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2024 Alzheimer\'s Association International Conference

The Alzheimer\'s Association International Conference (AAIC) is the largest international meeting dedicated to advancing dementia science and clinical practice. You can explore the conference materials the Graham Lab had contributed in the following tabs.

Brain glutathione in vascular mild cognitive impairment and cognitive correlates

Background: Oxidative stress (OS) has been implicated in age-related neurodegeneration and may be important in prodromal states such as vascular mild cognitive impairment (vMCI). Higher peripheral OS is reported in vMCI patients; however, the role of central antioxidant defenses in vMCI and their correlation to cognition is unclear. Glutathione (GSH) is a major brain antioxidant, and the current study assessed brain GSH in possible vMCI vs. controls.

Methods: Possible vMCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55-85, and currently enrolled in a 6-month exercise rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively-normal (CN) controls were recruited. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital lobe (OL). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).

Results/Conclusions: In 43 participants (mVCI n = 22, CN n = 21), AC-GSH (I.U. ± SD) was higher in mVCI (1.96 ± 0.29) compared to CN (1.64 ± 0.48) (F(1,29.7) = 6.9, p = .01); this difference remained after correcting for cerebrospinal fluid (CSF) volume (F(1,28.4) = 6.5, p = .02), and controlling for age and sex (B [SE] = 0.33 [0.11], p = .007). There was no difference in OL-GSH before or after correcting for CSF volume. Higher AC-GSH, but not OL-GSH, was correlated with poorer global cognition (Montreal Cognitive Assessment -Full score, B [SE] = 2.15, p = .03), and poorer EF performance (B [SE] = -0.67 [0.25], p < .001). These relationships remained significant after correcting for CSF volume.

The current study suggests an upregulation of AC glutathione in vMCI, which may reflect a compensatory increase in antioxidants as a response to oxidative stress challenges reported in these patients. Higher brain GSH in the AC region is correlated with poorer global cognition and executive function performance, suggesting a link between local brain antioxidant response and disease-relevant cognitive domains.

*J. J. CHEN1,2, N. HERRMANN1,3,4, K. SURVILLA5, E. MAH1,2,4, Y. KANG1, S. E. BLACK1,6,7,8, J. RAMIREZ8,9, A. C. ANDREAZZA10, A. KISS11,12, P. I. OH13, D. GALLAGHER1,2,8, S. J. GRAHAM4,14, K. L. lANCTÔT1,2,13,15,16.

1University of Toronto, Toronto, ON, Canada, 2Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada, 3Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada, 4Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada, 5Sunnybrook Research Institute, Toronto, ON, Canada, 6Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada, 7LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada, 8Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 9Sandra Black Centre for Brain Resilience and Recovery, Sunnybrook Research Institute, Toronto, ON, Canada, 10Temerty Faculty of Medicine, Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 11ICES, Toronto, ON, Canada, 12Department of Research Design and Biostatistics, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada, 13KITE Research Institute, Toronto Rehabilitation Institute, Toronto, ON, Canada, 14Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, 15Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada, 16Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

Sunday, July 28, 2024 at 8:00 AM-11:55 PM

A pilot study evaluating the feasibility, safety, and efficacy of transcranial photobiomodulation (tPBM) for the treatment of mild cognitive impairment (MCI): preliminary findings

