Inferior Temporal Regions Research Articles

Effects of List-Mode-Based Intraframe Motion Correction in Dynamic Brain PET Imaging.

Motion is unavoidable in dynamic [18F]-MK6240 Positron Emission Tomography (PET) imaging, especially in Alzheimer's disease (AD) research requiring long scan duration. To understand how motion correction affects quantitative analysis, we investigated two approaches: II-MC, which corrects for both inter-frame and intra-frame motion, and IO-MC, which only corrects for inter-frame motion. These methods were applied to 83 scans from 34 subjects, and we calculated distribution volume ratios (DVR) using the multilinear reference tissue model with two parameters (MRTM2) in tau-rich brain regions. Most of the studies yielded similar DVR results for both II-MC and IO-MC. However, in one scan of an AD subject, the inferior temporal region showed 14% higher DVR with II-MC compared to IO-MC. This difference was reasonable given the AD diagnosis, although similar results were not observed in other regions. Although discrepancies between IO-MC and II-MC results were rare, they underscore the importance of incorporating intra-frame motion correction for more accurate and dependable PET quantitation, particularly in the context of dynamic imaging. These findings suggest that while the overall impact of intra-frame motion correction may be subtle, it can improve the reliability of longitudinal PET data, ultimately enhancing our understanding of tau protein distribution in AD pathology.

Parietal memory network and memory encoding versus retrieval impairments in PD-MCI patients: A hippocampal volume and cortical thickness study.

The pathophysiology behind memory impairment in Parkinson's Disease Mild Cognitive Impairment (PD-MCI) is unclear. This study aims to investigate the hippocampal and cortical atrophy patterns in PD-MCI patients with different types of memory impairments, categorized as Retrieval Failure (RF) and Encoding Failure (EF). The study included 16 healthy controls (HC) and 34 PD-MCI patients, divided into RF (N = 18) and EF (N = 16) groups based on their Verbal Memory Processes Test (VMPT) scores, including spontaneous recall, recognition, and Index of Sensitivity to Cueing (ISC). Hippocampal subfields and cortical thicknesses were measured using the FreeSurfer software for automatic segmentation. Compared to the HC group, the EF group exhibited significant atrophy in the left lateral occipital region and the right caudal middle frontal, superior temporal, and inferior temporal regions (p⟨0.05). The RF group displayed significant atrophy in the left lateral occipital, middle temporal, and precentral regions, as well as the right pars orbitalis and superior frontal regions (p⟨0.05). Hippocampal subfield analysis revealed distinct volume differences between HC-EF and RF-EF groups, with significant reductions in the CA1, CA3, and CA4 subregions in the EF group, but no differences between HC and RF groups (p > 0.05). Gray matter atrophy patterns differ in PD-MCI patients with encoding and retrieval memory impairments. The significant hippocampal atrophy in the EF group, particularly in the CA subregions, highlights its potential role in disease progression and memory decline. Additionally, the convergence of atrophy in the lateral occipital cortex across both RF and EF groups suggests the involvement of the Parietal Memory Network (PMN) in PD-related memory impairment.

