Medial Cortex Research Articles

Causal associations between gut microbiota and regional cortical structure: a Mendelian randomization study.

Observational studies have reported associations between gut microbiota composition and central nervous system diseases. However, the potential causal relationships and underlying mechanisms remain unclear. Here, we applied Mendelian randomization (MR) to investigate the causal effects of gut microbiota on cortical surface area (SA) and thickness (TH) in the brain. We used genome-wide association study summary statistics of gut microbiota abundance in 18,340 individuals from the MiBioGen Consortium to identify genetic instruments for 196 gut microbial taxa. We then analyzed data from 56,761 individuals from the ENIGMA Consortium to examine associations of genetically predicted gut microbiota with alterations in cortical SA and TH globally and across 34 functional brain regions. Inverse-variance weighted analysis was used as the primary MR method, with MR Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out analysis to assess heterogeneity and pleiotropy. At the functional region level, genetically predicted higher abundance of class Mollicutes was associated with greater SA of the medial orbitofrontal cortex (β = 8.39 mm2, 95% CI: 3.08-13.70 mm2, p = 0.002), as was higher abundance of phylum Tenericutes (β = 8.39 mm2, 95% CI: 3.08-13.70 mm2, p = 0.002). Additionally, higher abundance of phylum Tenericutes was associated with greater SA of the lateral orbitofrontal cortex (β = 10.51 mm2, 95% CI: 3.24-17.79 mm2, p = 0.0046). No evidence of heterogeneity or pleiotropy was detected. Specific gut microbiota may causally influence cortical structure in brain regions involved in neuropsychiatric disorders. The findings provide evidence for a gut-brain axis influencing cortical development, particularly in the orbitofrontal cortex during adolescence.

Baseline GABA+ levels in areas associated with sensorimotor control predict initial and long-term motor learning progress.

Synaptic plasticity relies on the balance between excitation and inhibition in the brain. As the primary inhibitory and excitatory neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu), play critical roles in synaptic plasticity and learning. However, the role of these neurometabolites in motor learning is still unclear. Furthermore, it remains to be investigated which neurometabolite levels from the regions composing the sensorimotor network predict future learning outcome. Here, we studied the role of baseline neurometabolite levels in four task-related brain areas during different stages of motor skill learning under two different feedback (FB) conditions. Fifty-one healthy participants were trained on a bimanual motor task over 5 days while receiving either concurrent augmented visual FB (CA-VFB group, N = 25) or terminal intrinsic visual FB (TA-VFB group, N = 26) of their performance. Additionally, MRS-measured baseline GABA+ (GABA + macromolecules) and Glx (Glu + glutamine) levels were measured in the primary motor cortex (M1), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and medial temporal cortex (MT/V5). Behaviorally, our results revealed that the CA-VFB group outperformed the TA-VFB group during task performance in the presence of augmented VFB, while the TA-VFB group outperformed the CA-VFB group in the absence of augmented FB. Moreover, baseline M1 GABA+ levels positively predicted and DLPFC GABA+ levels negatively predicted both initial and long-term motor learning progress in the TA-VFB group. In contrast, baseline S1 GABA+ levels positively predicted initial and long-term motor learning progress in the CA-VFB group. Glx levels did not predict learning progress. Together, these findings suggest that baseline GABA+ levels predict motor learning capability, yet depending on the FB training conditions afforded to the participants.

Cortical myelin and thickness mapping provide insights into whole-brain tumor burden in diffuse midline glioma.

