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1. Peripheral Oxidative Stress Markers Are Related To Vascular Risk Factors And Subcortical Small Vessel Disease

Author

Warrick, N., Seitz, D., Prorok, J., Shawcross, D., Mahootchi, T., Esensoy, A., Yu, D., Danieli, E., Pushpakumar, D., Tony, J., Jacob, K., Dong, J., Javed, F., D’Souza, A., Mollayeva, T., Colantonio, A., Schulz, M., Burhan, A., Naidu, A. Srinivasan, Sarquis-Adamson, Y., Montero-Odasso, M., Cooper, N., Sekhon, H., Launay, C., Allali, G., Chabot, J., Beauchet, O., Watson, B., Lin, T., Korczak, A., Bartha, C., Best, S., Truemner, J., Borrie, M., Cammer, A., Whiting, S., Morgan, D., Newman, K., Duong, J. A., Mok, A., Wang, A. H., Lavoie, M., Bier, N., Macoir, J., Adlimoghaddam, A., Turner, R. S., Cadonic, C., Albensi, B. C., Davis, J., Lewis, V.-L., Pacione, J., Skanes, C., Feltz, N., Loncar, A., Naglie, G., Sanford, S., Stasiulis, E., Rapoport, M., Vrkljan, B., Tuokko, H., Porter, M., Polgar, J., Moorhouse, P., Mazer, B., Marshall, S., Gelinas, I, Crizzle, A, Belchior, P., Bedard, M, Kokorelias, K., Cameron, J., Gignac, M., Bechard, L., Beaton, D., McGilton, K.A., Tartaglia, M. C., Black, S., Mirza, S., Mutsaerts, H.-J., Cash, D., Bocchetta, M., Thomas, D., Dick, K., van Swieten, J., Borroni, B., Galimberti, D., Rowe, J., Bethell, J., Pringle, D., Commisso, E., Chambers, L., Cohen, C., Cowan, K., Fehr, P., Szeto, P., McGilton, K., Shaw, C., Okamura, H., Otani, M., Shimoyama, N., Fujii, T., Lusk, J., Punzalan, M., Dove, E., Cotnam, K., Astell, A., Chow, A. Froehlich, Bayly, M., Kosteniuk, J., Elliot, V., O’Connell, M. E., Kirk, A., Stewart, N., Holroyd-Leduc, J., Daku, J., Kennett-Russill, D., Hack, T., Dilara, A., Astell, A. J., Hernandez, A., Divine, A., Hunter, S., Jacova, C., Alexander, C., Joseph, J. T., Alvarez, A., Smith, E., Woo, S. M. S., Chan, P., Wilkins-Ho, M., Blackburn, P., Fernando, N., Mehra, A., Vasser, E., Musacchio, M., Waxman, R., Fischler, I., Ghaffar, O., DeBay, D. R., Macdonald, I. R., Reid, G. A., Pottie, I. R., Maxwell, S. P., Cash, M. K., Martin, E., Bowen, C. V., Darvesh, S., MacPhee, J., Jorgensen, M., Fogarty, J., Phillips, N., Diprospero, C., Parent, A., Whitehead, V., Campbell, T., Mohades, Z., Chertkow, H., Wong, S., Wilchesky, M., McCusker, J., Champoux, N., Vu, T.T. M., Ciampi, A., Monette, J., Lungu, O., Ballard, S. A., Belzile, E., Carmichael, P.-H., Voyer, P., Cetin-Sahin, D., Gore, B., Peretti, M., Gore, G., Landry, V., Yetman, L., MacDonald, E., McGibbon, C., MacNeil, D., Jarrett, P., Iaboni, A., Andrews, J., Hafezi, S., Marshall, C., Tsokas, M., Martin, L. Schindel, Van Ooteghem, K., Mansfield, A., Marcil, M., Gold, D., Musselman, K., Flint, A., Finger, E., Feldman, H., Cummings, J., Coleman, K., Boxer, A., Berry, S., Hsiung, R., Curtis, A., Zhang, K., Davidson, H. R., Boccone, G., Camicioli, R., Masellis, M., Tierney, M., Dolatabadi, E., Taati, B., Jonas-Simpson, C., Donovan, L., Cross, N., Keren, R., Shan, R., Holley, J., Waisman, Z., Katchaluba, J., Wimhurst, C., Steele, M., Loganathan, P., Gural, P., Shearer, T., Reardon, J., Pilgrim, J., Pitawanakwat, K., Jones, L., Piriano, E., Blind, M., Otowadjiwan, J., Makela, R., Spicer, B., Bretzlaff, M., Jacklin, K., McKay, Kristy, Graham, N., Tang-Wai, D., Leonard, C., Mitchell, S., Laird, L., Rochon, E., Maclagan, L., Maxwell, C., Guan, J., Campitelli, M., Herrmann, N., Lapane, K., Hogan, D., Amuah, J., Gill, S., Bronskill, S., Ebert, P., Kwok, J., Watt, A., Garrett, S., Hoefling, L., Ellery, C., Leggieri, M., Fornazzari, L., Thaut, M., Munoz, D., Barfett, J., Fischer, C., Schweizer, T., Yogaparan, T., Dallaire-Théroux, C., Potvin, O., Dieumegarde, L., Duchesne, Simon, Amini, A.E. Ebrahim, Amini, A.Z. Ebrahim, Dao, E., Barha, C. K., Best, J. R., Hsiung, G.-Y. R., Tam, R., Liu-Ambrose, T., Sztramko, R., Wurster, A., Papaiouannou, A., Cowan, D., St. Onge, J., Allaby, C., Harrison, L., Cimino, C., Marr, S., Patterson, C., Woo, T., Levinson, A., Fisher, S., Mojaverian, N., Hsu, A., Taljaard, M., Manuel, D., Tanuseputro, P., Park, E., Liu, L., VanderPloeg, K., Black, A., Bartha, R., Rabin, J., Yang, H.-S., Schultz, A., Hanseeuw, B., Marshall, G., Hedden, T., Rentz, D., Johnson, K., Sperling, R., Chhatwal, J., Desmarais, P., Miville, C., Keith, J., Lanctôt, K., Thomas, N., Mattek, N., Riley, T., Witter, P., Reynolds, C., Austin, J., Sharma, N., Kaye, J., Bechard, L. E., Mitchell, C. M., Regan, K., Bergelt, M. D., Middleton, L.E., Hewston, P., Kennedy, C., Merom, D., Trainor, L., Grenier, A., Ioannidis, G., Lee, J., Papaioannou, A., Qian, W., Churchill, N., Kumar, S., Rajji, T., Ojeda-López, C., Milán-Tomás, Á., Lam, B., Gao, F. Q., Cumberbatch, S., Gies, S., Tomas, A. Milan, Ojeda-Lopez, C., Lim, A. S., Black, S. E., Sharma, M. J., Ramirez, J., Holmes, M. F., Gao, F., Varatharajah, B., Yhap, V., Appel, L., Bogler, O., Appel, E., Wiseman, M., Cohen, L., Hill, D., Abrams, H., Campos, J., Sapkota, S., Adamo, S., Stuss, D. T., Martinez, M., Multani, N., Anor, C. J., Fox, S., Lang, A. E., Marras, C., Compagnone, J., Li, J., Freedman, M., Kleiner-Fisman, G., Kennedy, J., Chen, R., Lang, A., Sévigny-Dupont, P., Bocti, C., Joannette, M., Lavallée, M. M., Joubert, S., Knoefel, F., Goubran, R., Baker, A., Fraser, S., Allard, B., Wallace, B., Stroulia, E., Guana, V., Masson, P., Alli, S., Kolla, N., De Luca, V., Bouvier, L., Monetta, L., Vitali, P., Laforce, R., Martel-Sauvageau, V., Talebzadeh, A., Ashourinia, K., Moy, S., Lake, A., Cockburn, A., Krisman, D., Sadasivan, B., Sit, W., Stoops, S., McCurbin, S., Cullen, S., Carroll, S., Tasmim, S., Kapoor, E., Callahan, B., Sharma, M., Bierstone, D., Stuss, D., Kapadia, M., Mian, F., Ma, D., Rosa, E., Michalski, B., Zovkic, I., Forsythe, P., Sakic, B., Fahnestock, M., Baxter, J., Peloso, S., Tung, J., Cox, L., Benjamin, S., An, H., Ho, J., Turcotte, V., Parent, C., Gauthier-Beaupré, A., Biss, R., Sultana, A., Chu, C. H., Sun, W., Bartfay, E., Smye, V., Newton, D., Pepin, M., Biswas, S., Madahey, H., Crawford, S. J., Gutmanis, I., Blake, C., Duchesne, S., Hudon, C., Mah, L., Ali, A., Shorey, C., Szabuniewicz, C. M., Anderson, N. D., Verhoeff, N. P. L. G., Cheers, S., Penko, M., Gevaert, V., Yang, Y., Law, J., Modarresi, S., Grahn, J., Overend, T., Amini, D., Thiruparanathan, T., Cheung, T., Iskandar, S., Arone, Y., Young, C., Berezuk, C., and Zakzanis, K.