Cerebral cortex changes in FD, IBS, and GERD: A Mendelian randomization study

BackgroundProspective and cross-sectional studies have reported an association between functional gastrointestinal disorders and anxiety and depression. However, the causal relationship is unclear. Therefore, we used Mendelian randomization (MR) to determine the causal effects of common gastrointestinal disorders on cortical structures. MethodsGenome-wide association study (GWAS) data for functional dyspepsia (FD), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD) were obtained from 329,262, 16,792, and 602,604 Europeans, respectively. GWAS cerebral cortical architecture data for cortical thickness (TH) and surface area (SA) were obtained from 51,665 MRI scans. MR was used to analyze the casual relationship between FD, IBS, GERD, and cortical structures. Inverse-variance weighted, weighted median, and MR–Egger tests were performed as assessment indicators. We also evaluated heterogeneity and pleiotropy. ResultsThe results revealed that FD significantly decreases the TH in the rostral anterior cingulate cortex (βTH = −0.022 mm; 95%CI: −0.035 mm to −0.009 mm2; PTH = 6.89 × 10−4), and IBS significantly decreases the SA of the pars triangularis (βSA = −21.91 mm2; 95%CI: −32.99 mm to −10.83 mm2; PSA = 1.06 × 10−4), precuneus (βSA = −47.53 mm2; 95%CI: −73.57 mm to-21.48 mm2; PSA = 3.48 × 10−4) and superior frontal regions (βSA = −78.70 mm2; 95%CI: −122.61 mm to −34.78 mm2; PSA = 4.4 × 10−4). At the local functional level, GERD significantly increases the SA of the inferior temporal region (βSA = −113.58 mm2, 95%CI: −113.58 mm to −39.01 mm2, PSA = 6.05 × 10−5). ConclusionsFD, IBS and GERD can affect the cerebral cortex architecture through the brain-gut axis, thus increasing the risks of mental illness and cognitive dysfunction.

Functional Brain Adaptations During Speech Processing in 4-Month-Old Bilingual Infants.

Language learning is influenced by both neural development and environmental experiences. This work investigates the influence of early bilingual experience on the neural mechanisms underlying speech processing in 4-month-old infants. We study how an early environmental factor such as bilingualism interacts with neural development by comparing monolingual and bilingual infants' brain responses to speech. We used functional near-infrared spectroscopy (fNIRS) to measure 4-month-old Spanish-Basque bilingual and Spanish monolingual infants' brain responses while they listened to forward (FW) and backward (BW) speech stimuli in Spanish. We reveal distinct neural signatures associated with bilingual adaptations, including increased engagement of bilateral inferior frontal and temporal regions during speech processing in bilingual infants, as opposed to left hemispheric functional specialization observed in monolingual infants. This study provides compelling evidence of bilingualism-induced brain adaptations during speech processing in infants as young as 4 months. These findings emphasize the role of early language experience in shaping neural plasticity during infancy suggesting that bilingual exposure at this young age profoundly influences the neural mechanisms underlying speech processing.

Repetitive Transcranial Magnetic Stimulation Modulates Brain Connectivity in Children with Self-limited Epilepsy with Centrotemporal Spikes.

Interictal epileptiform discharges (IEDs) alter brain connectivity in children with epilepsy; this connectivity change may be a mechanism by which epilepsy induces cognitive deficits. Here, we test whether repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, modulates connectivity and reduces IEDs in children with epilepsy. Nineteen children with self-limited epilepsy with centrotemporal spikes (SeLECTS) participated in a cross-over study comparing the impact of active vs. sham rTMS on IEDs and brain connectivity. SeLECTS is an epilepsy syndrome affecting the motor cortex, and prior studies show that motor cortices become pathologically hyper-connected to frontal and temporal language cortices. Using a crossover design, we compared the effect of single doses of active versus sham motor cortex rTMS. Connectivity, which was quantified by the weighted phase lag index (wPLI), was measured before and after rTMS using single pulses of TMS combined with EEG (spTMS-EEG). Analyses focused on six regions: bilateral motor cortices and bilateral inferior frontal and superior temporal regions. IEDs were counted in the five minutes before and after rTMS. Active, but not sham, rTMS significantly and globally decreased wPLI connectivity between multiple regions, with the greatest reductions seen in the superior temporal region connections in the stimulated hemisphere. Additionally, there was a trend suggesting that rTMS decreases IED frequency. These findings underscore the potential of low-frequency rTMS to target pathologic hyperconnectivity and reduce IEDs in children with SeLECTS and potentially other pediatric epilepsy syndromes, offering a promising avenue for therapeutic intervention.

Peripheral ulcerative keratitis secondary to tuberculosis: A case report and literature review.