Systemic infiltration is a hallmark of diffuse midline glioma pathogenesis, which can trigger distant disturbances in cortical structure. However, the existence and effects of these changes have been underexamined. This study aimed to investigate whole-brain cortical myelin and thickness alternations induced by diffuse midline glioma. High-resolution T1- and T2-weighted images were acquired from 90 patients with diffuse midline glioma with H3 K27-altered and 64 patients with wild-type and 86 healthy controls. Cortical thickness and myelin content was calculated using Human Connectome Project pipeline. Significant differences in cortical thickness and myelin content were detected among groups. Short-term survival prediction model was constructed using automated machine learning. Compared with healthy controls, diffuse midline glioma with H3 K27-altered patients showed significantly reduced cortical myelin in bilateral precentral gyrus, postcentral gyrus, insular, parahippocampal gyrus, fusiform gyrus, and cingulate gyrus, whereas diffuse midline glioma with H3 K27 wild-type patients exhibited well-preserved myelin content. Furtherly, when comparing diffuse midline glioma with H3 K27-altered and diffuse midline glioma with H3 K27 wild-type, the decreased cortical thickness in parietal and occipital regions along with demyelination in medial orbitofrontal cortex was observed in diffuse midline glioma with H3 K27-altered. Notably, a combination of cortical features and tumor radiomics allowed short-term survival prediction with accuracy 0.80 and AUC 0.84. These findings may aid clinicians in tailoring therapeutic approaches based on cortical characteristics, potentially enhancing the efficacy of current and future treatment modalities.

Me, Myself, and I: Neural Activity for Self versus Other across Development.

Although adults and children differ in self-vs.-other perception, a developmental perspective on this discriminative ability at the brain level is missing. This study examined neural activation for self-vs.-other in a sample of 39 participants spanning four different age groups, from 4-year-olds to adults. Self-related stimuli elicited higher neural activity within two brain regions related to self-referential thinking, empathy, and social cognition processes. Second, stimuli related to 'others' (i.e., unknown peer) elicited activation within nine additional brain regions. These regions are associated with multisensory processing, somatosensory skills, language, complex visual stimuli, self-awareness, empathy, theory of mind, and social recognition. Overall, activation maps were gradually increasing with age. However, patterns of activity were non-linear within the medial cingulate cortex for 'self' stimuli and within the left middle temporal gyrus for 'other' stimuli in 7-10-year-old participants. In both cases, there were no self-vs.-other differences. It suggests a critical period where the perception of self and others are similarly processed. Furthermore, 11-19-year-old participants showed no differences between others and self within the left inferior orbital gyrus, suggesting less distinction between self and others in social learning. Understanding the neural bases of self-vs.-other discrimination during development can offer valuable insights into how social contexts can influence learning processes during development, such as when to introduce peer-to-peer teaching or group learning.

Previous pregnancies might mitigate cortical brain differences associated with surgical menopause.

Surgical menopause causes a sharp drop in estrogen levels in middle-aged women, thus preventing the gradual physiological adaptation that is characteristic of the perimenopause. Previous studies suggest that surgical menopause might increase the risk of dementia later in life. In addition, the transition to motherhood entails long-lasting endocrine and neuronal adaptations. We compared differences in whole-brain cortical volume between women who reached menopause by surgery and a group of women who reached spontaneous non-surgical menopause and determined whether these cortical differences were influenced by previous childbearing. Using surface-based neuroimaging techniques, we investigated cortical volume differences in 201 middle-aged women (134 women who experienced non-surgical menopause, 78 of whom were parous women; and 67 women who experienced surgical menopause, 39 of whom were parous women). We found significant atrophy in the frontal and temporal regions in women who experienced surgical menopause. Nulliparous women with surgical menopause showed significant lower cortical volume in the left temporal gyrus extending to the medial temporal lobe cortex, as well as in the precuneus bilaterally compared to parous women with surgical menopause; whereas our results revealed no significant differences between parous women with surgical menopause and both parous and nulliparous women who reached a non-surgical menopause. Furthermore, in the surgical menopause group, we found a negative correlation between cortical volume and age at first pregnancy in the temporal lobe. Our study suggests that the long-term brain remodeling of parity may mitigate the neural impact of the sudden drop in estrogen levels that characterizes surgical menopause.

Periodontitis causally affects the brain cortical structure: A Mendelian randomization study.

