrospective evaluation of ADNI1/GO.

Ann Nucl Med 2021 Jun 12;35(6):728-734. Epub 2021 Apr 12.

Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, M4N 3M5, Canada.

Introduction: Amyloid beta (Aβ) is partially cleared from the CSF via skull base perivascular and perineural lymphatic pathways, particularly at the nasal cavity. In vivo differences in Aβ level at the nasal cavity between patients with Alzheimer's disease (AD), subjects with mild cognitive impairment (MCI) and cognitively normal (CN) individuals have not been previously assessed.

Methods: This is a retrospective evaluation of subject level data from the ADNI-1/GO database. Standardized uptake value ratio (SUVR) maximum on C-Pittsburgh compound-B (PiB)-PET was assessed at the nasal cavity on 223 scans. Exploratory ROI analysis was also performed at other skull base sites. SUVR maximum values and their differences between groups (CN, MCI, AD) were assessed. CSF Aβ levels and CSF Aβ 42/40 ratios were correlated with SUVR maximum values.

Results: 103 subjects with 223 PiB-PET scans (47 CN, 32 AD and 144 MCI) were included in the study. The SUVR maxima at the nasal cavity were significantly lower in subjects with AD [1.35 (± 0.31)] compared to CN [1.54 (± 0.30); p = 0.024] and MCI [1.49 (± 0.33); p = 0.049]. At very low CSF Aβ, less than 132 pg/ml, there was significant correlation with nasal cavity SUVR maximum. The summed averaged SUVR maximum values were significantly lower in subjects with AD [1.35 (± 0.16)] compared to CN [1.49 (± 0.17); p = 0.003] and MCI [1.40 (± 0.17); p = 0.017].

Conclusion: Patients with AD demonstrate reduced nasal cavity PiB-PET radiotracer uptake compared to MCI and CN, possibly representing reduced Aβ clearance via perineural/perivascular lymphatic pathway. Further work is necessary to elucidate the true nature of this finding.
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http://dx.doi.org/10.1007/s12149-021-01614-7DOI Listing
June 2021

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

J Alzheimers Dis 2021 ;80(3):1119-1128

Baycrest Health Sciences, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.3233/JAD-200620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150498PMC
January 2021

Non-invasive brain stimulation as add-on therapy for subacute post-stroke aphasia: a randomized trial (NORTHSTAR).

Eur Stroke J 2020 Dec 30;5(4):402-413. Epub 2020 Jun 30.

Jewish General Hospital, Lady Davis Institute for Medical Research, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec.

Introduction: Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia.

Patients And Methods: Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01-2014/03-2018) and randomized to receive rTMS ( = 20), ctDCS ( = 24) or sham stimulation ( = 19) with ST for 10 days. Primary outcome variables were -score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca's area or not).

Results: Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/=.01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca's area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/=.062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca's area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/=.053) versus NIBS (median = 12.7%/interquartile range = 31.7). We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-stroke aphasia. This intervention may be beneficial only in patients with morphologically intact Broca's area.
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http://dx.doi.org/10.1177/2396987320934935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856587PMC
December 2020

Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study.

Alzheimers Dement 2021 Feb 16. Epub 2021 Feb 16.

Gait and Brain Lab, Parkwood Institute, Lawson Health Research Institute, London, Ontario, Canada.

Introduction: Gait impairment is common in neurodegenerative disorders. Specifically, gait variability-the stride-to-stride fluctuations in distance and time-has been associated with neurodegeneration and cognitive impairment. However, quantitative comparisons of gait impairments across the cognitive spectrum of dementias have not been systematically investigated.

Methods: Older adults (N = 500) with subjective cognitive impairment, Parkinson disease (PD), mild cognitive impairment (MCI), PD-MCI, Alzheimer's disease (AD), PD-dementia, Lewy body dementia, and frontotemporal dementia, as well cognitive normal controls, who were assessed for their gait and cognitive performance.

Results: Factor analyses grouped 11 quantitative gait parameters and identified four independent gait domains: rhythm, pace, variability, and postural control, for group comparisons and classification analysis. Among these domains, only high gait variability was associated with lower cognitive performance and accurately discriminated AD from other neurodegenerative and cognitive conditions.

