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The identification of a neurodegenerative disorders distributed pattern of atrophy-or atrophy signature-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Successful navigation of the environment requires attending and responding efficiently to objects and conspecifics with the potential to benefit or harm (i.e., that have value). In humans, this function is subserved by a distributed large-scale neural network called the "salience network". We have recently demonstrated that there are two anatomically and functionally dissociable salience networks anchored in the dorsal and ventral portions of the human anterior insula (Touroutoglou et al., 2012). In this paper, we test the hypothesis that these two subnetworks exist in rhesus macaques (Macaca mulatta). We provide evidence that a homologous ventral salience network exists in macaques, but that the connectivity of the dorsal anterior insula in macaques is not sufficiently developed as a dorsal salience network. The evolutionary implications of these finding are considered.

Oral contraceptive pills (OCs), which are used to prevent pregnancy by the majority of women in the United States, contain steroid hormones that may affect the brain's structure and function. In this investigation, we tested the hypothesis that OC use is associated with differences in brain structure using a hypothesis-driven, surface-based approach. In 90 women, (44 OC users, 46 naturally-cycling women), we compared the cortical thickness of brain regions that participate in the salience network and the default mode network, as well as the volume of subcortical regions in these networks. We found that OC use was associated with significantly lower cortical thickness measurements in the lateral orbitofrontal cortex and the posterior cingulate cortex. These regions are believed to be important for responding to rewards and evaluating internal states/incoming stimuli, respectively. Further investigations are needed to determine if cortical thinning in these regions are associated with behavioral changes, and also to identify whether OC use is causally or only indirectly related to these changes in brain morphology.

Background: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID‐19 pandemic, and lay the foundation for future work using this cohort. Methods: SAGES II is a prospective observational cohort study of community‐dwelling adults age 65 and older undergoing major non‐cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID‐19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. Results: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty‐eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID‐19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1‐month follow‐up; nearly 90% of enrolled participants completed interviews through 6‐month follow‐up. Conclusion: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers—including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early‐onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD‐signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early‐onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD‐signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD‐signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD‐signature atrophy is a reliable and clinically valid biomarker of AD‐related neurodegeneration that could be used in clinical trials for EOAD. Highlights: We developed an early‐onset Alzheimer's disease (EOAD)–signature of atrophy based on magnetic resonance imaging (MRI) scans.EOAD signature was robustly reproducible across two independent patient cohorts.EOAD signature included prominent atrophy in parietal and posterior temporal cortex.The EOAD‐signature atrophy was associated with the severity of cognitive impairment.EOAD signature is a reliable and clinically valid biomarker of neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Post‐surgical delirium is associated with increased morbidity, lasting cognitive decline, and loss of functional independence. Within a conceptual framework that delirium is triggered by stressors when vulnerabilities exist in cerebral connectivity and plasticity, we previously suggested that neurophysiologic measures might identify individuals at risk for post‐surgical delirium. Here we demonstrate the feasibility of the approach and provide preliminary experimental evidence of the predictive value of such neurophysiologic measures for the risk of delirium in older persons undergoing elective surgery. Methods: Electroencephalography (EEG) and transcranial magnetic stimulation (TMS) were collected from 23 patients prior to elective surgery. Resting‐state EEG spectral power ratio (SPR) served as a measure of integrity of neural circuits. TMS–EEG metrics of plasticity (TMS‐plasticity) were used as indicators of brain capacity to respond to stressors. Presence or absence of delirium was assessed using the confusion assessment method (CAM). We included individuals with no baseline clinically relevant cognitive impairment (MoCA scores ≥21) in order to focus on subclinical neurophysiological measures. Results: In patients with no baseline cognitive impairment (N = 20, age = 72 ± 6), 3 developed post‐surgical delirium (MoCA = 24 ± 2.6) and 17 did not (controls; MoCA = 25 ± 2.4). Patients who developed delirium had pre‐surgical resting‐state EEG power ratios outside the 95% confidence interval of controls, and 2/3 had TMS‐plasticity measures outside the 95% CI of controls. Conclusions: Consistent with our proposed conceptual framework, this pilot study suggests that non‐invasive and scalable neurophysiologic measures can identify individuals at risk of post‐operative delirium. Specifically, abnormalities in resting‐state EEG spectral power or TMS‐plasticity may indicate sub‐clinical risk for post‐surgery delirium. Extension and confirmation of these findings in a larger sample is needed to assess the clinical utility of the proposed neurophysiologic markers, and to identify specific connectivity and plasticity targets for therapeutic interventions that might minimize the risk of delirium. [ABSTRACT FROM AUTHOR]