To estimate whether genetically proxied periodontitis causally impacts the brain cortical structure using Mendelian randomization (MR). Periodontitis is one of the most prevalent inflammatory conditions globally, and emerging evidence has indicated its influences on distal organs, including the brain, whose disorders are always accompanied by magnetic resonance imaging (MRI)-identified brain cortical changes. However, to date, no available evidence has revealed the association between periodontitis and brain cortical structures. The instrumental variables (IVs) were adopted from previous genome-wide association study (GWAS) studies and meta-analyses of GWAS studies of periodontitis from 1844 to 5266 cases and 8255 to 12 515 controls. IVs were linked to GWAS summary data of 51 665 patients from the ENIGMA Consortium, assessing the impacts of genetically proxied periodontitis on the surficial area (SA) or the cortical thickness (TH) of the global and 34 MRI-identified functional regions of the brain. Inverse-variance weighted was used as the primary estimate; the MR pleiotropy residual sum and outlier (MR-PRESSO), the MR-Egger intercept test, and leave-one-out analyses were used to examine the potential horizontal pleiotropy. Genetically proxied periodontitis affects the SA of the medial orbitofrontal cortex, the lateral orbitofrontal cortex, the inferior temporal cortex, the entorhinal cortex, and the temporal pole, as well as the TH of the entorhinal. No pleiotropy was detected. Periodontitis causally influences the brain cortical structures, implying the existence of a periodontal tissue-brain axis.

Mapping brain functional networks topological characteristics in new daily persistent headache: a magnetoencephalography study

BackgroundThe brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings.MethodsResting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory.ResultsIn the delta (1–4 Hz) and beta (13–30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4–8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band.ConclusionThe FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [18F]FDG-PET

In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [18F]UCB-H. We hypothesized that in those regions hypometabolism may reflect reduced functional connectivity rather than synaptic damage. To test this hypothesis, we performed seed-based metabolic connectivity analyses using [18F]FDG-PET data in this mouse model. Eight rTg4510 mice at the age of seven months and 8 non-transgenic littermates were injected intraperitoneally with 11.1 ± 0.8 MBq [18F]FDG and spent a 35-min uptake period awake in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner for 30 min. Three seed-based connectivity analyses were performed per group. Seeds were selected for apparent mismatch between [18F]FDG and [18F]UCB-H. A seed was placed either in the medial orbitofrontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals. In the control group, the emerging correlative pattern was strongly overlapping for all three seed locations, indicating a uniform fronto-thalamo-hippocampal resting state network. In contrast, rTg4510 mice showed three distinct networks with minimal overlap. Frontal and thalamic networks were greatly diminished. The hippocampus, however, formed a new network with the whole parietal cortex. We conclude that resting-state functional networks are fragmented in the brain of rTg4510 mice. Thus, hypometabolism can be explained by reduced functional connectivity of brain areas devoid of tau-related pathology, such as the thalamus.

How many anchors to use in arthroscopic Bankart repairs? A biomechanical study of postage-stamp glenoid fractures.

Deciding how many anchors to use in a Bankart repair is challenging because of the desire to enhance stability while avoiding a postage-stamp fracture of the glenoid rim. This controlled laboratory study investigated load to fracture of the anterior glenoid rim after drilling holes of varying number and diameter and inserting anchors of 2 different types and sizes, with and without perforation of the medial cortex of the glenoid, creating postage-stamp fractures using a metallic humeral head that was compressed against the anterior glenoid rim. A destructive model with a servohydraulic load frame was used to test 46 synthetic scapulae with compressive strength and elastic modulus similar to that of a human glenoid. Load to fracture of the intact glenoid was compared with groups with a varying number of anchor holes of different diameters, with anchors of different sizes and types, and with anchors perforating or not perforating the glenoid medial cortex. The percentage of force to fracture an intact specimen was used to identify relative risk of fracture: low risk >75%, moderate risk 75%-50%, and high risk <50% of intact load. The load to fracture of intact glenoids was 1276±42 N. Loads decreased linearly as the number of holes drilled on the glenoid rim increased. Compared with the 1.6-mm group, the 3.0-mm group had significantly lower glenoid rim strength in specimens with 4, 5, and 7 holes (P=.013, .032, and .045, respectively). All-suture anchors in 1.6-mm holes did not alter the glenoid rim strength, and up to 5 anchors were associated with low risk of fracture. Load to fracture was significantly higher with 3.0-mm rigid core bioabsorbable anchors with 4 anchors (1081±6 N) compared with the 4-hole condition (838±107 N; P=.033). Perforating the glenoid medial cortex with five 1.6-mm anchors significantly weakened the glenoid rim to 58% of intact (P=.012). Perforating the medial cortex weakened the glenoid rim to 52% and 42% (P<.001 for both) of intact in the 3.0-mm 4-anchor and 5-anchor constructions, constituting moderate and high risk of fracture, respectively. Up to five 1.6-mm all-suture anchors and four 3.0-mm bioabsorbable rigid-core anchors were associated with low risk of fracture of the glenoid rim. Smaller diameter all-suture anchors best preserved structural integrity of the glenoid rim, whereas tunnel enlargement and perforation of the glenoid medial cortex were associated with moderate or high risk of a postage-stamp fracture.