Compared with intraocular tuberculosis, ocular tuberculosis with ocular surface involvement is rare. Corneal involvement in ocular tuberculosis may include interstitial keratitis or peripheral ulcerative keratitis. We report a case of peripheral ulcerative keratitis directly caused by tuberculosis. A 20-year-old man complained of vision loss and pain in the left eye that had lasted for 1 week. A slit lamp examination of the left eye showed a corneal epithelial defect, interstitial corneal edema, and a white irregular infiltrative lesion and ulcer (with the dimension of 2 × 2.5 mm) in the inferior temporal region. The corneal ulcer was scraped, and the Mycobacterium tuberculosis deoxyribonucleic acid polymerase chain reaction was positive. After a month of oral antituberculosis treatment, the corneal ulcer resolved, and the intraocular inflammation improved. Peripheral ulcerative keratitis secondary to tuberculosis can be directly caused by M tuberculosis.

A ventromedial visual cortical ‘Where’ stream to the human hippocampus for spatial scenes revealed with magnetoencephalography

The primate including the human hippocampus implicated in episodic memory and navigation represents a spatial view, very different from the place representations in rodents. To understand this system in humans, and the computations performed, the pathway for this spatial view information to reach the hippocampus was analysed in humans. Whole-brain effective connectivity was measured with magnetoencephalography between 30 visual cortical regions and 150 other cortical regions using the HCP-MMP1 atlas in 21 participants while performing a 0-back scene memory task. In a ventromedial visual stream, V1–V4 connect to the ProStriate region where the retrosplenial scene area is located. The ProStriate region has connectivity to ventromedial visual regions VMV1–3 and VVC. These ventromedial regions connect to the medial parahippocampal region PHA1–3, which, with the VMV regions, include the parahippocampal scene area. The medial parahippocampal regions have effective connectivity to the entorhinal cortex, perirhinal cortex, and hippocampus. In contrast, when viewing faces, the effective connectivity was more through a ventrolateral visual cortical stream via the fusiform face cortex to the inferior temporal visual cortex regions TE2p and TE2a. A ventromedial visual cortical ‘Where’ stream to the hippocampus for spatial scenes was supported by diffusion topography in 171 HCP participants at 7 T.

Transformer-Based Deep Learning Prediction of 10-Degree Humphrey Visual Field Tests From 24-Degree Data.

To predict 10-2 Humphrey visual fields (VFs) from 24-2 VFs and associated non-total deviation features using deep learning. We included 5189 reliable 24-2 and 10-2 VF pairs from 2236 patients, and 28,409 reliable pairs of macular OCT scans and 24-2 VF from 19,527 eyes of 11,560 patients. We developed a transformer-based deep learning model using 52 total deviation values and nine VF test features to predict 68 10-2 total deviation values. The mean absolute error, root mean square error, and the R2 were evaluation metrics. We further evaluated whether the predicted 10-2 VFs can improve the structure-function relationship between macular thinning and paracentral VF loss in glaucoma. The average mean absolute error and R2 for 68 10-2 VF test points were 3.30 ± 0.52dB and 0.70 ± 0.11, respectively. The accuracy was lower in the inferior temporal region. The model placed greater emphasis on 24-2 VF points near the central fixation point when predicting the 10-2 VFs. The inclusion of nine VF test features improved the mean absolute error and R2 up to 0.17 ± 0.06dB and 0.01 ± 0.01, respectively. Age was the most important 24-2 VF test parameter for 10-2 VF prediction. The predicted 10-2 VFs achieved an improved structure-function relationship between macular thinning and paracentral VF loss, with the R2 at the central 4, 12, and 16 locations of 24-2 VFs increased by 0.04, 0.05 and 0.05, respectively (P < 0.001). The 10-2 VFs may be predicted from 24-2 data. The predicted 10-2 VF has the potential to improve glaucoma diagnosis.