Research Objective: Mild Cognitive Impairment (MCI) is often a precursor to Alzheimer\'s dementia (AD). Recent research underscores the relationship between mitochondrial dysfunction and amyloid-beta accumulation, raising the prospect of targeting mitochondrial function for intervention. Transcranial photobiomodulation (tPBM), a non-invasive technique utilizing near-infrared light, has been shown to enhance mitochondrial function. Therefore, our study aimed to investigate the efficacy of tPBM in improving brain functions in MCI.
Methods: Fourteen (N=14) participants with MCI recruited at St. Michael’s Hospital Memory Disorders Clinic were randomized (1:1) to either active or sham tPBM (Neuro RX Gamma, Vielight Inc). Participants underwent daily home-based active or sham tPBM sessions over 6 weeks. Pre- and post-treatment assessments included a comprehensive battery of tests, encompassing the Trail Making Test (TMT B & A), Mini-Mental State Examination (MMSE), Proton Magnetic Resonance Spectroscopy (H-MRS) of the posterior cingulate cortex, structural MRI, resting-state functional MRI (rsfMRI), and blood-based biomarker was collected using NMR spectroscopy quantitative and Neurology 3-Plex A (N3PA) Assays.
Results/Conclusions: Comparing pre-post changes in the active vs. sham group, we found significant differences favoring the active group (p’s<0.05) in: completing TMT-B (t-statistic=-2.1); for H-MRS, decline in N-acetyl aspartate to total creatine ratio (NAA/Cr) (t-statistic=2.8); increase in right thalamic volume (t-statistic=3.2); for rsfMRI, higher absolute change in functional connectivity in the default mode network (DMN) (t-statistic=3.5) and limbic network (t- statistic=3.3), and between DMN and executive control network (ECN) (t-statistic=2.8); for blood results, decrease in isoleucine (t-statistic=3.0), methionine (t-statistic=3.1), and sarcosine (t-statistic=3.2) levels—markers linked to AD and amyloid plaque formation; and increase in butyrate (t-statistic=-2.5) and L-carnitine (t-statistic=-2.6) levels—markers indicative of improved mitochondrial function. Furthermore, a notable trend was observed towards improved TMT B/A (p=0.05, t-statistic=-2.2) and MMSE (p=0.06, t-statistic=2.0). Although the reduction in plasma tau levels within the active group was not statistically significant, it was notable (t-statistic=1.8).
Our pilot study suggests that tPBM could improve executive function, neuronal health, functional connectivity, and mitochondrial function, and decrease AD markers in patients with MCI. Further research with larger sample sizes is essential to replicate and validate these results.
N. RASHIDI-RANJBAR1, N. W. CHURCHILL1, S. J. GRAHAM2,3, R. SCHNEIDER1,4, T. K. RAJJI5,6, A. C. ANDREAZZA7,8, L. LIM9, J. COULL10, D. G. MUNOZ1,11, L. R. FORNAZZARI4, T. A. SCHWEIZER1,12, C. E. FISCHER1,6,7.
1Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael\'s Hospital, Toronto, ON, Canada, 2Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, 3Sunnybrook Research Institute, Toronto, ON, Canada, 4Temerty Faculty of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada, 5Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada, 6Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada, 7Temerty Faculty of Medicine, Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 8Department of Pharmacology & Toxicology, Mitochondrial Innovation Initiative, University of Toronto, Toronto, ON, Canada, 9Vielight Inc., Toronto, ON, Canada, 10Weston Family Foundation, Hilary and Galen Weston Foundation, Toronto, ON, Canada, 11Temerty Faculty of Medicine, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, 12Temerty Faculty of Medicine, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada
Virtual Only Poste

Lipid peroxidation in patients with vascular mild cognitive impairment from a memory and antioxidants in vascular impairment trial (MOVE-IT)