Out‐of‐the box automated computation of cortical thickness of the medial perirhinal cortex does not replace segmentation by hand

AbstractBackgroundCortical thickness of the medial perirhinal cortex (mPRC) is a promising marker of early, potentially pre‐clinical Alzheimer’s disease (AD) because atrophy of this region is causally linked to intracellular neurofibrillary tangles. Neurofibrillary pathology, a major neuropathological characteristic of AD, typically starts in the mPRC, also referred to as the transentorhinal cortex. From there it spreads to the entorhinal cortex and eventually to the hippocampus. To date, no tools exist that automatically compute the cortical thickness of the mPRC, most likely because of the novelty and complexity of the manual segmentation protocol and the large variability of the morphology of the mPRC. Herein, we aimed to develop an automated segmentation algorithm for the mPRC.MethodAn experienced rater (SK) manually segmented the mPRC from two data sets (train: n = 103; test: n = 44) using the FreeSurfer segmentation tools. The train data set (mean age = 76.4 ± 7.0 years; normal controls and patients with AD) was used to train the native FreeSurfer segmentation algorithm with the custom region as well as a voxel‐based deep convolutional neural network based on nnUNet with minimal adaptations to the training protocol. In a next step, the trained models were applied to the test data set (mean age = 69.2 ± 10.4 years; normal controls, AD, major depression, and mild cognitive impairment or dementia due to other etiologies than AD) and cortical thickness values were extracted. Finally, cortical thickness values of both segmentations were compared individually to the manual segmentation.ResultsIntraclass correlation coefficients (ICCs) between FreeSurfer and the manual segmentation reached .768 for the left hemisphere (lh) and .835 for the right hemisphere (rh). The deep learning method compared to the manual segmentation achieved ICCs of .840 for lh and .896 for rh.ConclusionThe deep learning based procedure outperformed the native FreeSurfer segmentation in this complicated segmentation task. Nevertheless, it did not reach inter‐human reliability (SK vs. unexperienced rater (NAH): lh = .953 and rh = .986). Next steps are customization of the deep learning algorithm and validation of clinical usefulness.

Longitudinal cortical thinning is associated with cognitive decline in MCI and Alzheimer’s disease in the Korean population

AbstractUndAlzheimer’s disease (AD) is characterized by cognitive dysfunction likely secondary to progressive neurodegeneration in the brain. However, to what extent regional cortical thickness (CT) changes are related to cognitive decline in the Asian population remains unclear.MethodWe measured CT using Freesurfer v6 from T1‐weighted magnetic resonance imaging (MRI) data in 603 Korean participants, including 71 young and 288 old cognitively unimpaired (CU young and CU old), 149 with mild cognitive impairment (MCI), and 92 AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). Cognitive function of each participant was quantified by the MMSE. MRI and cognitive data were acquired at baseline (n = 603) and a 2‐year follow‐up visit (n = 380). Linear mixed‐effect models were used to estimate diagnosis group, time, and group‐by‐time interaction effects on CT measurements, with age, sex, and education as covariates. Pearson’s correlations between CT measurements and MMSE total score were computed, corrected for multiple comparisons by false discovery rate (FDR).ResultAt baseline, CU old participants had lower CT values than CU young participants in the inferior parietal cortex and frontal and parietal regions. In comparison with CU old participants, MCI and AD showed widespread lower CT values, more pronounced in the medial temporal lobe (i.e., the entorhinal cortex and parahippocampal gyrus), inferior temporal cortex, medial prefrontal cortex, and medial parietal cortex (i.e., the posterior cingulate cortex and precuneus), with AD lower than MCI in these regions. These regions also showed the most longitudinal atrophy in both AD and MCI over 2 years. AD patients showed faster and more widespread atrophy patterns than MCI and CU old participants. We identified significant (PFDR&lt;0.05) positive linear correlations between cognitive decline and regional CT measurements, particularly in regions showing significant cortical thinning across time.ConclusionIn this study, we replicated the typical cross‐sectional and longitudinal brain atrophy patterns, and relationships with cognitive decline in an Asian cohort. Our findings support the generalizability of atrophy patterns in MCI and AD, suggesting common neurobiological mechanisms underlying AD symptoms across different ethnoracial populations.