Subjects
Abstracts
Published
2018

2. Predicting Alzheimer’s Disease Development: a Comparison of Cognitive Criteria and Associated Neuroimaging Biomarkers

Author

Fischer, C., Qian, W., Schweizer, T., Millikin, C., Ismail, Z., Smith, E., Lix, L., Shelton, P., Munoz, D., Callahan, B., Ramirez, J., Berezuk, C., Duchesne, S., Black, S., Johnston, A., Kelly, S., Bai, A., Chen, L., Wells, G., Kotb, A., Skidmore, B., Gomes., T., Warren, L., Qiyun, S., Young, K., Borenstein, A., Martiniuk, A., Saeed, U., Yu, Q., McIntosh, B., Herrmann, N., Rogaeva, E., and Masellis, M.

Subjects
Abstracts, Oral Abstracts, Geriatrics and Gerontology, Gerontology
Abstract

Background/Objectives: Psychosis (delusions or hallucinations) is a common clinical feature in patients with Alzheimer’s disease (AD), and is estimated to affect up to half of this patient population. Psychosis is associated with increased cognitive and functional decline as well as greater caregiver burden. However, lack of understanding of the pathobiological mechanisms behind psychosis limits our ability to manage and treat these symptoms. The current literature is mixed, with some studies showing a correlation between psychosis and Alzheimer pathology, while others find no such association. Using data from the large National Alzheimer’s Coordinating Center (NACC) database, we aimed to determine the demographic, clinical, and neuropathological features associated with psychotic symptoms, separated into delusions and/or hallucinations, in patients who were clinically or neuropathologically diagnosed with AD. Methods: All data were obtained from the NACC database. Our sample of consisted of 1073 subjects broken down into: 1) 890 clinically diagnosed AD (cAD) patients with neuro-pathology data, and 2) 728 neuropathologically confirmed AD (npAD) patients based on the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria of “definite” AD with any clinical diagnosis. The two groups overlapped, but each was reviewed separately. Delusions and hallucinations were identified by the delusional and hallucinatory sub-scores of the Neuropsychiatric Inventory (NPI-Q), respectively. Results: Over one-third of our AD subjects (cAD and npAD) had psychotic symptom(s) during the course of their illness. There were no apparent differences between patients with psychosis (cAD+P n=307; npAD+P n=271) and without psychosis (cAD-P n=583; npAD-P n=457), defined globally, on functional (FAQ) and cognitive outcomes (MMSE, global CDR). However, further breakdown by psychotic symptoms showed that patients with hallucinations (cAD+H n=57; npAD+H n=52) were more severely cognitively and functionally impaired at the last visit prior to death, while patients with delusions (cAD+D n=164; npAD+D n=140) were less impaired than non-psychotic patients, consistent across both cAD and npAD groups. We found that, in the cAD group, psychosis was associated with greater levels of plaques and tangles, but this association was not present in the npAD group. Lewy body pathology, sub-cortical arteriosclerotic leukoencephalopathy (SAL) and vascular risk factors, particularly a history of hypertension and diabetes, were associated with psychotic symptoms in both the cAD and npAD groups. Conclusion: Markers of AD pathology (plaques, tangles) are associated with psychotic symptoms in clinically diagnosed AD patients. However, in neuropathologically confirmed AD patients, AD pathology does not correlate with psychotic symptoms, suggesting that the association in the clinical group is driven by misdiagnosis. Instead, in the neuropathologically confirmed AD group, psychosis is associated with Lewy body pathology, vascular risk factors, and vascular pathology. The findings suggest that modifiable factors such as vascular pathology may play a role in psychosis in AD., Background: There exist multiple criteria for identifying mild cognitive impairment (MCI) (Albert et al., 2011; APA, 2013; Petersen, 2004). All require the presence of “objective impairment” in ≥1 cognitive domains, typically including memory. These criteria have been crucial in conceptualizing MCI. However, to improve their ability to assess dementia risk, four critical issues remain. First, it is unclear which cut-off on normative tests should be used to operationalize cognitive impairment. Second, no criteria specify how many measures of a cognitive domain should be administered. Third, it is unclear which domain(s) should be assessed in addition to memory, if any, to determine dementia risk. Fourth, although current guidelines (Albert et al., 2011) emphasize the importance of considering biomarkers, it is unclear how these inform dementia risk above and beyond cognitive testing. This study aims to determine whether prediction of dementia is improved by: 1) using different cut-off scores on standardized tests to define cognitive impairment; 2) assessing memory using one or two tests; 3) considering non-memory domains; and 4) accounting for genetic and image-based anatomical biomarkers. Methods: Non-demented seniors from the Alzheimer’s Disease Neuroimaging Initiative (N=494) underwent cognitive assessment for global function (Mini-Mental State Exam [MMSE]), memory (Logical Memory Story A Delayed Recall [LM-II], Rey Auditory Verbal Learning Test Delayed Recall [AVLT]), language (Category Fluency, Boston Naming Test), and executive functions (Trails A & B). Standardized scores were calculated based on age-adjusted norms. Biomarkers included brain parenchymal fraction (BPF), ventricular cerebrospinal fluid, hippocampal (HP) and white matter hyperintensity volumes, obtained via automated processing, and APOEε4 status. The presence of AD at 24 months was defined as: 1) MMSE 0.75 were entered into logistic regression analyses, with age, sex, education, and MMSE in a first block. The second and third blocks included non-memory tests and biomarkers, respectively. Results: The most accurate cut-off for predicting dementia at 24-months was ≤ −1 SD on two memory tests (76.92% accuracy; AUC=.788). In addition to this cut-off, dementia was associated with the presence of two APOEε4-positive alleles (B=1.15, SE=0.45, p=.011). The second most accurate cut-off was ≤ −1.5 SD on one test (68.02% accuracy; AUC=.765). In addition to this cut-off, dementia was associated with HP volume (B=−4.84, SE=2.43, p=.047), BPF (B=−15.97, SE=7.58, p=.035), and presence of one (B=0.60, SE=0.29, p=.042) or two APOEε4-positive alleles (B=1.08, SE=0.45, p =.017). Conclusions: Prediction of dementia is improved by defining cognitive impairment as performance ≤ −1 SD on two memory tests. Clinicians or researchers administering one test should opt for a more stringent cut-off (≤−1 SD) and analyze available imaging data, particularly whole-brain and hippocampal volumes. When feasible, ascertaining APOEε4 status can further improve prediction., Background: Dementia is characterized by a progressive decline in cognitive ability and memory resulting in an impaired ability to function independently. Behavioural and psychological symptoms of dementia (BPSD) (e.g., psychosis, agitation/aggression) are common and constitute a major component of all dementia sub-types. These symptoms are often distressful to caregivers, and are a leading cause of long-term-care placement. A variety of drugs are used on and off-label for adults with BPSD who are unresponsive to behavioural or caregiver support. Indeed, choosing the “right” medication involves complex treatment decisions. Atypical antipsychotics (AAPs) are commonly used to manage symptoms of dementia; however, their use is controversial, given their limited benefits as demonstrated in placebo trials, along with a high risk of treatment emergent adverse events—particularly among elderly