Background: The Successful Aging after Elective Surgery (SAGES) II study was designed to increase knowledge of the pathophysiology and linkages between delirium and dementia. We examine novel biomarkers potentially associated with delirium, including inflammation, Alzheimer's disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers. The goal of this paper is to describe the study design and methods for the SAGES II study. Methods: The SAGES II study is a 5‐year prospective observational study of 400–420 community dwelling persons, aged 65 years and older, assessed prior to scheduled surgery and followed daily throughout hospitalization to observe for development of delirium and other clinical outcomes. Delirium is measured with the Confusion Assessment Method (CAM), long form, after cognitive testing. Cognitive function is measured with a detailed neuropsychologic test battery, summarized as a weighted composite, the General Cognitive Performance (GCP) score. Other key measures include magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS)/electroencephalography (EEG), and Amyloid positron emission tomography (PET) imaging. We describe the eligibility criteria, enrollment flow, timing of assessments, and variables collected at baseline and during repeated assessments at 1, 2, 6, 12, and 18 months. Results: This study describes the hospital and surgery‐related variables, delirium, long‐term cognitive decline, clinical outcomes, and novel biomarkers. In inter‐rater reliability assessments, the CAM ratings (weighted kappa = 0.91, 95% confidence interval, CI = 0.74–1.0) in 50 paired assessments and GCP ratings (weighted kappa = 0.99, 95% CI 0.94–1.0) in 25 paired assessments. We describe procedures for data quality assurance and Covid‐19 adaptations. Conclusions: This complex study presents an innovative effort to advance our understanding of the inter‐relationship between delirium and dementia via novel biomarkers, collected in the context of major surgery in older adults. Strengths include the integration of MRI, TMS/EEG, PET modalities, and high‐quality longitudinal data. [ABSTRACT FROM AUTHOR]

Posterior cortical atrophy (PCA), usually an atypical clinical syndrome of Alzheimer's disease, has well-characterized patterns of cortical atrophy and tau deposition that are distinct from typical amnestic presentations of Alzheimer's disease. However, the mechanisms underlying the cortical spread of tau in PCA remain unclear. Here, in a sample of 17 biomarker-confirmed (A+/T+/N+) individuals with PCA, we sought to identify functional networks with heightened vulnerability to tau pathology by examining the cortical distribution of elevated tau as measured by 18F-flortaucipir (FTP) PET. We then assessed the relationship between network-specific FTP uptake and visuospatial cognitive task performance. As predicted, we found consistent and prominent localization of tau pathology in the dorsal attention network and visual network of the cerebral cortex. Elevated FTP uptake within the dorsal attention network (particularly the ratio of FTP uptake between the anterior and posterior nodes) was associated with poorer visuospatial attention in PCA; associations were also identified in other functional networks, although to a weaker degree. Furthermore, using functional MRI data collected from each patient at wakeful rest, we found that a greater anterior-to-posterior ratio in FTP uptake was associated with stronger intrinsic functional connectivity between anterior and posterior nodes of the dorsal attention network. Taken together, we conclude that our cross-sectional marker of anterior-to-posterior FTP ratio could indicate tau propagation from posterior to anterior dorsal attention network nodes, and that this anterior progression occurs in relation to intrinsic functional connectivity within this network critical for visuospatial attention. Our findings help to clarify the spatiotemporal pattern of tau propagation in relation to visuospatial cognitive decline and highlight the key role of the dorsal attention network in the disease progression of PCA. [ABSTRACT FROM AUTHOR]