Individual‐specific change in Alzheimer’s disease vulnerable brain regions across the healthy adult lifespan is associated with genetic AD risk

AbstractBackgroundAcross the healthy adult lifespan, our brain’s undergo widespread structural change. Many of these changes – occurring gradually across life – are not qualitatively distinct from atrophy patterns seen in Alzheimer’s disease (AD), raising the possibility accelerated longitudinal brain change across healthy adult life may relate to genetic AD‐risk.MethodWe modelled subject‐specific structural brain change relative to that expected given age, in dense longitudinal adult lifespan data (1430 scans from 420 individuals aged 30 to 89 years; 2‐7 timepoints). Using polygenic AD scores (PRS‐AD) from four GWAS, we tested PRS‐AD associations with age‐relative change in early Braak stage regions – namely hippocampus, entorhinal cortex, amygdala, and medial temporal cortex. Next, to empirically identify features with accelerated change in AD, in ADNI data (scans = 4410; N = 978) we applied machine learning classification on the subject‐specific slopes estimated from individuals classed as consistently healthy over time versus those succumbing to AD. In healthy adult lifespan data, we then tested PRS‐AD associations with age‐relative change, in many combinations of brain features with model‐implied importance. Lastly, we tested whether high PRS‐AD individuals showing more negative brain change exhibit more longitudinal memory decline over healthy adult life.ResultIn healthy adult lifespan data, we observed many significant PRS‐AD associations with age‐relative change in hippocampus (bilateral), right entorhinal cortex, amygdala (bilateral), and left medial temporal cortex, and typically for all four scores (FDR‐corrected). We show that age‐relative change across the healthy adult lifespan in many combinations of AD‐accelerated features is significantly associated with PRS‐AD. As proof‐of‐principle, applying the ADNI‐derived model weights to the healthy adult lifespan data also enabled detection of PRS‐AD associations in healthy adults, but only using models trained on age‐relative change. Most, but not all, of the observed PRS‐AD associations were driven by APOE. Finally, we find high PRS‐AD individuals with more negative brain change exhibit significantly more memory decline, relative to high PRS‐AD individuals with less brain change.ConclusionThe results support a dimensional account linking gradual lifespan brain changes with pathological aging, and demonstrate PRS‐AD impacts the slope of brain aging in most AD‐relevant brain regions in healthy adults.

Validating noninvasive techniques for 11C‐ER176 PET quantification in controls and Alzheimer’s disease patients

AbstractBackgroundNoninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer’s disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies.MethodDynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (V T) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived V T vs. RR‐derived SUVR) and across groups (controls vs. patients).ResultWithin each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p &lt; 0.001; Patients: R2 = 0.983, p &lt; 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for V T and 10.65% between groups for SUVR, but lower variance for SUVR compared to V T (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3).ConclusionResults suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than V T in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification.