adults. Objective: To identify, synthesize, and appraise the available randomized comparative evidence on the efficacy and safety of AAPs among community and long-term care–dwelling elderly patients with BPSD. Methods: A systematic review and Bayesian network meta-analysis. Randomized controlled trials (RCT) were included if they had at least 10 participants (mean age ≥ 65 years) diagnosed with dementia who were experiencing BPSD at baseline. Patients could be treated with any dose of 9 eligible AAP medications. Studies that compared an AAP to placebo, another AAP, or any active comparator were considered. To build the evidence base, we identified two high quality evidence syntheses that met our inclusion requirements. Two reviewers then screened the full text of their included studies for eligibility. To augment this evidence, a systematic literature search strategy was carried out in MEDLINE, EMBASE, PsychInfo, and the Cochrane Central Register of Controlled Trials (January 2009 to October 2014), along with a search for grey literature. Two reviewers screened titles/abstracts, reviewed full-text, extracted data, and carried out a critical appraisal using the Cochrane Risk of Bias tool. All eligible studies were included; however, data were only extracted from studies reporting outcomes of interest (5 efficacy, 4 safety). Results: We included 37 unique RCTs published between 1995 and 2014, with 32 reporting outcomes of interest. On average, caregiver burden was reduced in patients who took olanzapine, risperidone, or quetiapine compared to placebo; however, the reductions were modest and not statistically significant. Similar results were found among patients living in long-term-care facilities. There were no significant differences between the AAPs and placebo, or among the AAPs, in reducing overall BPSD or individual symptom scores. We found a significantly higher risk of all-cause mortality associated with the use of any AAP relative to placebo (OR 1.9, 95% Crl 1.19, 3.16). There were, however, no significant differences in mortality between individual AAPs. Sensitivity analyses revealed similar results for community and long-term-care dwellers. Many studies (43%) had small sample size (< 100 participants) and the quality of the reporting of trials varied. Conclusions: Evidence suggests a modest benefit from the use of AAPs among elderly patients with BPSD. Given the increased risk of death, clinical judgment is required when applying these research findings to every day practice., Background: Indigenous populations may be at increased risk, compared with majority populations, for the development of dementia due to lower education levels and socioeconomic status, higher rates of diabetes, hypertension, cardiovascular disease and alcohol abuse, an aging population structure, and poorer overall health. This is the first systematic review investigating the prevalence and incidence of dementia in Indigenous populations worldwide. Methods: This systematic review was conducted in accordance with PRISMA guidelines. We searched MEDLINE, Embase, PsycInfo, and grey literature for relevant articles published up to April 2015. Studies were included if they reported prevalence or incidence, the disease typically occurred after the age of 45, the study population included Indigenous people, and the study was conducted in the general population. Prevalence rates for individuals ≥ 65 were age-standardized to the 2014 Canadian population, where data permitted. Results: Fifteen studies representing five countries (Canada, Australia, United States, Guam, Brazil) met the inclusion criteria. Four studies presented incidence data, which were all conducted in Guam, and 11 studies reported prevalence data. Seven of the prevalence studies were based on primary data collection and developed or modified cognitive assessment tools for use in indigenous populations, while the other four were based on pre-existing data. Dementia prevalence ranged from 0.5% to 20%. The age-standardized prevalence rates were the same for the two Canadian studies (3.5%), which was much lower than the age-standardized rates for Guam (16%) and Australia (15–27%). In Australia, the age-standardized prevalence rate was higher for the prevalence study (27%) than it was for the study based on pre-existing data on treated dementia patients (15%). Retrospective studies relying on medical records for diagnoses had much lower prevalence rates and a higher risk of bias than population-based prospective studies performing their own diagnoses with culturally appropriate cognitive assessment methods. Conclusion: The prevalence of dementia among Indigenous populations appears to be higher than it is for non-Indigenous populations. Despite a building body of evidence supporting the need for dementia research among Indigenous populations, there is a paucity of epidemiological research, none of which is of high quality., Background: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative dementias. There is an urgent need to develop disease-modifying agents to prevent, delay or slow the progression of these dementias at early stages. The development of such interventions is challenged by substantial clinical heterogeneity observed within a single clinical diagnosis and this may in part be due to mixed pathologies on a shared genetic background. For example, carriers of the Apolipoprotein E (APOE) gene ε4 variant are known to have a higher risk of developing pathologically-proven AD, DLB, and mixed AD/DLB. In existing literature, the ε4 allele is consistently associated with smaller hippocampal volumes among AD patients. To our knowledge, however, this association has not been studied in DLB and mixed dementias. This warrants further investigation to see if ε4 consistently associates with hippocampal measures across different groups of dementias. Objectives: 1) To investigate whether APOE ε4 allele associates with hippocampal volumetric measures across dementia sub-types in a dose-dependent manner. 2) To investigate differences in hippocampal volumetrics across dementia sub-types based on an extreme genetic subgroup approach (i.e., non-carriers vs. homozygous carriers of ε4). 3) To investigate the association between hippocampal volumes and verbal episodic memory within APOE sub-groups. Methods: The study included 261 patients with a clinical diagnosis of dementia (160 AD, 46 AD with small vessel disease [SVD], 35 mixed AD/DLB, 20 pure DLB). MRI data were pre-processed using the Semi-Automated Brain Region Extraction (SABRE) pipeline followed by estimation of hippocampal volumetrics using Sunnybrook Hippocampal Volumetry tools. The first analysis (objective 1) assessed dose-dependent effects of ε4 on hippocampal volumetric measures by stratifying the sample into non-carriers ‘’−/−’’, heterozygous carriers ‘’+/−’’, or homozygous carriers ‘’+/+’’. The second analysis (objective 2) examined hippocampal volumetric measures in the extreme subgroups of ε4 ‘’+/+’’ vs. ‘’−/−’’. The third analysis (objective 3) evaluated the linear relationship between hippocampal measures and performance on the California Verbal Learning Test (CVLT). Between-group differences in baseline hippocampal volumes were analyzed using analysis of covariance (ANCOVA). Linear regressions were used to examine the associations of hippocampal measures with CVLT. Results: There were 104 APOE ε4 ‘’non-carriers’’ and 157 ‘’carriers’’ in our sample (104 ‘’−/−’’, 119 ‘’+/−’’, and 38 ‘’+/+’’). There was a trend for total bilateral hippocampal volume (HV) and individual left and right HVs to be smaller in a dose-dependent fashion: ε4 ‘’+/+’’ < ε4 ‘’+/−’’ < ε4 ‘’−/−’’. The total bilateral HV, and individual left and right HVs were significantly smaller (p