Selective activations and functional connectivities to the sight of faces, scenes, body parts and tools in visual and non-visual cortical regions leading to the human hippocampus

Connectivity maps are now available for the 360 cortical regions in the Human Connectome Project Multimodal Parcellation atlas. Here we add function to these maps by measuring selective fMRI activations and functional connectivity increases to stationary visual stimuli of faces, scenes, body parts and tools from 956 HCP participants. Faces activate regions in the ventrolateral visual cortical stream (FFC), in the superior temporal sulcus (STS) visual stream for face and head motion; and inferior parietal visual (PGi) and somatosensory (PF) regions. Scenes activate ventromedial visual stream VMV and PHA regions in the parahippocampal scene area; medial (7m) and lateral parietal (PGp) regions; and the reward-related medial orbitofrontal cortex. Body parts activate the inferior temporal cortex object regions (TE1p, TE2p); but also visual motion regions (MT, MST, FST); and the inferior parietal visual (PGi, PGs) and somatosensory (PF) regions; and the unpleasant-related lateral orbitofrontal cortex. Tools activate an intermediate ventral stream area (VMV3, VVC, PHA3); visual motion regions (FST); somatosensory (1, 2); and auditory (A4, A5) cortical regions. The findings add function to cortical connectivity maps; and show how stationary visual stimuli activate other cortical regions related to their associations, including visual motion, somatosensory, auditory, semantic, and orbitofrontal cortex value-related, regions.

Specific Association of Worry With Amyloid-β But Not Tau in Cognitively Unimpaired Older Adults

Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory-6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD.

Increased brain gyrification and cortical thinning in winter-born patients with schizophrenia spectrum.

The findings of epidemiological studies suggest that a relationship exists between the risk of schizophrenia and winter births in the Northern Hemisphere, which may affect the process of fetal neurodevelopment. However, it remains unclear whether birth seasons are associated with the brain morphological characteristics of patients within the schizophrenia spectrum. The present magnetic resonance imaging study using FreeSurfer software examined the effects of birth seasons (i.e., summer-born vs. winter-born) on the comprehensive brain surface characteristics of 101 patients with schizophrenia (48 summer- and 53 winter-born), 46 with schizotypal disorder (20 summer- and 26 winter-born), and 76 healthy control subjects (28 summer- and 48 winter-born). In comparisons with summer-born patients, winter-born patients, particularly those with schizophrenia, showed significantly increased gyrification mainly in the left lateral occipital and inferior temporal regions and right fronto-parietal region as well as cortical thinning in the right superior frontal region. Birth seasons did not significantly affect the local gyrification index or cortical thickness in healthy controls. The present whole-brain surface-based analysis demonstrated that brain morphological characteristics reported in the schizophrenia spectrum were more pronounced in winter-born patients than in summer-born patients, suggesting the contribution of early neurodevelopmental factors associated with birth seasons to the pathophysiology of the schizophrenia spectrum.

Altered cortical thickness-based structural covariance networks in type 2 diabetes mellitus

Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM), and early cognitive dysfunction may be associated with abnormal changes in the cerebral cortex. This retrospective study aimed to investigate the cortical thickness-based structural topological network changes in T2DM patients without mild cognitive impairment (MCI). Fifty-six T2DM patients and 59 healthy controls underwent neuropsychological assessments and sagittal 3-dimensional T1-weighted structural magnetic resonance imaging. Then, we combined cortical thickness-based assessments with graph theoretical analysis to explore the abnormalities in structural covariance networks in T2DM patients. Correlation analyses were performed to investigate the relationship between the altered topological parameters and cognitive/clinical variables. T2DM patients exhibited significantly lower clustering coefficient (C) and local efficiency (Elocal) values and showed nodal property disorders in the occipital cortical, inferior temporal, and inferior frontal regions, the precuneus, and the precentral and insular gyri. Moreover, the structural topological network changes in multiple nodes were correlated with the findings of neuropsychological tests in T2DM patients. Thus, while T2DM patients without MCI showed a relatively normal global network, the local topological organization of the structural network was disordered. Moreover, the impaired ventral visual pathway may be involved in the neural mechanism of visual cognitive impairment in T2DM patients. This study enriched the characteristics of gray matter structure changes in early cognitive dysfunction in T2DM patients.