Background: Oxidative stress (OS) has been a target of interest for vascular dementia, given its implications in pathogenesis. OS may be important in prodromal stage, such as vascular mild cognitive impairment (vMCI), and examining OS markers in vMCI may help better understand biological processes in the onset of cognitive impairment. Our study compared OS levels in vMCI vs controls, and explored whether OS markers predicted the response to antioxidant treatments in vMCI.
Methods: Cardiac rehabilitation patients with cardiovascular risk factors (CVRFs) were recruited as vMCI (1SD below norms in executive function (EF), memory, processing speed or working memory) or cognitively-healthy controls. vMCI patients were classified as probable vMCI if they had neuroimaging evidence of vascular pathology. vMCI patients were randomized to 2400mg N-acetylcysteine (NAC) or placebo in a 24-week, double-blind trial. Serum 8-isoprostane (8ISO), 4-hydroxynonenal (4HNE) and lipid hydroperoxides (LPH) collection and cognitive assessments were done at three time points. ANCOVA models adjusting for age, sex and CVRFs compared OS markers between groups at baseline. Linear mixed-effects models were used for longitudinal analyses.
Results/Conclusions: LPH levels were significantly lower in vMCI (n=60) compared to controls (n=16) (0.86±0.45 vs 1.18±0.31, F(1,62)=7.0, p=0.011). 4HNE were significantly higher in vMCI compared to controls (1.03±0.06 vs 0.99±0.04, F(1,70)=6.6, p=0.012). vMCI patients had significantly higher 4HNE/LPH (0.17±0.44 vs –0.18±0.29, F(1,62)=9.3, p=0.003) and (8ISO+4HNE)/LPH ratio (0.41±0.45 vs 0.13±0.38, F(1,62)=5.9, p=0.018) compared to controls. In probable vMCI group (n=25), there was significant decreases in 4HNE/LPH (β=-0.68, SE=0.27, p=0.02) and (8ISO+4HNE)/LPH ratio (β=-0.65, SE=0.28, p=0.028) after NAC treatment. A significant time by baseline 8ISO effect on EF in the NAC group was observed (β=0.78, SE=0.26, p<0.01) after adjusting for age, sex and education.
This study showed that the ratios of late- to early-phase lipid peroxidation markers were significantly elevated in vMCI groups compared to controls. This aligns with existing literature that altered lipid peroxidation may be implicated in vMCI. Antioxidant treatments decreased OS in probable vMCI groups, and higher baseline 8ISO was associated with greater improvement in EF in the NAC group, suggesting that probable vMCI patients with high OS may be appropriately targeted for antioxidant treatments.
Y. KANG1,2, J. J. CHEN1,2, E. MAH1,2, K. SURVILLA2; D. VIEIRA2, N. HERRMANN1,2, D. GALLAGHER1,2,3, A. C. ANDREAZZA1,4, S. E. BLACK1,2,3, P. I. OH5, W. SWARDFAGER1,2, S. J. GRAHAM2,6, J. RAMIREZ1,2, S. MARZOLINI5, K. L. LANCTÔT1,2,3.

1University of Toronto, Toronto, ON, Canada, 2Sunnybrook Research Institute, Toronto, ON, Canada, 3Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 4Center for Addiction and Mental Health, Toronto, ON, Canada, 5KITE Research Institute, Toronto Rehabilitation Institute, Toronto, ON, Canada, 6University of Toronto, Torono, ON, Canada.

2023 Society for Neuroscience Annual Conference

Dr. Graham and members of the Graham Lab attended the Society for Neuroscience\'s Annual Conference in Washington, D.C. You can explore the conference abstracts they contributed in the following tabs.

Brain Effects of Post-COVID-19 Condition Observed by Dynamic Susceptibility Contrast Magnetic Resonance Imaging

Background: Post-coronavirus disease 2019 condition (PCC) is prevalent, with high socioeconomic and healthcare burden internationally. Many common PCC symptoms suggest brain injury, but the underlying biological mechanisms remain poorly understood. Towards filling this knowledge gap and developing targeted brain treatments, the NeuroCOVID19 study commenced in spring 2020 involving detailed magnetic resonance imaging (MRI) of the brain; electroencephalography; and assessment of symptoms and behaviors[1]. Notably, dynamic susceptibility contrast (DSC) MRI is included to assess cerebral microvessel pathophysiology [2], and test whether DSC cerebral blood flow (CBF) and vascular leakage parameter K2 are altered in PCC individuals compared to controls.

Methods: To date, DSC data have been collected for 14 healthy controls (9 female (F), mean (standard deviation) age = 44(13)), and 63 PCC participants (55 self-isolated while infected, 37 F, age = 42(12); 8 hospitalized while infected, 5 F, age=54(11)). DSC MRI was performed at 3 T (1.74 mm in-plane resolution, 8 mm slices, 140 time points, 1.25 s temporal resolution) using Gadovist contrast agent. Data were analyzed with a custom pipeline to generate CBF and K2 maps (see representative healthy control data, Fig. 1) followed by voxel-wise two-tailed t-tests with correction for multiple comparisons.

Results/Conclusions: No statistically significant group differences were observed, but there were notable trends between self-isolated PCC individuals and controls for CBF and K2 when a region of interest analysis was conducted for the thalamus - consistent with previous NeuroCOVID19 CBF results obtained using arterial spin labeling[3], and with reports that leaky brain vasculature elevates risk of acute COVID19[1]. These results help confirm that there are observable changes in cerebrovascular physiological parameters due to PCC, either as a direct or indirect consequence of SARS-CoV2 infection. 1. Macintosh BJ et al., CMAJ Open 2021.2. Boxerman JL et al., AJNR 2006.3. Kim WSH et al., JMRI 2022.