Published
2015
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3. Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

Author

Andriuta D, Ottoy J, Ruthirakuhan M, Feliciano G, Dilliott AA, Hegele RA, Gao F, McLaughlin PM, Rabin JS, Wood Alexander M, Scott CJM, Yhap V, Berezuk C, Ozzoude M, Swardfager W, Zebarth J, Tartaglia MC, Rogaeva E, Tang-Wai DF, Casaubon L, Kumar S, Dowlatshahi D, Mandzia J, Sahlas D, Saposnik G, Fischer CE, Borrie M, Hassan A, Binns MA, Freedman M, Chertkow H, Finger E, Frank A, Bartha R, Symons S, Zetterberg H, Swartz RH, Masellis M, Black SE, and Ramirez J

Subjects
Humans, Female, Male, Aged, Cognitive Dysfunction blood, Alzheimer Disease blood, Alzheimer Disease pathology, Frontotemporal Dementia blood, Frontotemporal Dementia pathology, Frontotemporal Dementia diagnostic imaging, Cerebrovascular Disorders blood, Cerebrovascular Disorders diagnostic imaging, Cerebrovascular Disorders pathology, Brain pathology, Brain diagnostic imaging, Cohort Studies, Middle Aged, Glial Fibrillary Acidic Protein blood, Executive Function physiology, Neurodegenerative Diseases blood, Biomarkers blood, Glymphatic System pathology, Glymphatic System diagnostic imaging, Magnetic Resonance Imaging, White Matter pathology, White Matter diagnostic imaging
Abstract

Introduction: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases., Methods: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative., Results: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH., Discussion: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia., Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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4. Sleep functional connectivity, hyperexcitability, and cognition in Alzheimer's disease.

Author

Moguilner SG, Berezuk C, Bender AC, Pellerin KR, Gomperts SN, Cash SS, Sarkis RA, and Lam AD

Subjects
Humans, Male, Female, Aged, Cognitive Dysfunction physiopathology, Cognition physiology, Sleep Wake Disorders physiopathology, Epilepsy physiopathology, Machine Learning, Neuropsychological Tests statistics & numerical data, Middle Aged, Alzheimer Disease physiopathology, Electroencephalography, Sleep physiology, Brain physiopathology, Brain diagnostic imaging
Abstract

Introduction: Sleep disturbances are common in Alzheimer's disease (AD) and may reflect pathologic changes in brain networks. To date, no studies have examined changes in sleep functional connectivity (FC) in AD or their relationship with network hyperexcitability and cognition., Methods: We assessed electroencephalogram (EEG) sleep FC in 33 healthy controls, 36 individuals with AD without epilepsy, and 14 individuals with AD and epilepsy., Results: AD participants showed increased gamma connectivity in stage 2 sleep (N2), which was associated with longitudinal cognitive decline. Network hyperexcitability in AD was associated with a distinct sleep connectivity signature, characterized by decreased N2 delta connectivity and reversal of several connectivity changes associated with AD. Machine learning algorithms using sleep connectivity features accurately distinguished diagnostic groups and identified "fast cognitive decliners" among study participants who had AD., Discussion: Our findings reveal changes in sleep functional networks associated with cognitive decline in AD and may have implications for disease monitoring and therapeutic development., Highlights: Brain functional connectivity (FC) in Alzheimer's disease is altered during sleep. Sleep FC measures correlate with cognitive decline in AD. Network hyperexcitability in AD has a distinct sleep connectivity signature., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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5. Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