Neuropsychological insights into exercise addiction: the role of brain structure and self-efficacy in middle-older individuals.

This study aimed to investigate the relationship between exercise addiction and brain structure in middle-older individuals, and to examine the role of self-efficacy in mediating physiological changes associated with exercise addiction. A total of 133 patients exhibiting symptoms of exercise addiction were recruited for this study (male = 43, age 52.86 ± 11.78years). Structural magnetic resonance imaging and behavioral assessments were administered to assess the study population. Voxel-based morphological analysis was conducted using SPM12 software. Mediation analysis was employed to explore the potential neuropsychological mechanism of self-efficacy in relation to exercise addiction. The findings revealed a positive correlation between exercise addiction and gray matter volume in the right inferior temporal region and the right hippocampus. Conversely, there was a negative correlation with gray matter volume in the left Rolandic operculum. Self-efficacy was found to indirectly influence exercise addiction by affecting right inferior temporal region gray matter volume and acted as a mediating variable in the relationship between the gray matter volume of right inferior temporal region and exercise addiction. In summary, this study elucidates the link between exercise addiction and brain structure among middle-older individuals. It uncovers the intricate interplay among exercise addiction, brain structure, and psychological factors. These findings enhance our comprehension of exercise addiction and offer valuable insights for the development of interventions and treatments.

Neurophysiological mechanisms of exploration and exploitation in high-functioning autism: Magnetoencephalographic study

Intolerance of uncertainty and high sensitivity to the threat of failure are believed to contribute to chronic anxiety in individuals with high-functioning autism. This study examines the influence of these personality traits on the brain processes involved in decision-making in a probabilistic setting among autism patients. Furthermore, we explore the causal relationship between these personality traits and chronic anxiety in individuals with high-functioning autism. Twenty-one high-functioning autistic individuals who are intolerant to uncertainty, aged 19 to 46, and 21 neurotypical volunteers of the same age, carried out a probabilistic choice experiment with two alternatives. One option yielded a monetary profit of 70% of the time, while the other brought only a 30% gain. Following each selection, the subjects received feedback on their decision and gradually learned, through trial and error, to prefer the more advantageous option. From this point forward, we consider frequent selections of a beneficial stimulus to align with the internal utility model, specifically the exploitation strategy. On the other hand, sporadic choices of a detrimental stimulus correspond to an exploration strategy, which may prove disadvantageous in a stable environment but enables adaptation to unforeseen changes in the surroundings. We hypothesized that there are characteristic differences in brain activity reflecting exploration and exploitation strategies between groups, which would emerge during the decision-making period and after internal feedback evaluation regarding advantageous and disadvantageous choices [1]. Beta oscillations (16–30 Hz) were analyzed in the magnetoencephalographic recordings. The decrease in beta oscillation power below baseline during the period between stimulus presentation and subjects’ response indicates activation in brain regions related to decision-making strategy. Conversely, an increase in beta oscillation power following feedback signaling a disadvantageous choice reflects a mechanism that reinforces internal value models in current task conditions [1]. The cortical sources of beta oscillations in 448 cortical areas were estimated using the sLoreta technique at the single-trial level. Mixed linear models (LMM) were used for statistical analysis with correction for multiple comparisons via the FDR method for the number of cortical areas analyzed. The study concentrated on the time interval for decision-making (–900 to –300 ms prior to the motor action of choice) and the post-feedback period (500 to 900 ms after the commencement of the feedback presentation) [1]. Based on questionnaire results, individuals with high-functioning autism exhibited a significantly lower tolerance for uncertainty and a greater intolerance for uncertainty when compared to neurotypical participants. The study generated two primary findings. Initially, the extent of brain activity during decision-making differed in control subjects and subjects with autism based on the type of choice, with exact opposition. Opting for an advantageous vs. disadvantageous choice was linked with reduced activation of the inferior temporal, parietal, and medial frontal cortex regions in control subjects and elevated activation in these regions for subjects with autism spectrum disorder. These findings suggest that neurotypical individuals utilize fewer neural resources and exhibit decreased emotional response while deciding in favor of a known profitable outcome compared to opting for an uncertain choice — one that is more likely to result in a negative outcome based on previous experiences. Individuals with autism allocate disproportionate amounts of attention and emotional resources towards planning actions that are deemed safe and offer only a probable (though not definite) advantage. Conversely, the prospect of failure due to risky behavior induces a comparatively muted response in their brains. Second, our internal evaluation of feedback focused on variations in functional activity within the orbitofrontal and lateral prefrontal cortical areas during exploratory (disadvantageous) choices between individuals with autism and control subjects. As previously reported, neurotypical subjects demonstrated significant beta synchronization following negative feedback after disadvantageous choices [1]. Contrary to control participants, individuals with autism spectrum disorder exhibited a lack of synchronization in frontal beta oscillations following losses incurred from unfavorable selections. This observation may indicate insufficient reinforcement of the internal utility model, which typically strengthens in response to negative outcomes that align with predicted results [1]. Overall, our study found that individuals on the autism spectrum with a high intolerance for uncertainty exhibit significantly increased activation of brain decision-making systems in situations that are perceived to be low-risk and with a high probability of a successful outcome. These findings clarify the reasons behind the puzzling rise in anxiety and autonomic reactivity among individuals in situations where they anticipate rewards, which are not inherently aversive unlike fear of punishment [2].