P168: Resilience and cortical thickness in the medial orbitofrontal cortex in Japanese older cancer survivors: A population-based cross-sectional study

P168: Resilience and cortical thickness in the medial orbitofrontal cortex in Japanese older cancer survivors: A population-based cross-sectional study

Cerebral perfusion and amyloidosis in the oldest‐old

AbstractBackgroundCerebrovascular contributions to cognitive aging and Alzheimer’s disease (AD) risk represent a growing field in aging research. Studies in the young‐old have demonstrated the critical role of vascular dysregulation (i.e., altered cerebral blood flow) in relation to cognitive decline prior to the appearance of amyloid/tau biomarkers. However, cerebral perfusion has not been well‐studied in the oldest‐old (ages 90 and over), a rapidly growing population that may provide unique insight into resilience and protective factors against dementia in later life. We characterized amyloid and cerebral perfusion profiles of cognitively normal (CN) and cognitively impaired without dementia (CIND) oldest‐old individuals.MethodParticipants were 97 dementia‐free older adults (70 CN and 27 CIND) from the 90+ Study who had available neuroimaging (T1‐MRI, ASL‐MRI, Florbetapir‐PET), demographic, and clinical data. We examined differences between CN and CIND in regional perfusion in areas associated with AD risk (medial temporal lobe, posterior cingulate, precuneus, frontal cortex, inferior parietal lobe) and in amyloid burden using linear regression models controlling for age, sex, education, APOE4 status, and vascular risk factors.ResultCN and CIND groups did not differ in the characteristics compared (Table 1). CIND participants had lower CBF in the posterior cingulate/precuneus than the CN group, but groups did not differ in posterior cingulate/precuneus amyloid SUVR (Figure 1). Additionally, CIND had lower CBF than CN in the inferior parietal lobe but higher CBF in the medial temporal lobe and orbitofrontal cortex (Figure 2).ConclusionCIND individuals had lower regional perfusion in the posterior cingulate/precuneus, but groups did not differ in amyloidosis, highlighting the relationship between cerebrovascular function and cognitive status in the oldest‐old independent of amyloidosis. Our findings complement previously reported posterior cingulate/precuneus hypoperfusion in younger‐old individuals with cognitive impairment and AD. Interestingly, we observed greater medial temporal/frontal perfusion in CIND than CN, similar to previous studies demonstrating initial hyperperfusion preceding hypoperfusion across the CN‐CIND‐Dementia spectrum. This may represent a compensatory vascular mechanism supporting cognition in individuals at greater risk of developing dementia. Future studies will further characterize this cohort with longitudinal perfusion analyses, neuropsychological correlates, and relationships between perfusion and other indices of cerebrovascular dysfunction.

Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network

AbstractBackgroundStudies suggest distinct differences in the development, presentation and longitudinal progression of Alzheimer’s Disease (AD) between women and men. However, most of these sex‐specific differences have been explored in symptomatic stages of sporadic AD. We investigated cross‐sectional sex differences in clinical‐cognitive assessments as well as fluid and imaging biomarkers in the spectrum of dominantly inherited AD (DIAD).Method319 DIAD mutation carriers of the Dominantly Inherited Alzheimer Network‐Observational study (DIAN‐OBS) were included in the analysis and, according to Clinical Dementia Rating® (CDR®) scores, classified as presymptomatic (CDR = 0, 66,1%) or symptomatic (CDR&gt;0). All participants underwent clinical and neuropsychological assessment; lumbar puncture, structural MRI and 11C‐PiB‐PET imaging for amyloid‐β detection were conducted. Mann‐Whitney‐U‐test, Fisher’s Exact and linear mixed models with fixed effects for sex, estimated age of onset (EYO) and their interaction, a random effect for family, and years of education and CDR Sum of Boxes as covariates (where appropriate) were used to explore cross‐sectional sex differences.ResultDemographics showed no significant sex differences in presymptomatic (pMC, 56.4% women, p&gt;0.05) or symptomatic mutation carriers (sMC, 52,7% women, p&gt;0.05). In pMC, men showed a worse performance on the Digit Symbol test (p&lt;0.01, Fig.1) than women, and, in interaction with EYO, a better performance in immediate (p&lt;0.05) and delayed (p&lt;0.05) prose recall. In contrast, sMC men performed better on the Animal Naming test (p&lt;0.05), but, in interaction with EYO, worse on the Digit Span forward (p&lt;0.01). CSF analysis did not indicate sex‐related differences in Aβ42/Aβ40‐Ratio, phosphorylated Tau‐181 or total Tau levels (all p&gt;0.05) in either group. In pMC men, PET imaging revealed significantly less tracer binding in the medial orbitofrontal cortex, the frontal pole and the rostral &amp; caudal anterior cingulate in interaction with EYO (all p&lt;0.05, Fig. 2). Furthermore, MRI volume analysis showed a significant reduction in the amygdala in women compared to men (p&lt;0.01) in sMC.ConclusionWe report preliminary results suggesting cross‐sectional sex differences in presymptomatic and symptomatic DIAD mutation carriers regarding episodic, verbal and working memory; processing speed; as well as differential patterns of PiB‐PET burden within cerebral areas related to emotion, decision making and cognitive flexibility.