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*S. J. GRAHAM1, A. PAVEL1, F. O\'HARA1, N. W. CHURCHILL3, F. TAM1, F. GAO2, M. MASELLIS2, B. LAM2, I. CHENG2, C. HEYN2, E. ROUDAIA4, J. CHEN4, S. E. BLACK2, A. B. SEKULER4, T. A. SCHWEIZER3, B. MACINTOSH2

1Physical Sciences, Sunnybrook Res. Inst., 2Hurvitz Brain Sci. Program, Sunnybrook Res. Inst., Sunnybrook Hlth. Sci. Ctr., Toronto, ON, Canada; 3St. Michael\'s Hospital, Unity Hlth. Syst., Toronto, ON, Canada; 4Rotman Res. Inst., Baycrest, Toronto, ON, Canada

Sunday, November 12, 2023 at 1:00 PM-5:00 PM

Post-covid fatigue is associated with abnormal subcortical texture in T1-weighted MRI

Background: The coronavirus disease 2019 (COVID-19) represents an unprecedented public health crisis. These is also growing evidence that the disease affects the central nervous system, via both direct and indirect pathways. These effects may be long-lasting, with growing case numbers of post-acute COVID-19 syndrome (PACS), in which symptoms and neurological issues persist more than 12 weeks post-infection. Among the symptoms associated with PACS, fatigue is a major concern, given its high prevalence and impact on daily functioning.
In other disorders with high rates of fatigue, subcortical structures are frequently implicated, such as the brainstem, basal ganglia and thalamus. These areas are also vulnerable to COVID-related injury, identified via clinical imaging and neuropathology. Hence, imaging biomarkers of microstructural injury that correlate with post-COVID fatigue are of significant interest.
A promising approach to this challenge is texture-based analysis (TBA) of structural brain scans. This approach can provide information about subtle changes in tissue microstructure that cannot be discerned by eye.
Methods: In the present study, we apply TBA to subcortical structures of T1-weighted anatomical scans collected as part of the Toronto-based NeuroCOVID-19 study. We compared Haralick texture features for self-isolating individuals who tested positive for SARS-CoV-2 and had persistent symptoms, along with controls who had cold or flulike symptoms but tested negative for SARS-CoV-2, with both groups imaged an average of 4-5 months after COVID testing.
Results: Significant differences were seen in grey matter texture for COVID-19 patients with persistent fatigue, relative to both COVID-19 patients without fatigue and controls. This included decreased Energy (-15.0% ± 2.1%) and increased Entropy (7.9% ± 1.0%) in the brain stem and thalamus, along with decreased Correlation (-25.3% ± 4.1%) in the putamen, all at p<0.001. These findings provide encouraging evidence for abnormal tissue texture as a biomarker of post-COVID fatigue, providing new insights into this highly prevalent disorder.
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*N. CHURCHILL1, E. ROUDAIA2, J. J. CHEN3, A. B. SEKULER3, F. GAO4, M. MASELLIS5, B. LAM4, I. CHENG4, C. HEYN4, S. E. BLACK6, B. J. MACINTOSH4, S. J. GRAHAM7, T. A. SCHWEIZER8

1St. Michael\'s Hosp., Toronto, ON, Canada; 2Rotman Res. Inst., Montreal, QC, Canada; 3Baycrest Hosp., Toronto, ON, Canada; 4Sunnybrook Hosp., Toronto, ON, Canada; 5Sunnybrook Res. Inst., Toronto, ON, Canada; 6Dept Med. (Neurol), Sunnybrook Hlth. Sci. Cntr, Toronto, ON, Canada; 7Research, Physical Sci., Sunnybrook Hlth. Sci. Ctr., Toronto, ON, Canada; 8Univ. of Toronto, Toronto, ON, Canada

Sunday, November 12, 2023 at 1:00 PM-5:00 PM

Measures of cortical thickness in Alzheimer\'s disease with and without history of traumatic brain injury

Background: There is evidence that traumatic brain injury (TBI) has long-term consequences for brain health, including an increased risk for dementia and progressive brain atrophy. To date, however, there has been little direct examination of how TBI affects the rate of neurodegeneration for individuals with Alzheimer’s disease (AD).