Commonalities and distinctions between the type 2 diabetes mellitus and Alzheimer's disease: a systematic review and multimodal neuroimaging meta-analysis.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are aging related diseases with high incidence. Because of the correlation of incidence rate and some possible mechanisms of comorbidity, the two diseases have been studied in combination by many researchers, and even some scholars call AD type 3 diabetes. But the relationship between the two is still controversial. This study used seed-based d mapping software to conduct a meta-analysis of the whole brain resting state functional magnetic resonance imaging (rs-fMRI) study, exploring the differences in amplitude low-frequency fluctuation (ALFF) and cerebral blood flow (CBF) between patients (AD or T2DM) and healthy controls (HCs), and searching for neuroimaging evidence that can explain the relationship between the two diseases. The final study included 22 datasets of ALFF and 22 datasets of CBF. The results of T2DM group showed that ALFF increased in both cerebellum and left inferior temporal gyrus regions, but decreased in left middle occipital gyrus, right inferior occipital gyrus, and left anterior central gyrus regions. In the T2DM group, CBF increased in the right supplementary motor area, while decreased in the middle occipital gyrus and inferior parietal gyrus. The results of the AD group showed that the ALFF increased in the right cerebellum, right hippocampus, and right striatum, while decreased in the precuneus gyrus and right superior temporal gyrus. In the AD group, CBF in the anterior precuneus gyrus and inferior parietal gyrus decreased. Multimodal analysis within a disease showed that ALFF and CBF both decreased in the occipital lobe of the T2DM group and in the precuneus and parietal lobe of the AD group. In addition, there was a common decrease of CBF in the right middle occipital gyrus in both groups. Based on neuroimaging evidence, we believe that T2DM and AD are two diseases with their respective characteristics of central nervous activity and cerebral perfusion. The changes in CBF between the two diseases partially overlap, which is consistent with their respective clinical characteristics and also indicates a close relationship between them. PROSPERO [CRD42022370014].