Author

Rashidi-Ranjbar N, Churchill NW, Black SE, Kumar S, Tartaglia MC, Freedman M, Lang A, Steeves TDL, Swartz RH, Saposnik G, Sahlas D, McLaughlin P, Symons S, Strother S, Pollock BG, Rajji TK, Ozzoude M, Tan B, Arnott SR, Bartha R, Borrie M, Masellis M, Pasternak SH, Frank A, Seitz D, Ismail Z, Tang-Wai DF, Casaubon LK, Mandzia J, Jog M, Scott CJM, Dowlatshahi D, Hassan A, Grimes D, Marras C, Zamyadi M, Munoz DG, Ramirez J, Berezuk C, Holmes M, Fischer CE, and Schweizer TA

Subjects
Humans, Cross-Sectional Studies, Longitudinal Studies, Brain diagnostic imaging, Brain pathology, Neuropsychological Tests, Parkinson Disease psychology, Cognitive Dysfunction psychology, Alzheimer Disease psychology, Cerebrovascular Disorders complications
Abstract

Objectives: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses., Methods: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits., Results: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively., Conclusions: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences., (© 2024 John Wiley & Sons Ltd.)

Published
2024
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6. Association of Dual-Task Gait Cost and White Matter Hyperintensity Burden Poststroke: Results From the ONDRI.

Author

Pieruccini-Faria F, Cornish B, Binns M, Fraser J, Haddad SMH, Sunderland K, Ramirez J, Beaton D, Kwan D, Dilliott AA, Scott C, Sarquis-Adamson Y, Black A, Van Ooteghem K, Casaubon L, Dowlatshahi D, Hassan A, Mandzia J, Sahlas D, Saposnik G, Tan B, Hegele R, Bulman D, Ghani M, Robinson J, Rogaeva E, Farhan S, Symons S, Nanayakkara N, Arnott SR, Berezuk C, Holmes M, Adamo S, Ozzoude M, Zamyadi M, Lou W, Sujanthan S, Bartha R, Black SE, Swartz RH, McIlroy W, and Montero-Odasso M

Subjects
Humans, Aged, Cohort Studies, Brain diagnostic imaging, Brain pathology, Gait, Magnetic Resonance Imaging, White Matter diagnostic imaging, White Matter pathology, Neurodegenerative Diseases pathology, Stroke complications, Stroke diagnostic imaging, Stroke pathology
Abstract

Background: Acute change in gait speed while performing a mental task [dual-task gait cost (DTC)], and hyperintensity magnetic resonance imaging signals in white matter are both important disability predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke., Methods: This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume., Results: There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks' λ = .87, P  = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted β = .008, η 2  = .03; P  = .04), independently of brain atrophy., Conclusions: In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients' locomotion.

Published
2023
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7. Sex differences in risk factors that predict progression from mild cognitive impairment to Alzheimer's dementia.

Author

Berezuk C, Khan M, Callahan BL, Ramirez J, Black SE, and Zakzanis KK

Subjects
Humans, Female, Male, Sex Characteristics, Brain diagnostic imaging, Biomarkers cerebrospinal fluid, Risk Factors, Disease Progression, Neuropsychological Tests, Amyloid beta-Peptides cerebrospinal fluid, Alzheimer Disease diagnosis, Cognitive Dysfunction diagnosis
Abstract

Objectives: To evaluate whether cerebrospinal fluid biomarkers, apolipoprotein e4, neuroimaging abnormalities, and neuropsychological data differentially predict progression from mild cognitive impairment (MCI) to dementia for men and women., Methods: Participants who were diagnosed with MCI at baseline ( n = 449) were classified as either progressing to Alzheimer's dementia at follow-up or as not progressing. Men and women were first compared using bivariate analyses. Sex-stratified Cox proportional hazard regressions were performed examining the relationship between baseline data and the likelihood of progressing to dementia. Sex interactions were subsequently examined., Results: Cox proportional hazard regression controlling for age and education indicated that all variables significantly predicted subsequent progression to dementia for men and women. Sex interactions indicated that only Rey Auditory Verbal Learning Test (RAVLT) delayed recall and Functional Activities Questionnaire (FAQ) were significantly stronger risk factors for women. When all variables were entered into a fully adjusted model, significant risk factors for women were Aβ42, hippocampal volume, RAVLT delayed recall, Boston Naming Test, and FAQ. In contrast, for men, Aβ42, p-tau181, p-tau181/Aβ42, hippocampal volume, category fluency and FAQ were significant risk factors. Interactions with sex were only significant for p-tau181/Aβ42 and RAVLT delayed recall for the fully adjusted model., Conclusions: Men and women with MCI may to differ for which factors predict subsequent dementia although future analyses with greater power are needed to evaluate sex differences. We hypothesize that brain and cognitive reserve theories may partially explain these findings.

Published
2023
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8. White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

Author

Carvalho de Abreu DC, Pieruccini-Faria F, Sarquis-Adamson Y, Black A, Fraser J, Van Ooteghem K, Cornish B, Grimes D, Jog M, Masellis M, Steeves T, Nanayakkara N, Ramirez J, Scott C, Holmes M, Ozzoude M, Berezuk C, Symons S, Mohammad Hassan Haddad S, Arnott SR, Binns M, Strother S, Beaton D, Sunderland K, Theyers A, Tan B, Zamyadi M, Levine B, Orange JB, Roberts AC, Lou W, Sujanthan S, Breen DP, Marras C, Kwan D, Adamo S, Peltsch A, Troyer AK, Black SE, McLaughlin PM, Lang AE, McIlroy W, Bartha R, and Montero-Odasso M

Subjects
Humans, Aged, Ontario, Magnetic Resonance Imaging methods, Cognition physiology, White Matter pathology, Parkinson Disease, Neurodegenerative Diseases pathology, Gait Disorders, Neurologic, Cognitive Dysfunction pathology
Abstract

Background and Purpose: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years., Methods: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale., Results: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline., Conclusion: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology., (© 2023 European Academy of Neurology.)

Published
2023
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9. Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke.