Methods: The present study examined this issue using a mixed design approach, applied to a cohort of 1124 participants from the National Alzheimer’s Coordinating Center (NACC) including 343 with AD, 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. For these groups, cortical thickness measures were obtained from T1-weighted magnetic resonance imaging (MRI) data using FreeSurfer and in-house software. An initial cross-sectional analysis of this group at baseline used multiple linear regression to determine the interaction effects of AD and TBI on measures of cortical thickness. Among those with AD, TBI was associated with an earlier age of AD onset but, counter-intuitively, less cortical thinning in fronto-temporal regions, relative to non-AD controls.

Results/Conclusion: The results suggest that AD with TBI represents a physiologically distinct group from AD at baseline assessment. A second longitudinal analysis of this group used a partial least squares approach to measure group differences in the longitudinal change of cortical thickness values, for a subset of 154 participants with follow-up scans, assessed over an average time span of 33 months. The AD groups with and without TBI history more strongly expressed patterns of longitudinal frontal and temporal atrophy, while the cognitively normal control group displayed an intermediate pattern of atrophy, and the cognitively normal TBI group expressed the least atrophy.

Further, comparison of AD and AD+TBI to their respective control groups showed a more pronounced effect of AD for the TBI groups. These results provide preliminary evidence of a relationship between TBI history and risk of accelerated cortical thinning in frontal and temporal regions. An improved understanding of the long-term outcomes of TBI has the potential to aid in the diagnosis and treatment of individuals with AD combined with history of TBI.

*G. M. D\'SOUZA1,2, , N.W. CHURCHILL2,3, D. X. GUAN4, M. A. KHOURY1,2, S. J. GRAHAM1,5, S. KUMAR1,6, C. E. FISCHER1,2, T. A. SCHWEIZER1,2 1Univ. of Toronto, Toronto, ON, Canada; 2St. Michael\'s Hosp., Toronto, ON, Canada; 3Toronto Metropolitan Univ., Toronto, ON, Canada; 4Univ. of Calgary, Calgary, AB, Canada; 5Sunnybrook Res. Inst., Toronto, ON, Canada; 6Ctr. for Addiction and Mental Hlth., Toronto, ON, Canada

Wednesday, November 15, 2023 at 8:00AM-12:00PM

Post-concussion changes in functional network connectivity relative to the pre-injury brain

Background: Concussion is a major health concern, with an estimated 4 million cases occurring annually in sport and recreation in North America alone. Recent neuroimaging studies have raised concerns about persistent post-concussion brain changes, suggesting that recovery of brain function is incomplete at medical clearance, potentially the increasing risk of subsequent injury. However, these studies are cross-sectional in design, comparing brain networks of concussed individuals to uninjured controls. It is essential that we measure how brain function is altered relative to its \"pre-injury\" state, in order to determine whether it has truly recovered at medical clearance or shows persistent changes.

Methods: In this study, a large sample of 167 varsity athletes had resting-state functional magnetic resonance imaging (fMRI) collected at pre-season baseline. Of this cohort, 25 were later concussed, with imaging at acute injury, medical clearance, and up to one year later. An additional 27 athletes without concussion were re-imaged as controls.

Results/Conclusion: Concussed athletes showed significant post-concussion declines in anterior brain connectivity lasting beyond medical clearance. This study provides the first characterization of brain function after concussion, relative to the pre-injury brain. The results of this study indicate that disturbances in connectivity are present at and beyond medical clearance, highlighting the complex, long-term nature of recovery after injury.

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N. CHURCHILL1, M. HUTCHISON2, S. J. GRAHAM3, *T. SCHWEIZER2; 1St. Michael\'s Hosp., Toronto, ON, Canada; 2Univ. of Toronto, Toronto, ON, Canada; 3Research, Physical Sci., Sunnybrook Hlth. Sci. Ctr., Toronto, ON, Canada

Wednesday, November 15, 2023 at 8:00AM-12:00PM

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