Serum FOXO3A: A potent marker for early diagnosis of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. In any ageing society it’s a major health concern and a public health challenge. Diagnosis of Alzheimer’s disease (AD) is often difficult because of distinct and subjective clinical features, especially in the early stage. FOXO3a protein present in the cognitive centre of brain in inferior temporal region and parahippocampus. FOXO3a can be a potential novel target against AD.MethodAD, Mild Cognitive impairment (MCI) and Geriatric Control (GC) were recruited after diagnosis by clinical assessment, MRI, Tau PET and FDG PET. We have quantified serum FOXO3a by surface plasmon resonance (SPR) and compare with Tau PET between of AD, MCI patients and GC.ResultSerum FOXO3A was significantly lower in AD (1.42 ± 0.09 ng/μl) compare to MCI (1.61 ± 0.14 ng/μl) and GC (1.89 ± 0.07 ng/μl). ROC curve for FOXO3A protein level was plotted and showed a reasonably good sensitivity and specificity at the cut‐off value for detecting cognitively impaired patients (AD and MCI) in compared to control older subjects. For Tau PET in inferior temporal region, the AUC for predicting AD from GC was 0.72 and AD from MCI was 0.71.ConclusionSerum FOXO3A could significantly differentiate AD vs MCI, MCI vs GC and AD vs GC. It may serve as novel blood marker for early detection for AD and target for therapeutic intervention.

Sex hormone binding globulin and total testosterone levels are associated with in vivo tau burden differentially between the sexes: findings from the Framingham Study

AbstractBackgroundIn men and women, sex steroid hormones are associated with increased risk of Alzheimer’s disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults.Method175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4.ResultIn men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3).ConclusionHigher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline.

Novel Framework for Brain Age Prediction using Graph Neural Networks

AbstractBackgroundAging is among the largest risk factors for neurodegeneration which can be accelerated by age‐related pathologies. Hence, individuals may age at different rates reflected by a gap in biological estimates of age and actual chronological age. Graph neural networks (GNN) are deep learning models that leverage spatial information inherent in the dataset for inference. Here, we develop an MRI cortical thickness (CT) based brain age prediction framework using GNNs and illustrate that it provides a feasible mechanism to identify contributing regions leading to elevated brain age gap in Alzheimer’s disease (AD).MethodWe used ANTs to calculate CT in 100 parcels from 3T MRI of 170 healthy controls (HC; age = 64.26±8.27y, 101 females), 53 mild cognitive impairment (MCI; age = 68.56±8.58y, 22 females), and 62 AD (age = 67.25±8.83y, 30 females) individuals. A GNN model based on the anatomical covariance matrix from HC cohort was trained to predict chronological age from associated CT for HC cohort. GNN output was evaluated as an unweighted mean of entities associated with the brain regions in the final layer. Hence, individual contributions to the GNN output by each brain region could be quantified. Final brain age prediction was obtained after removing age‐bias from GNN outputs using linear regression model. For all subjects, we evaluated residuals at regional level (regional age‐gap) by comparing the contribution of each parcel with corresponding GNN output. The residual between predicted brain age and chronological age (age‐gap) was also evaluated. See Figure 1 for an overview.ResultANCOVA (with correction for age and gender) with post‐hoc analyses revealed that regional age‐gap was greater for AD relative to HC in inferior parietal, temporal pole, inferior temporal, medial temporal, and superior frontal regions (Bonferroni corrected p‐value&lt;0.05). Also, regional age‐gap was greater for MCI relative to HC for inferior parietal and temporal pole regions (Figure 2). Subsequently, age‐gap was elevated in AD (mean = 5.64y) and MCI (mean = 2.66y) relative to HC (mean = 0y) reflecting a linear increase in age‐gap with disease stage (Figure 3).ConclusionOur novel framework identified regional CT associations with age‐gap in AD and MCI, suggesting that this GNN approach may be used to further our understanding between aging and neurodegeneration.

