Cheryl L. Grady

Early midlife bilateral salpingo‐oophorectomy (BSO) is associated with greater Alzheimer's disease risk compared to spontaneous/natural menopause. Previously, we found that participants with BSO had lower volume in the hippocampal dentate gyrus and cornu ammonis 2/3 composite subfield (DG‐CA2/3). We sought to extend those hippocampal subfield findings by assessing whether BSO affected volumes along the anteroposterior hippocampal axis, anterolateral entorhinal cortex, and perirhinal cortex subregions (Brodmann area (BA) 35 and 36). We also correlated volumes with key demographic and wellbeing‐related factors (age, depressive mood, education), hormone therapy characteristics, and recognition memory performance. Early midlife participants with BSO (with and without 17β‐estradiol therapy (ET)) and age‐matched control participants with intact ovaries (AMC) completed high‐resolution T2‐weighted structural magnetic resonance imaging (MRI). Medial temporal lobe volumes and Remember‐Know task recognition memory performance were compared between groups—BSO ( n = 23), BSO + ET ( n = 28), AMC ( n = 34) using univariate analyses. Multivariate Partial Least Squares (PLS) analyses were used to examine how volumes related to demographic and wellbeing‐related factors, as well as hormone therapy characteristics. Relative to BSO + ET, BSO had lower posterior hippocampal and DG‐CA2/3 volumes but greater perirhinal BA 36 volumes. Compared to age, depressive mood, and education, ET was the strongest positive predictor of hippocampal volumes and negative predictor of perirhinal BA 36 volumes. For BSO + ET, hippocampal volumes were negatively related to ET duration and positively related to concurrent progestogen therapy. Relative to AMC, BSO had greater anterolateral entorhinal cortex and perirhinal BA 35 and BA 36 volumes. BSO groups (with and without ET) relied more on familiarity than recollection for successful recognition memory. BSO and ET may have distinct effects on medial temporal lobe volumes, with potential implications for memory processes affected by Alzheimer's disease risk.

Similarity analyses between multiple correlation or covariance tables constitute the cornerstone of network neuroscience. Here, we introduce covSTATIS, a versatile, linear, unsupervised multi-table method designed to identify structured patterns in multi-table data, and allow for the simultaneous extraction and interpretation of both individual and group-level features. With covSTATIS, multiple similarity tables can now be easily integrated, without requiring a priori data simplification, complex black-box implementations, user-dependent specifications, or supervised frameworks. Applications of covSTATIS, a tutorial with Open Data and source code are provided. CovSTATIS offers a promising avenue for advancing the theoretical and analytic landscape of network neuroscience.

Background: Plasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.Method: 290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.Result: There was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).Conclusion: We conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

Temporal variability of the fMRI-derived blood-oxygen-level-dependent (BOLD) signal during cognitive tasks shows important associations with individual differences in age and performance. Less is known about relations between spontaneous BOLD variability measured at rest and relatively stable cognitive measures, such as IQ or socioemotional function. Here, we examined associations among resting BOLD variability, cognitive/socioemotional scores from the NIH Toolbox and optimal time of day for alertness (chronotype) in a sample of 157 adults from 20 to 86 years of age. To investigate individual differences in these associations independently of age, we regressed age out from both behavioral and BOLD variability scores. We hypothesized that greater BOLD variability would be related to higher fluid cognition scores, more positive scores on socioemotional scales and a morningness chronotype. Consistent with this idea, we found positive correlations between resting BOLD variability, positive socioemotional scores (e.g. self-efficacy) and morning chronotype, as well as negative correlations between variability and negative emotional scores (e.g. loneliness). Unexpectedly, we found negative correlations between BOLD variability and fluid cognition. These results suggest that greater resting brain signal variability facilitates optimal socioemotional function and characterizes those with morning-type circadian rhythms, but individuals with greater fluid cognition may be more likely to show less temporal variability in spontaneous measures of BOLD activity.

Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729–12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) “within” single voxels over time, termed single-voxel autocorrelation and (ii) “between” different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.

The human angular gyrus (AG) is implicated in recollection, or the ability to retrieve detailed memory content from a specific episode. A separate line of research examining the neural bases of more general mnemonic representations, extracted over multiple episodes, also highlights the AG as a core region of interest. To reconcile these separate views of AG function, the present fMRI experiment used a Remember-Know paradigm with famous (prior knowledge) and non-famous (no prior knowledge) faces to test whether AG activity could be modulated by both task-specific recollection and general prior knowledge within the same individuals. Increased BOLD activity in the left AG was observed during both recollection in the absence of prior knowledge (recollected > non-recollected or correctly rejected non-famous faces) and when prior knowledge was accessed in the absence of experiment-specific recollection (famous > non-famous correct rejections). This pattern was most prominent for the left AG as compared to the broader inferior parietal lobe. Recollection-related responses in the left AG increased with encoding duration and prior knowledge, despite prior knowledge being incidental to the recognition decision. Overall, the left AG appears sensitive to both task-specific recollection and the incidental access of general prior knowledge, thus broadening our notions of the kinds of mnemonic representations that drive activity in this region.

Βeta‐amyloid (Aβ) is a neurotoxic protein that deposits early in the pathogenesis of preclinical Alzheimer's disease. We aimed to identify network connectivity that may alter the negative effect of Aβ on cognition. Following assessment of memory performance, resting‐state fMRI, and mean cortical PET‐Aβ, a total of 364 older adults (286 with clinical dementia rating [CDR‐0], 59 with CDR‐0.5 and 19 with CDR‐1, mean age: 74.0 ± 6.4 years) from the OASIS‐3 sample were included in the analysis. Across all participants, a partial least squares regression showed that lower connectivity between posterior medial default mode and frontoparietal networks, higher within‐default mode, and higher visual–motor connectivity predict better episodic memory. These connectivities partially mediate the effect of Aβ on episodic memory. These results suggest that connectivity strength between the precuneus cortex and the superior frontal gyri may alter the negative effect of Aβ on episodic memory. In contrast, education was associated with different functional connectivity patterns. In conclusion, functional characteristics of specific brain networks may help identify amyloid‐positive individuals with a higher likelihood of memory decline, with implications for AD clinical trials.

According to the cortical disconnection hypothesis, age-related changes in white matter may disrupt neural communication, which in turn can impair behavioral performance, including response inhibition and processing speed. In addition, older adults sometimes over-recruit regions of the frontoparietal network as measured using fMRI. To determine whether frontoparietal over-recruitment compensates for white matter dysconnectivity in aging, 145 healthy adults (18-86 years old) underwent a diffusion-weighted imaging scan and completed a response inhibition task (Go/No-go) in the fMRI scanner. Older adults and female participants were slower but equally as accurate compared to younger adults and male participants, respectively. We observed differential frontoparietal recruitment across the cerebral hemispheres, with increasing activity in the right hemisphere in older age. Moreover, frontoparietal white matter mediated the association between age and processing speed (Go reaction times), but not between age and inhibition (No-go accuracy). These results add to the literature on age-related frontoparietal over-recruitment in the domain of response inhibition and suggest that cortical disconnection is an underlying driver of selective age-related differences in behavioral performance.