Author

Yu D, Liang N, Zebarth J, Shen Q, Ozzoude M, Goubran M, Rabin JS, Ramirez J, Scott CJM, Gao F, Bartha R, Symons S, Haddad SMH, Berezuk C, Tan B, Kwan D, Hegele RA, Dilliott AA, Nanayakkara ND, Binns MA, Beaton D, Arnott SR, Lawrence-Dewar JM, Hassan A, Dowlatshahi D, Mandzia J, Sahlas D, Casaubon L, Saposnik G, Otoki Y, Lanctôt KL, Masellis M, Black SE, Swartz RH, Taha AY, and Swardfager W

Subjects
Humans, Linoleic Acid, Oxylipins, Epoxide Hydrolases, Magnetic Resonance Imaging, Atrophy, Water, Stroke diagnostic imaging, Stroke pathology, Cerebral Small Vessel Diseases diagnostic imaging
Abstract

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P =0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P <0.001; β=0.362, P <0.001) and white matter MRI-visible perivascular spaces (β=0.302, P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (β=-0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Published
2023
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10. Comparison of Diffusion Tensor Imaging Metrics in Normal-Appearing White Matter to Cerebrovascular Lesions and Correlation with Cerebrovascular Disease Risk Factors and Severity.

Author

Haddad SMH, Scott CJM, Ozzoude M, Berezuk C, Holmes M, Adamo S, Ramirez J, Arnott SR, Nanayakkara ND, Binns M, Beaton D, Lou W, Sunderland K, Sujanthan S, Lawrence J, Kwan D, Tan B, Casaubon L, Mandzia J, Sahlas D, Saposnik G, Hassan A, Levine B, McLaughlin P, Orange JB, Roberts A, Troyer A, Black SE, Dowlatshahi D, Strother SC, Swartz RH, Symons S, Montero-Odasso M, Ondri Investigators, and Bartha R

Abstract

Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T 1 -weighted, proton density-weighted, T 2 -weighted, and fluid attenuated inversion recovery MRI scans. Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function., Competing Interests: All authors have no conflicts of interest that relate to this manuscript., (Copyright © 2022 Seyyed M. H. Haddad et al.)

Published
2022
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11. Increased brain volumetric measurement precision from multi-site 3D T1-weighted 3 T magnetic resonance imaging by correcting geometric distortions.

Author

Nanayakkara ND, Arnott SR, Scott CJM, Solovey I, Liang S, Fonov VS, Gee T, Broberg DN, Haddad SMH, Ramirez J, Berezuk C, Holmes M, Adamo S, Ozzoude M, Theyers A, Sujanthan S, Zamyadi M, Casaubon L, Dowlatshahi D, Mandzia J, Sahlas D, Saposnik G, Hassan A, Swartz RH, Strother SC, Szilagyi GM, Black SE, Symons S, Investigators ONDRI, and Bartha R

Subjects
Humans, Phantoms, Imaging, Brain diagnostic imaging, Magnetic Resonance Imaging methods
Abstract

Purpose: Magnetic resonance imaging (MRI) scanner-specific geometric distortions may contribute to scanner induced variability and decrease volumetric measurement precision for multi-site studies. The purpose of this study was to determine whether geometric distortion correction increases the precision of brain volumetric measurements in a multi-site multi-scanner study., Methods: Geometric distortion variation was quantified over a one-year period at 10 sites using the distortion fields estimated from monthly 3D T1-weighted MRI geometrical phantom scans. The variability of volume and distance measurements were quantified using synthetic volumes and a standard quantitative MRI (qMRI) phantom. The effects of geometric distortion corrections on MRI derived volumetric measurements of the human brain were assessed in two subjects scanned on each of the 10 MRI scanners and in 150 subjects with cerebrovascaular disease (CVD) acquired across imaging sites., Results: Geometric distortions were found to vary substantially between different MRI scanners but were relatively stable on each scanner over a one-year interval. Geometric distortions varied spatially, increasing in severity with distance from the magnet isocenter. In measurements made with the qMRI phantom, the geometric distortion correction decreased the standard deviation of volumetric assessments by 35% and distance measurements by 42%. The average coefficient of variance decreased by 16% in gray matter and white matter volume estimates in the two subjects scanned on the 10 MRI scanners., Conclusion: Geometric distortion correction using an up-to-date correction field is recommended to increase precision in volumetric measurements made from MRI images., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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12. Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

Author

Ramirez J, Berberian SA, Breen DP, Gao F, Ozzoude M, Adamo S, Scott CJM, Berezuk C, Yhap V, Mestre TA, Marras C, Tartaglia MC, Grimes D, Jog M, Kwan D, Tan B, Binns MA, Arnott SR, Bartha R, Symons S, Masellis M, Black SE, and Lang AE

Subjects
Basal Ganglia diagnostic imaging, Basal Ganglia pathology, Cross-Sectional Studies, Humans, Magnetic Resonance Imaging, Persons with Disabilities, Motor Disorders, Neurodegenerative Diseases pathology, Parkinson Disease complications
Abstract

Background: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested., Objective: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD., Methods: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study., Results: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition., Conclusions: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Published
2022
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13. Cognitive reserve, cognition, and real-world functioning in MCI: A systematic review and meta-analysis.

Author

Berezuk C, Scott SC, Black SE, and Zakzanis KK

Subjects
Activities of Daily Living, Cognition, Executive Function, Female, Humans, Male, Neuropsychological Tests, Cognitive Dysfunction diagnosis, Cognitive Reserve
Abstract

Objective: To synthesize quantitatively the mild cognitive impairment (MCI) literature with respect to the relationship between cognitive reserve and neuropsychological and functional outcomes., Method: 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., Results: 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)., Conclusions: 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.

Published
2021
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14. MRI-visible perivascular space volumes, sleep duration and daytime dysfunction in adults with cerebrovascular disease.

Author

Ramirez J, Holmes MF, Berezuk C, Kwan D, Tan B, Beaton D, Scott CJM, Ozzoude M, Gao F, Yu D, Swardfager W, Lawrence-Dewar J, Dowlatshahi D, Saposnik G, Boulos MI, Murray BJ, Symons S, Bartha R, Black SE, Swartz RH, and Lim A

Subjects
Adult, Animals, Humans, Magnetic Resonance Imaging, Ontario, Sleep, Cerebral Small Vessel Diseases, Cerebrovascular Disorders complications, Cerebrovascular Disorders diagnostic imaging, Glymphatic System, Neurodegenerative Diseases
Abstract

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Published
2021
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15. Managing money matters: Managing finances is associated with functional independence in MCI.