Validating noninvasive techniques for 11C‐ER176 PET quantification in controls and Alzheimer’s disease patients

AbstractBackgroundNoninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer’s disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies.MethodDynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (VT) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived VT vs. RR‐derived SUVR) and across groups (controls vs. patients).ResultWithin each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p &lt; 0.001; Patients: R2 = 0.983, p &lt; 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for VT and 10.65% between groups for SUVR, but lower variance for SUVR compared to VT (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3).ConclusionResults suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than VT in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification.

Protective effects of sleep duration and physical activity on cognitive performance are influenced by β‐amyloid and brain volume but not tau burden among cognitively unimpaired older adults

AbstractBackgroundSleep and physical activity have gained traction as modifiable risk factors for Alzheimer’s disease (AD). Sleep duration is linked to amyloid‐β (Aβ) clearance while physical activity is associated with brain volume maintenance. We investigate associations between sleep duration and physical activity and cognition by testing if sleep duration—cognition and physical activity—cognition are explained by Aβ deposition and brain volume, respectively. Additionally, we explore the mediating role of tau burden in these relationships.MethodThis cross‐sectional study obtained data from participants in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a randomized clinical trial. Cognitively unimpaired participants underwent Aβ and tau PET and brain MRI prior to randomization. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Self‐reported nightly sleep duration and weekly physical activity were the primary predictors. Regional Aβ and tau pathologies and volumes were the proposed variables influencing sleep duration—cognition or physical activity—cognition relationships.ResultAβ PET data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with an Aβ composite burden (β = ‐0.005,CI:(‐0.01,‐0.001)) and Aβ burden in the anterior cingulate (ACC) (β = ‐0.012,CI:(‐0.017,‐0.006)) and medial orbitofrontal cortices (MOC) (β = ‐0.009,CI:(‐0.014,‐0.005)) but not with brain structure. Composite (β = ‐1.54,CI:(‐1.93,‐1.15)), ACC (β = ‐1.22,CI:(‐1.54,‐0.90)) and MOC (β = ‐1.44,CI:(‐1.86,‐1.02)) Aβ burden were also associated with PACC. Sleep duration—PACC association was explained by Aβ burden in path analyses (Figure 1). Physical activity was not associated with Aβ but was associated with hippocampal (β = 10.57,CI: (1.06,20.08)), parahippocampal (β = 9.3,CI:(1.69,16.91)), entorhinal (β = 14.68,CI:(1.75,27.61), and fusiform gyral (β = 38.38,CI:(5.57, 71.18)) volumes, which were also positively associated with PACC (p&lt;0.02 for hippocampus, entorhinal cortex, and fusiform gyrus). Physical activity—cognition relationship was explained by regional volumes (Figure 2). Tau was not related to sleep duration or physical activity, and it did not moderate relationships between cognition and sleep duration or physical activity.ConclusionSleep duration and physical activity are associated with cognition through independent paths of brain Aβ and brain volume, respectively, but not tau burden. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for AD.