Discussion: Our findings indicate that high gait variability is a marker of cognitive-cortical dysfunction, which can help to identify Alzheimer's disease dementia.
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http://dx.doi.org/10.1002/alz.12298DOI Listing
February 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer's disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status.

Alzheimers Res Ther 2021 02 11;13(1):43. Epub 2021 Feb 11.

Department of Pharmacology & Toxicology Room 4207, University of Toronto, Medical Sciences Building 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.

Background: The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition.

Methods: Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers.

Results: Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers.

Conclusions: Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.
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http://dx.doi.org/10.1186/s13195-021-00778-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876820PMC
February 2021

Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs.

Neuroinformatics 2021 Feb 1. Epub 2021 Feb 1.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N = 528 subjects for ICV, N = 501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer, DeepMedic), as well as two ventricular segmentation tools (FreeSurfer, DeepMedic). Our multi-contrast models outperformed other methods across many of the evaluation metrics, with average Dice coefficients of 0.98 and 0.96 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.
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http://dx.doi.org/10.1007/s12021-021-09510-1DOI Listing
February 2021

Vascular Contributions to Neurodegeneration: Protocol of the COMPASS-ND Study.

Can J Neurol Sci 2021 Jan 28:1-8. Epub 2021 Jan 28.

Department of Medicine (Neurology), Hurvitz Brain Sciences Research Program, LC Campbell Cognitive Neurology Unit, Canadian Partnership for Stroke Recovery, University of Toronto, London, Ontario, Canada.

Objective: To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants.

Methods: COMPASS-ND includes persons with Alzheimer's disease (AD; n = 150), Parkinson's disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c.

Results: Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%-40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent.

Conclusion: COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.
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http://dx.doi.org/10.1017/cjn.2021.19DOI Listing
January 2021

Associations between brain amyloid accumulation and the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.

Neurobiol Aging 2021 04 16;100:22-31. Epub 2020 Dec 16.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Toronto, Ontario, Canada; KITE - Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

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 F-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 ε4 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.12.011DOI Listing
April 2021

Canadian Platform for Trials in Noninvasive Brain Stimulation (CanStim) Consensus Recommendations for Repetitive Transcranial Magnetic Stimulation in Upper Extremity Motor Stroke Rehabilitation Trials.

Neurorehabil Neural Repair 2021 02;35(2):103-116

McGill University, Montreal, Quebec, Canada.

. To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. . The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. . Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. . Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. . The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.
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http://dx.doi.org/10.1177/1545968320981960DOI Listing
February 2021

Cortical Thickness Estimation in Individuals With Cerebral Small Vessel Disease, Focal Atrophy, and Chronic Stroke Lesions.

Front Neurosci 2020 14;14:598868. Epub 2020 Dec 14.

LC Campbell Cognitive Neurology Research, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

Background: Regional changes to cortical thickness in individuals with neurodegenerative and cerebrovascular diseases (CVD) can be estimated using specialized neuroimaging software. However, the presence of cerebral small vessel disease, focal atrophy, and cortico-subcortical stroke lesions, pose significant challenges that increase the likelihood of misclassification errors and segmentation failures.

Purpose: The main goal of this study was to examine a correction procedure developed for enhancing FreeSurfer's (FS's) cortical thickness estimation tool, particularly when applied to the most challenging MRI obtained from participants with chronic stroke and CVD, with varying degrees of neurovascular lesions and brain atrophy.

Methods: In 155 CVD participants enrolled in the Ontario Neurodegenerative Disease Research Initiative (ONDRI), FS outputs were compared between a fully automated, unmodified procedure and a corrected procedure that accounted for potential sources of error due to atrophy and neurovascular lesions. Quality control (QC) measures were obtained from both procedures. Association between cortical thickness and global cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) score was also investigated from both procedures.