Author

Berezuk C, Ramirez J, Black SE, and Zakzanis KK

Subjects
Aged, Aged, 80 and over, Female, Humans, Male, Neuropsychological Tests, Activities of Daily Living psychology, Alzheimer Disease psychology, Banking, Personal, Cognitive Dysfunction psychology, Independent Living psychology
Abstract

Objective: Previous research suggests that overall experience participating in instrumental activities of daily living (IADLs) is associated with reduced IADL impairment in individuals with mild cognitive impairment, possibly because of an increased functional reserve. Given that difficulties managing finances tend to occur with mild cognitive impairment, this study explores whether experience managing one's finances is associated with independence across various IADLs., Methods: Participants with a screen or baseline diagnosis of mild cognitive impairment (n = 862) were taken from the Alzheimer's Disease Neuroimaging Initiative study. Functional dependence and experience were quantified from the Functional Activities Questionnaire., Results: No group differences between those with and without financial management experience existed in Mini-Mental State Examination scores, age, and years of education, although women were more likely to have experience managing finances (P < .001). Final chi-square analyses suggest that financial management experience is significantly associated with greater independence in the ability to follow TV, books, or magazines (P = .009) and remember appointments and important dates (P = .002)., Conclusions: Individuals who are rated as having experience in managing their finances were also rated as being less dependent in their ability to follow and understand TV and books and in their ability to remember appointments and important dates. Neither causation nor the mechanisms underlying this relationship can be discerned from these analyses. Therefore, further research is needed to investigate whether engaging in financial tasks protects against early financial impairment, potentially through an increased functional reserve., (Copyright © 2017 John Wiley & Sons, Ltd.)

Published
2018
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16. Functional Reserve: Experience Participating in Instrumental Activities of Daily Living is Associated with Gender and Functional Independence in Mild Cognitive Impairment.

Author

Berezuk C, Zakzanis KK, Ramirez J, Ruocco AC, Edwards JD, Callahan BL, and Black SE

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Apolipoproteins E genetics, Cognitive Dysfunction physiopathology, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Recognition, Psychology, Regression Analysis, Verbal Learning, Activities of Daily Living psychology, Alzheimer Disease psychology, Cognitive Dysfunction psychology, Sex Characteristics
Abstract

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 < 0.05) until adjusting for IADL experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p < 0.001), although IADL experience was the most important single variable (4.8% explained, p < 0.001). Stratification by gender revealed that IADL experience accounted for 6.6% of the variance in FAQ score in men (p < 0.001) but only 2.4% in women (p = 0.001); however, the interaction between gender and experience was not statistically significant., Discussion: A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment.

Published
2017
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17. Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study.

Author

Edwards JD, Ramirez J, Callahan BL, Tobe SW, Oh P, Berezuk C, Lanctôt K, Swardfager W, Nestor S, Kiss A, Strother S, and Black SE

Subjects
Aged, Aged, 80 and over, Angiotensin Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Cohort Studies, Female, Humans, Hypertension diagnostic imaging, Linear Models, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Treatment Outcome, Alzheimer Disease diagnostic imaging, Alzheimer Disease prevention & control, Antihypertensive Agents therapeutic use, Brain diagnostic imaging, Brain drug effects, Brain pathology, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction prevention & control, Hypertension drug therapy
Abstract

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 < 0.05)., 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.

Published
2017
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18. Dynamic Progression of White Matter Hyperintensities in Alzheimer's Disease and Normal Aging: Results from the Sunnybrook Dementia Study.

Author

Ramirez J, McNeely AA, Berezuk C, Gao F, and Black SE

Abstract

Although white matter hyperintensities (WMH), markers of cerebral small vessel disease (SVD), are believed to generally increase over time, some studies have shown sharp decreases after therapeutic intervention, suggesting that WMH progression may be more dynamic than previously thought. Our primary goal was to examine dynamic progression of WMH in a real-world sample of Alzheimer's disease (AD) patients and normal elderly (NC), with varying degrees of SVD. WMH volumes from serial magnetic resonance imaging (MRI; mean = 1.8 years) were measured from NC (n = 44) and AD patients (n = 113) with high and low SVD burden. Dynamic progression for each individual was measured using spatial overlap images to assess shrinkage, growth, and stable WMH volumes. Significant group differences were found for shrinkage (p < 0.001), growth (p < 0.001) and stable (p < 0.001) WMH, where the AD high SVD group showed the largest changes relative to low SVD and NC. Our results suggest spatial progression measured at the individual patient level may be more sensitive to the dynamic nature of WMH.

Published
2016
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19. Imaging the Perivascular Space as a Potential Biomarker of Neurovascular and Neurodegenerative Diseases.

Author

Ramirez J, Berezuk C, McNeely AA, Gao F, McLaurin J, and Black SE

Subjects
Animals, Cerebrovascular Disorders immunology, Humans, Lymphatic System immunology, Neurodegenerative Diseases immunology, Translational Research, Biomedical, Cerebrovascular Disorders diagnostic imaging, Cerebrovascular Disorders pathology, Lymphatic System diagnostic imaging, Lymphatic System pathology, Neurodegenerative Diseases diagnostic imaging, Neurodegenerative Diseases pathology, Neuroimaging methods
Abstract

Although the brain lacks conventional lymphatic vessels found in peripheral tissue, evidence suggests that the space surrounding the vasculature serves a similar role in the clearance of fluid and metabolic waste from the brain. With aging, neurodegeneration, and cerebrovascular disease, these microscopic perivascular spaces can become enlarged, allowing for visualization and quantification on structural MRI. The purpose of this review is to: (i) describe some of the recent pre-clinical findings from basic science that shed light on the potential neurophysiological mechanisms driving glymphatic and perivascular waste clearance, (ii) review some of the pathobiological etiologies that may lead to MRI-visible enlarged perivascular spaces (ePVS), (iii) describe the possible clinical implications of ePVS, (iv) evaluate existing qualitative and quantitative techniques used for measuring ePVS burden, and (v) propose future avenues of research that may improve our understanding of this potential clinical neuroimaging biomarker for fluid and metabolic waste clearance dysfunction in neurodegenerative and neurovascular diseases.

Published
2016
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20. Predicting Alzheimer's disease development: a comparison of cognitive criteria and associated neuroimaging biomarkers.