Blood‐based markers of neurodegeneration linked with brain atrophy and cognition in aging

AbstractBackgroundNeurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been linked to aging‐related brain tissue loss and cognitive decline, both related to neurodegeneration. Recently, NfL and GFAP have become quantifiable in blood; little is known about their association with brain structure in aging adults.MethodSingle‐Molecule Array (SIMOA) technology was used for ultra‐sensitive detection and quantification of NfL and GFAP in blood plasma at baseline in healthy volunteers (N = 102, 52 female, 52‐79 years old). These individuals also underwent magnetic resonance imaging twice, 3 years apart (N = 72 at follow‐up), and cognitive testing. We examined the relationships among NfL, GFAP, age, brain atrophy parameters (gray‐matter volume ‐ GMV, cortical thickness ‐ CT) and cognitive performance (composite score of episodic and working memory, executive functions and perceptual speed). The relationships between blood markers, GMV and CT were assessed using voxel‐ and surface‐based morphometry, cross‐sectionally and longitudinally, adjusting for age, sex and education.ResultOlder age was related to higher levels of NfL and GFAP (ps &lt; .001; Figure 1). Cross‐sectionally, older age was related to lower GMV in the hippocampi and lateral middle temporal regions, and lower CT in lateral frontoparietal areas. Longitudinally, atrophy was located in fronto‐parieto‐temporal regions, more strongly in the left hemisphere (all ps &lt; .05 Family‐Wise Error corrected). Controlling for age, sex, education and total intracranial volume, higher NfL levels were associated with lower volume in inferior temporal regions (cross‐sectionally), and with atrophy in right hippocampus (longitudinally) (p &lt; .001 uncorrected; Figure 2). Higher GFAP levels were associated with lower volume and thinner cortex in frontoparietal regions, and atrophy in right frontal cortex (p &lt; .001; Figure 2). After splitting the individuals as decliners and non‐decliners based on their cognitive‐performance changes, it was found that the negative associations between NfL and inferior‐temporal volume, and between GFAP and fronto‐temporal volume, were driven by the decliners (Figure 3).ConclusionHigher NfL or GFAP levels are related to atrophy, beyond age, in key regions known to be affected in neurodegenerative disorders, possibly indicating early neuropathological changes.

PET biomarkers in behavioral variant Frontotemporal dementia: analysis of an Argentine cohort.

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by early and progressive changes in behavior, emotional processing and executive control. This entity represents a diagnostic challenge in which positron emission tomography (PET) may play a key role in the diagnosis and follow‐up in vivo with a minimally invasive method. The aim of this work is to evaluate PET biomarkers in a cohort of patients with a clinical diagnosis of bvFTD.Method21 normal controls (NC: 64 ± 9 years) and 20 patients with a diagnosis of probable bvFTD (65 ± 7 years) were evaluated by: neurological, neuropsychological, neuropsychiatric evaluation and PET imaging biomarkers: [18F]‐FDG, [18F]‐AV1451 (TAU), [11C]‐PIB. For neuroimaging processing and analysis, they were spatially normalized to an FDG template. Group comparisons (voxel‐based) of each biomarker were performed by t‐test (SPM12) using cerebellar gray matter as reference tissue, and for inter‐biomarker uncoupling comparison a covariate of uptake in total cortex was used.ResultIn the statistical comparison between NC vs. bvFTD groups (p&lt;0.05), hypometabolism is observed at the frontotemporal level and hypermetabolism in the precentral region (FDG). Amyloid marker (PIB) uptake shows no significant difference between groups in much of the cortex, except in the precentral region. TAU uptake shows a significant difference, greater in bvFTD, at frontal, parietal and precuneus levels. In the uncoupling between FDG and TAU biomarkers, it is observed that hypometabolism is related to an increase in TAU uptake in medial and inferior temporal regions. Differences between PIB and TAU are mainly observed in frontotemporal regions. There was an association between clinical symptoms (mainly apathy) and the anatomical distribution of [18F]‐FDG, [18F]‐AV1451 radiotracers (TAU).ConclusionPET biomarkers are a valuable tool in the diagnosis of bvFTD. The [11C]‐PIB may be of paramount importance in the differential diagnosis of FTvc FTD with Alzheimer’s disease. FDG is a very sensitive biomarker of neuronal metabolism and its variations, sometimes losing specificity. Advances in tracers such as [18F]‐AV1451 (TAU) can provide important information on the underlying neuropathological process. The combined use of these tools brings us closer to understanding the biological phenomena behind the cardinal symptoms of bvFTD.