Results: Corrected procedures increased "Acceptable" QC ratings from 18 to 76% for the cortical ribbon and from 38 to 92% for tissue segmentation. Corrected procedures reduced "Fail" ratings from 11 to 0% for the cortical ribbon and 62 to 8% for tissue segmentation. FS-based segmentation of T1-weighted white matter hypointensities were significantly greater in the corrected procedure (5.8 mL vs. 15.9 mL, < 0.001). The unmodified procedure yielded no significant associations with global cognitive status, whereas the corrected procedure yielded positive associations between MoCA total score and clusters of cortical thickness in the left superior parietal ( = 0.018) and left insula ( = 0.04) regions. Further analyses with the corrected cortical thickness results and MoCA subscores showed a positive association between left superior parietal cortical thickness and Attention ( < 0.001).

Conclusion: These findings suggest that correction procedures which account for brain atrophy and neurovascular lesions can significantly improve FS's segmentation results and reduce failure rates, thus maximizing power by preventing the loss of our important study participants. Future work will examine relationships between cortical thickness, cerebral small vessel disease, and cognitive dysfunction due to neurodegenerative disease in the ONDRI study.
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http://dx.doi.org/10.3389/fnins.2020.598868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768006PMC
December 2020

Depression and Diabetes Mellitus Multimorbidity Is Associated With Loss of Independence and Dementia Poststroke.

Stroke 2020 12 14;51(12):3531-3540. Epub 2020 Oct 14.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON (M.O., C.-Y.W., J.C.-M., N.H., K.L.L., E.L., R.H.S., S.E.B., B.J.M., W.S.).

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=5.4; =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=1.57 [1.24-1.98]) and incident dementia (aHR=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=1.20 [1.12-1.29]; aHR=1.19 [1.04-1.37]), incident dementia (aHR=1.14 [1.06-1.23]; aHR=1.27 [1.08-1.49]), stroke/transient ischemic attack readmission (aHR=1.18 [1.10-1.26]; aHR=1.24 [1.07-1.42]), and all-cause mortality (aHR=1.29 [1.23-1.36]; aHR=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.
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http://dx.doi.org/10.1161/STROKEAHA.120.031068DOI Listing
December 2020

Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)5: Guidelines for management of vascular cognitive impairment.

Alzheimers Dement (N Y) 2020 11;6(1):e12056. Epub 2020 Nov 11.

Department of Medicine (Neurology) Hurvitz Brain Sciences Research Program LC Campbell Cognitive Neurology Unit Canadian Partnership for Stroke Recovery University of Toronto Toronto Canada.

Introduction: Vascular disease is a common cause of dementia, and often coexists with other brain pathologies such as Alzheimer's disease to cause mixed dementia. Many of the risk factors for vascular disease are treatable. Our objective was to review evidence for diagnosis and treatment of vascular cognitive impairment (VCI) to issue recommendations to clinicians.

Methods: A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed areas of emerging evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assign the quality of the evidence and strength of the recommendations.

Results: Using standardized diagnostic criteria, managing hypertension to conventional blood pressure targets, and reducing risk for stroke are strongly recommended. Intensive blood pressure lowering in middle-aged adults with vascular risk factors, using acetylsalicylic acid in persons with VCI and covert brain infarctions but not if only white matter lesions are present, and using cholinesterase inhibitors are weakly recommended.

Conclusions: The CCCDTD has provided evidence-based recommendations for diagnosis and management of VCI for use nationally in Canada, that may also be of use worldwide.
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http://dx.doi.org/10.1002/trc2.12056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657196PMC
November 2020

Diabetes, Brain Infarcts, Cognition, and Small Vessels in the Canadian Alliance for Healthy Hearts and Minds Study.

J Clin Endocrinol Metab 2021 Jan;106(2):e891-e898

Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.

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.
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http://dx.doi.org/10.1210/clinem/dgaa815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823245PMC
January 2021

Feasibility of unattended home sleep apnea testing in a cognitively impaired clinic population.

J Clin Sleep Med 2021 Mar;17(3):435-444

L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada.

Study Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.5664/jcsm.8918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927336PMC
March 2021

Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.

BMJ Open 2020 10 14;10(10):e040466. Epub 2020 Oct 14.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

Introduction: Cerebral small vessel disease (cSVD) accounts for 20%-25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.