Author

Callahan BL, Ramirez J, Berezuk C, Duchesne S, and Black SE

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Apolipoprotein E4 genetics, Area Under Curve, Databases, Factual, Female, Follow-Up Studies, Humans, Male, Memory Disorders diagnosis, Memory Disorders genetics, Memory Disorders pathology, Memory, Episodic, Middle Aged, Prognosis, ROC Curve, Sensitivity and Specificity, Alzheimer Disease diagnosis, Alzheimer Disease pathology, Brain pathology, Magnetic Resonance Imaging, Neuropsychological Tests
Abstract

Introduction: The definition of "objective cognitive impairment" in current criteria for mild cognitive impairment (MCI) varies considerably between research groups and clinics. This study aims to compare different methods of defining memory impairment to improve prediction models for the development of Alzheimer's disease (AD) from baseline to 24 months., Methods: The sensitivity and specificity of six methods of defining episodic memory impairment (< -1, -1.5 or -2 standard deviations [SD] on one or two memory tests) were compared in 494 non-demented seniors from the Alzheimer's Disease Neuroimaging Initiative using the area under the curve (AUC) for receiver operating characteristic analysis. The added value of non-memory measures (language and executive function) and biomarkers (hippocampal and white-matter hyperintensity volume, brain parenchymal fraction [BPF], and APOEε4 status) was investigated using logistic regression., Results: Baseline scores < -1 SD on two memory tests predicted AD with 75.91 % accuracy (AUC = 0.80). Only APOE ε4 status further improved prediction (B = 1.10, SE = 0.45, p = .016). A < -1.5 SD cut-off on one test had 66.60 % accuracy (AUC = 0.77). Prediction was further improved using Trails B/A ratio (B = 0.27, SE = 0.13, p = .033), BPF (B = -15.97, SE = 7.58, p = .035), and APOEε4 status (B = 1.08, SE = 0.45, p = .017). A cut-off of < -2 SD on one memory test (AUC = 0.77, SE = 0.03, 95 % CI 0.72-0.82) had 76.52 % accuracy in predicting AD. Trails B/A ratio (B = 0.31, SE = 0.13, p = .017) and APOE ε4 status (B = 1.07, SE = 0.46, p = .019) improved predictive accuracy., Conclusions: Episodic memory impairment in MCI should be defined as scores < -1 SD below normative references on at least two measures. Clinicians or researchers who administer a single test should opt for a more stringent cut-off and collect and analyze whole-brain volume. When feasible, ascertaining APOE ε4 status can further improve prediction.

Published
2015
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21. Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters.

Author

Berezuk C, Ramirez J, Gao F, Scott CJ, Huroy M, Swartz RH, Murray BJ, Black SE, and Boulos MI

Subjects
Adult, Aged, Aged, 80 and over, Animals, Basal Ganglia metabolism, Cross-Sectional Studies, Female, Humans, Imaging, Three-Dimensional, Magnetic Resonance Imaging, Male, Middle Aged, Retrospective Studies, Brain Ischemia metabolism, Polysomnography, Sleep physiology, Stroke metabolism
Abstract

Study Objectives: To test the hypothesis that enlarged Virchow-Robin space volumes (VRS) are associated with objective measures of poor quality sleep., Design: Retrospective cross-sectional study., Setting: Sunnybrook Health Sciences Centre., Patients: Twenty-six patients being evaluated for cerebrovascular disease were assessed using polysomnography and high-resolution structural magnetic resonance imaging., Measurements and Results: Regionalized VRS were quantified from three-dimensional high-resolution magnetic resonance imaging and correlated with measures of polysomnography-derived sleep parameters while controlling for age, stroke volume, body mass index, systolic blood pressure, and ventricular cerebrospinal fluid volume. Sleep efficiency was negatively correlated with total VRS (rho = -0.47, P = 0.03) and basal ganglia VRS (rho = -0.54, P = 0.01), whereas wake after sleep onset was positively correlated with basal ganglia VRS (rho = 0.52, P = 0.02). Furthermore, VRS in the basal ganglia were negatively correlated with duration of N3 (rho = -0.53, P = 0.01)., Conclusions: These preliminary results suggest that sleep may play a role in perivascular clearance in ischemic brain disease, and invite future research into the potential relevance of Virchow-Robin spaces as an imaging biomarker for nocturnal metabolite clearance., (© 2015 Associated Professional Sleep Societies, LLC.)

Published
2015
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22. Visible Virchow-Robin spaces on magnetic resonance imaging of Alzheimer's disease patients and normal elderly from the Sunnybrook Dementia Study.

Author

Ramirez J, Berezuk C, McNeely AA, Scott CJ, Gao F, and Black SE

Subjects
Aged, Aged, 80 and over, Female, Humans, Imaging, Three-Dimensional, Male, Reproducibility of Results, Alzheimer Disease pathology, Cerebral Ventricles pathology, Dura Mater pathology, Magnetic Resonance Imaging, Pia Mater pathology
Abstract

Background: Visible Virchow-Robin spaces (VRS) are commonly used markers for small vessel disease in aging and dementia., Objective: However, as previous reports were based on subjective visual ratings, the goal of this project was to validate and apply an MRI-based quantitative measure of VRS as a potential neuroimaging biomarker., Methods: A modified version of Lesion Explorer was applied to MRIs from Alzheimer's disease patients (AD: n = 203) and normal elderly controls (NC: n = 94). Inter-rater reliability, technique validity, group/gender differences, and correlations with other small vessel disease markers were examined (lacunes and white matter hyperintensities, WMH)., Results: Inter-rater reliability and spatial congruence was excellent (ICC = 0.99, SI = 0.96), and VRS volumes were highly correlated with established rating scales (CS: ρ = 0.84, p < 0.001; BG: ρ = 0.75, p < 0.001). Compared to NC, AD had significantly greater volumes of WMH (p < 0.01), lacunes (p < 0.001), and VRS in the white matter (p < 0.01), but not in the basal ganglia (n.s.). Compared to women, demented and non-demented men had greater VRS in the white matter (p < 0.001), but not in the basal ganglia (n.s.). Additionally, VRS were correlated with lacunes and WMH, but only in AD (r = 0.3, p < 0.01)., Conclusion: Compared to women, men may be more susceptible to greater volumes of VRS, particularly in the white matter. RESULTS support the hypothesis that VRS in the white matter may be more related to AD-related vascular pathology compared to VRS found in the basal ganglia. Future work using this novel VRS segmentation tool will examine its potential utility as an imaging biomarker of vascular rather than parenchymal amyloid.

Published
2015
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23. Lesion Explorer: a video-guided, standardized protocol for accurate and reliable MRI-derived volumetrics in Alzheimer's disease and normal elderly.

Author

Ramirez J, Scott CJ, McNeely AA, Berezuk C, Gao F, Szilagyi GM, and Black SE

Subjects
Alzheimer Disease pathology, Humans, Reference Values, Reproducibility of Results, Video Recording, Alzheimer Disease diagnosis, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods
Abstract

Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests(1,2). However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs. LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors. While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures.

Published
2014
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