Predicting change in depressive symptoms using longitudinal regional amyloid and cognition in cognitively unimpaired older adults

AbstractBackgroundDepression is a neuropsychiatric symptom of Alzheimer’s disease (AD) and has been linked to greater cortical amyloid burden in preclinical AD. We sought to examine whether amyloid accumulation in brain regions subserving emotional control and changes in cognitive performance may contribute to increased depressive symptomatology over time.Method155 cognitively unimpaired participants who were below the cortical amyloid (&lt;0.86DVR) and clinical depression thresholds (&lt;12 on Geriatric Depression Scale (GDS); mean age = 72.6) at baseline were included from the Harvard Aging Brain Study, with annual GDS and Preclinical Alzheimer Cognitive Composite (PACC) assessment and MRI/PiB‐PET every three years (mean years follow‐up = 7.06). PiB slopes were calculated for FreeSurfer‐defined bilateral regions of interest (ROI) implicated in emotional control: amygdala, medial and lateral orbitofrontal cortices (mOFC, lOFC), superior and middle frontal (MFC) cortices, anterior cingulate (ACC), posterior cingulate (PCC), and isthmus cingulate (IC). Linear mixed‐effects models assessed whether main‐effects of ROI PiB slope and PACC slope predicted longitudinal GDS scores for each ROI, covarying for age, sex, education, and random intercept/slope, adjusted for multiple comparisons. Post‐hoc linear regression models assessed relationships between PiB and PACC slopes.ResultSteeper PiB slopes in the mOFC, MFC, ACC, and IC were associated with increasing GDS scores over time, while a decreasing PACC slope was predictive of increasing GDS scores over time in all regions (Table 1). Post‐hoc analyses indicated that PiB slopes were not significantly correlated with PACC slope (Figure 1).ConclusionIn a cohort of cognitively unimpaired older adults with low cortical amyloid and no/subclinical depressive symptoms at baseline, increasing depressive symptoms over time were significantly associated with both amyloid accumulation in specific regions associated with emotional control (i.e., mOFC, MFC, ACC, and IC) and worsening cognitive performance. Furthermore, changes in cognition were not significantly associated with changes in amyloid accumulation in regions involved in emotional control, suggesting that different factors may be independently influencing trajectories in depression versus cognition over time. These results shed light on the neurobiology of depression in older individuals and underscore the importance of monitoring new and increasing neuropsychiatric symptoms in addition to cognitive symptoms when screening for AD.

The impact of sex on the progression of AD atrophy‐based subtypes

AbstractBackgroundRecently, longitudinal subtypes in AD have been identified based on their different brain atrophy trajectories (Poulakis et al. 2022 Nat Commun), which follow either mediotemporal or cortical pathways. The mediotemporal pathway, which is the most prevalent, includes three longitudinal subtypes: the limbic predominant plus (LPA+), the limbic predominant (LPA), and the minimal atrophy (MA) subtypes. While the LPA+ is characterised by the fastest rate of atrophy starting in the entorhinal cortex and later spreading to the temporal lobe and the rest of the cortex, the LPA is restrained to atrophy in temporal regions. The MA subtype, on the other side, is characterised by minimal atrophy in mediotemporal areas. Although the discovery of brain atrophy trajectories in AD represents a significant contribution towards precision medicine, the impact of sex – a major risk factor for AD – on these trajectories has yet to be explored.MethodWe used longitudinal magnetic resonance imaging data as well as clinical data (up to 5 timepoints) from 3 international AD cohorts (ADNI, J‐ADNI and AIBL). AD individuals had previously been identified, as one of the following longitudinal subtypes: LPA+ (N = 23, 61% females), LPA (N = 93, 48% females), and MA subtype (N = 189, 48% females). We applied linear mixed effect models (LMMs) on 34 cortical and 7 subcortical regions to assess differences in sex within each AD longitudinal subtype. Results were adjusted for ageing effects, cohort, disease duration and intracranial volume.ResultLPA+ females showed greater atrophy over time compared to LPA+ males in frontal regions as well as in the lingual and the parahippocampal gyri. LPA females tended to show greater atrophy in the medial orbitofrontal cortex compared to LPA males. Finally, within the MA subtype, females showed greater atrophy than males in the hippocampus over time.ConclusionThis study demonstrates that sex‐specific regional vulnerabilities are crucial to consider in the study of AD heterogeneity, particularly within the mediotemporal pathway. Our results reveal that females exhibit distinct atrophy patterns over time compared to males in different AD subtypes, emphasizing the importance of investigating sex‐related differences to develop more targeted and effective interventions for AD.