Methods And Analysis: This prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60-85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13-24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.

Ethics And Dissemination: Research Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.

Trial Registration Number: NCT04109963.
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http://dx.doi.org/10.1136/bmjopen-2020-040466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559076PMC
October 2020

Machine Learning in Nuclear Medicine: Part 2-Neural Networks and Clinical Aspects.

J Nucl Med 2021 01 25;62(1):22-29. Epub 2020 Sep 25.

Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

This article is the second part in our machine learning series. Part 1 provided a general overview of machine learning in nuclear medicine. Part 2 focuses on neural networks. We start with an example illustrating how neural networks work and a discussion of potential applications. Recognizing that there is a spectrum of applications, we focus on recent publications in the areas of image reconstruction, low-dose PET, disease detection, and models used for diagnosis and outcome prediction. Finally, since the way machine learning algorithms are reported in the literature is extremely variable, we conclude with a call to arms regarding the need for standardized reporting of design and outcome metrics and we propose a basic checklist our community might follow going forward.
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http://dx.doi.org/10.2967/jnumed.119.231837DOI Listing
January 2021

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease.

Transl Stroke Res 2021 02 16;12(1):15-30. Epub 2020 Sep 16.

Brain Research Imaging Centre, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.
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http://dx.doi.org/10.1007/s12975-020-00843-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803876PMC
February 2021

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures.

Front Neurol 2020 11;11:847. Epub 2020 Aug 11.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.
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http://dx.doi.org/10.3389/fneur.2020.00847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431907PMC
August 2020

Thickness of the cerebral cortex shows positive association with blood levels of triacylglycerols carrying 18-carbon fatty acids.

Commun Biol 2020 08 20;3(1):456. Epub 2020 Aug 20.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1038/s42003-020-01189-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441395PMC
August 2020

Variation in the hemostatic complement (C5a) responses to in vitro nitrogen bubbles in monodontids and phocids.

J Comp Physiol B 2020 11 20;190(6):811-822. Epub 2020 Aug 20.

Mystic Aquarium, a Division of SeaResearch Inc., Mystic, CT, 06355, USA.

Immune responses to nitrogen gas bubbles, particularly activation of inflammation via the complement cascade, have been linked to the development of symptoms and damage associated with decompression sickness (DCS) in humans. Marine mammals were long thought not to be susceptible to such dive-related injury, yet evidence of DCS-like injury and new models of tissue nitrogen super-saturation suggest that bubbles may routinely form. As such, it is possible that marine mammals have protective adaptations that allow them to deal with a certain level of bubble formation during normal dives, without acute adverse effects. This work evaluated the complement response, indicative of inflammation, to in vitro nitrogen bubble exposures in several marine mammal species to assess whether a less-responsive immune system serves a protective role against DCS-like injury in these animals. Serum samples from beluga (Delphinapterus leucas), and harbor seals (Phoca vitulina) (relatively shallow divers) and deep diving narwhal (Monodon monoceros), and Weddell seals (Leptonychotes weddellii) were exposed to nitrogen bubbles in vitro. Complement activity was evaluated by measuring changes in the terminal protein C5a in serum, and results suggest marine mammal complement is less sensitive to gas bubbles than human complement, but the response varies between species. Species-specific differences may be related to dive ability, and suggest moderate or shallow divers may be more susceptible to DCS-like injury. This information is an important consideration in assessing the impact of changing dive behaviors in response to anthropogenic stressors, startle responses, or changing environmental conditions that affect prey depth distributions.
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http://dx.doi.org/10.1007/s00360-020-01297-yDOI Listing
November 2020

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status.

Alzheimers Dement 2020 12 16;16(12):1663-1673. Epub 2020 Aug 16.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/alz.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754496PMC
December 2020

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

Alzheimers Dement 2020 11 12;16(11):1571-1581. Epub 2020 Aug 12.

Department of Geriatric Medicine Peninsula Health, Peninsula Clinical School, Monash University, Clayton, Victoria, Australia.

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.
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http://dx.doi.org/10.1002/alz.12143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436526PMC
November 2020