Heather Brooks’s research while affiliated with Centre for Addiction and Mental Health and other places

Importance Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active − sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active − sham] at month 2, 0.06, 95% CI, −0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis ( P = .01) and APOE ε4 ( P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration ClinicalTrials.gov Identifier: NCT02386670

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer’s disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ² = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ² = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen’s d of the difference in global cognition between the high and low TGC groups to Cohen’s d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen’s d values using the whole sample. As hypothesized, Cohen’s d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen’s d’ s of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.

Background Alzheimer’s disease dementia (AD) and mild cognitive impairment (MCI) are often associated with abnormalities in full power spectrum of electroencephalogram (EEG), including the ratio of beta/theta. Full spectrum EEG consists of aperiodic and periodic components with the latter being better associated with cognition. We investigated whether the aperiodic and periodic power components of EEGs are disrupted differently in individuals with MCI vs. AD vs. healthy controls (HC), and whether a periodic based beta/theta ratio better differentiates the three groups than a ratio based on the full spectrum. Method Data were collected in 199 participants ‐ 44 with HC (mean (SD) age: 69.1 (5.3) years), 114 with MCI (72.3 (7.5)), and 41 with AD (75.6 (6.5)). We cleaned the data using a band‐pass filter with cut‐off frequencies 1 and 45 Hz and then independent component analysis. We then used the “fooof” toolbox to decompose the EEGs into their aperiodic and periodic components. We used the area under the receiver operating characteristic curve (AUC ROC ) of a logistic regression classifier to distinguish HC from MCI and AD participants, and MCI from AD participants, using beta/theta ratios based on the periodic power spectrum vs. full power spectrum. Result There was an increase in full spectrum powers for delta, theta, and gamma, and a decrease of relative power for beta in AD participants compared to HC and MCI participants. In contrast, there were no differences in aperiodic background EEG components among HC, MCI, and AD participants. Overall, the periodic and full spectrum comparisons among the three groups were comparable except for the periodic based analysis that showed a difference between MCI and HC in the occipital beta/theta ratio (Bonferroni corrected p = 0.036). Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI with high AUC ROC values (0.94 and 0.83, respectively), and outperformed classifiers based on beta/theta power ratio in EEG all oscillations (0.078 and 0.67, respectively). Conclusion This study supports an advantage of a periodic based analysis over a full EEG spectrum analysis and the use of occipital beta/theta power ratio based on periodic components as a screening tool for AD.

Background Interventions to prevent cognitive decline and dementia in high‐risk populations such as those with remitted Major Depressive Disorder (rMDD) or Mild Cognitive Impairment (MCI) are urgently needed. Method PACt‐MD was a double‐blind randomized trial conducted between 2015 and 2022 comparing cognitive remediation (CR) plus transcranial Direct Current Stimulation (tDCS) vs. sham‐CR+sham‐tDCS delivered 5 days/week for 8 weeks followed by 5‐day semi‐annual boosters and at‐home daily CR, in participants with rMDD or MCI. Participants were assessed at baseline, week‐8, and yearly. The hypotheses were that compared to sham+sham, CR+tDCS would: slow cognitive decline (H1); reduce progression to MCI or dementia (H2); and acutely improve cognition (H3). The primary outcome composite score was calculated when at least half of the tests for at least four of six cognitive domains were completed. Due to COVID‐19, some participants did not complete enough tests and a second composite score using all available data was generated. Result 375 participants were randomized (Active: N = 188, Mean Age = 72.1 ± 6.3; Sham: N = 187, Mean Age = 72.3 ± 6.4) and received at least one intervention session. Over up to six years, there was no time‐by‐treatment interaction using the primary composite score but there was using the all‐data score. Change in composite score differed between the two intervention groups for the primary and all‐data scores for all years except for year‐6 primary score. The year‐5 adjusted z‐score difference was ‐0.15 (95%CI [‐0.29, ‐0.005]) for the primary and ‐0.21 (95%CI [‐0.34, ‐0.067]) for all‐data score (Fig.1). Comparing active vs. sham at 8‐week (H3), the adjusted z‐score difference was ‐0.06 (95%CI: [‐0.12, 0.005]; p = 0.072); and for progression (H2), HR was 0.66 (95%CI [0.40, 1.08] p = 0.101) in a stratified Cox model. In a preplanned secondary analysis of domain scores, there was a time‐by‐treatment interaction for verbal memory with a year‐5 adjusted z‐score difference of ‐0.30 (95%CI [‐0.53, ‐0.074]) (Fig.2) but not the other domains. In another preplanned secondary analysis, the model with a randomization diagnosis‐by‐time‐by‐treatment was different from the model without this three‐way interaction (p = 0.012; Fig.3). Conclusion CR+tDCS may be effective in slowing cognitive decline (particularly verbal memory) in older patients with rMDD or MCI.

Background Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase‐gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cut‐off is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC‐based groups than diagnostic groups. Method We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N‐back task. An optimal TGC cut‐off was determined during performance of the 2‐back. This TGC cut‐off was used to classify participants into low vs. high TGC groups. We then compared the Cohen’s d of the difference in global cognition between the high and low TGC groups to the Cohen’s d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen’s d values using the whole sample. Result As hypothesized, Cohen’s d for the difference in global cognition between the TGC groups was larger (0.64 [0.32,0.88]) than between the diagnostic groups (0.10 [0.004,0.37]) with a difference between these two Cohen’s d’ s of 0.54[0.10, 0.80]. Conclusion Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.

Background Alzheimer’s dementia (AD) is associated with electroencephalography (EEG) abnormalities including in the power ratio of beta to theta frequencies. EEG studies in mild cognitive impairment (MCI) have been less consistent in identifying such abnormalities. One potential reason is not excluding the EEG aperiodic components, which are less associated with cognition than the periodic components. Here, we investigate whether aperiodic and periodic EEG components are disrupted differently in AD or MCI vs. healthy control (HC) individuals and whether a periodic based beta/theta ratio differentiates better MCI from AD and HC groups than a ratio based on the full spectrum. Methods Data were collected from 44 HC (mean age (SD) = 69.1 (5.3)), 114 MCI (mean age (SD) = 72.2 (7.5)), and 41 AD (mean age (SD) = 75.7 (6.5)) participants. Aperiodic and periodic components and full spectrum EEG were compared among the three groups. Receiver operating characteristic curves obtained via logistic regression classifications were used to distinguish the groups. Last, we explored the relationships between cognitive performance and the beta/theta ratios based on the full or periodic spectrum. Results Aperiodic EEG components did not differ among the three groups. In contrast, AD participants showed an increase in full spectrum and periodic relative powers for delta, theta, and gamma and a decrease for beta when compared to HC or MCI participants. As predicted, MCI group differed from HC participants on the periodic based beta/theta ratio (Bonferroni corrected p-value = 0.036) measured over the occipital region. Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI participants, and outperformed classifiers based on beta/theta power ratio in full spectrum EEG. Beta/theta ratios were comparable in their association with cognition. Conclusions In contrast to a full spectrum EEG analysis, a periodic-based analysis shows that MCI individuals are different on beta/theta ratio when compared to healthy individuals. Focusing on periodic components in EEG studies with or without other biological markers of neurodegenerative diseases could result in more reliable findings to separate MCI from healthy aging, which would be valuable for designing preventative interventions.