Posterior Cingulate Regions Research Articles

Structure-function coupling in highly sampled individual brains.

Structural connectivity (SC) between distant regions of the brain support synchronized function known as functional connectivity (FC) and give rise to the large-scale brain networks that enable cognition and behavior. Understanding how SC enables FC is important to understand how injuries to SC may alter brain function and cognition. Previous work evaluating whole-brain SC-FC relationships showed that SC explained FC well in unimodal visual and motor areas, but only weakly in association areas, suggesting a unimodal-heteromodal gradient organization of SC-FC coupling. However, this work was conducted in group-averaged SC/FC data. Thus, it could not account for inter-individual variability in the locations of cortical areas and white matter tracts. We evaluated the correspondence of SC and FC within three highly sampled healthy participants. For each participant, we collected 78min of diffusion-weighted MRI for SC and 360min of resting state fMRI for FC. We found that FC was best explained by SC in visual and motor systems, as well as in anterior and posterior cingulate regions. A unimodal-to-heteromodal gradient could not fully explain SC-FC coupling. We conclude that the SC-FC coupling of the anterior-posterior cingulate circuit is more similar to unimodal areas than to heteromodal areas.

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

Physical function is associated with cognitive status, brain amyloid-beta deposition, and blood biomarkers in Chinese Han population.

The physical function of elderly individuals reflects whether they have had a history of regular physical activity over the long term. Such indicators have been found to have a certain connection with cognitive function these years. However, there is limited research that associates it with mechanisms such as cerebral Aβ deposition. We aim to investigate this relationship and unveil the underlying mechanisms. Physical function and cognition data of 4189 participants were obtained from the Chinese preclinical Alzheimer's disease study. Participants were divided into six groups according to disease severity. Among them, 1048 participants underwent the positron emission tomography-computed tomography (PET-CT) and plasma biomarker test. Grip strength and gait were combined into a score indicating physical function. Multiple linear regression models and logistic regression models were mainly used to conduct the analysis. There was a significant positive correlation between physical function and cognitive function (R = 0.48, p < 0.001), independent of sex, age, apolipoprotein E-ε4 genotype, and disease stages (p < 0.001). Physical function was effective in distinguishing individuals with cognitive impairment from those without (AUC = 0.835). Physical function was negatively associated with brain Aβ deposition (p = 0.008) and brain Aβ had an intermediary effect (p < 0.01) on the association between physical function and cognition in women. This association was mainly evident in the lateral parietal, lateral temporal, posterior cingulate, frontal, occipital, and precuneus regions. Physical function was negatively associated with plasma neurofilament light-chain (Nfl) level (p < 0.001). Physical function is strongly associated with cognitive function in the Chinese elderly, and brain Aβ deposition partly mediates the linkage in women. Plasma Nfl can be used as a potential target for exercise intervention in cognitive function. Improving physical function will contribute to the alleviation of cognition decline.

Identification of neurotransmitter imbalances in the cingulate cortex of NMOSD patients using magnetic resonance spectroscopy.

Cognitive impairment affects 29-67% of patients with neuromyelitis optica spectrum disorder. Previous studies have reported glutamate homeostasis disruptions in astrocytes, leading to imbalances in gamma-aminobutyric acid levels. However, the association between these neurotransmitter changes and cognitive deficits remains inadequately elucidated. Point RESolved Spectroscopy and Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy techniques were utilized to evaluate gamma-aminobutyric acid, glutamate, glutathione levels, and excitation/inhibition balance in the anterior cingulate cortex, posterior cingulate cortex, and occipital cortex of 39 neuromyelitis optica spectrum disorder patients and 41 healthy controls. Cognitive function was assessed using neurocognitive scales. Results showed decreased gamma-aminobutyric acid levels alongside increased glutamate, glutathione, and excitation/inhibition ratio in the anterior cingulate cortex and posterior cingulate cortex of neuromyelitis optica spectrum disorder patients. Specifically, within the posterior cingulate cortex of neuromyelitis optica spectrum disorder patients, decreased gamma-aminobutyric acid levels and increased excitation/inhibition ratio correlated significantly with anxiety scores, whereas glutathione levels predicted diminished executive function. The results suggest that neuromyelitis optica spectrum disorder patients exhibit dysregulation in the GABAergic and glutamatergic systems in their brains, where the excitation/inhibition imbalance potentially acts as a neuronal metabolic factor contributing to emotional disorders. Additionally, glutathione levels in the posterior cingulate cortex region may serve as predictors of cognitive decline, highlighting the potential benefits of reducing oxidative stress to safeguard cognitive function in neuromyelitis optica spectrum disorder patients.

Change in Resting-State Functional Connectivity Following Working Memory Training in Individuals With Repetitive Negative Thinking

BackgroundRepetitive negative thinking (RNT) symptoms, which are characterized by pervasive, uncontrollable negative thoughts, are common in individuals with mood, anxiety, and traumatic stress disorders. Inability to regulate the contents of working memory is a hypothesized etiological factor in RNT, which suggests that training to improve working memory may be beneficial. This study examined the effects of working memory training on resting-state functional connectivity (rsFC) in individuals with elevated RNT and whether such changes would be associated with clinical improvement. MethodsWe conducted a secondary analysis of pre-post resting-state data collected as part of a randomized controlled trial (NCT04912089) of working memory training interventions (n = 42) compared with a waitlist control group (n = 23). We hypothesized that individuals who completed training would show increased rsFC between the 2 key intrinsic connectivity networks—the default mode network (posterior cingulate cortex) and the frontoparietal network (dorsolateral prefrontal cortex). We explored whether the magnitude of rsFC change was associated with change in RNT symptom severity. ResultsrsFC increased between the posterior cingulate cortex and regions including the frontal and parietal cortex in the training group compared with the waitlist group. Increased connectivity between the posterior cingulate cortex and superior frontal cortex was associated with RNT symptom reduction. ConclusionsThese data provide evidence that working memory training can modulate neural circuitry at rest in individuals with RNT. Results are consistent with accounts of working memory training effects on large-scale neurocircuitry changes and suggest that these changes may contribute to clinical promise of this type of intervention on transdiagnostic RNT symptoms.

Clinical and Neuroimaging Predictors of Alzheimer's Dementia Conversion in Patients with Mild Cognitive Impairment Using Amyloid Positron Emission Tomography by Quantitative Analysis over 2 Years.

Patients with mild cognitive impairment (MCI) have a relatively high risk of developing Alzheimer's dementia (AD), so early identification of the risk for AD conversion can lessen the socioeconomic burden. In this study, 18F-Florapronol, newly developed in Korea, was used for qualitative and quantitative analyses to assess amyloid positivity. We also investigated the clinical predictors of the progression from MCI to dementia over 2 years. From December 2019 to December 2022, 50 patients with MCI were recruited at a single center, and 34 patients were included finally. Based on visual analysis, 13 (38.2%) of 34 participants were amyloid-positive, and 12 (35.3%) were positive by quantitative analysis. Moreover, 6 of 34 participants (17.6%) converted to dementia after a 2-year follow-up (p = 0.173). Among the 15 participants who were positive for amyloid in the posterior cingulate region, 5 (33.3%) patients developed dementia (p = 0.066). The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) at baseline was significantly associated with AD conversion in multivariate Cox regression analyses (p = 0.043). In conclusion, these results suggest that amyloid positivity in the posterior cingulate region and higher CDR-SOB scores at baseline can be useful predictors of AD conversion in patients with MCI.

Brain activation during scene encoding fMRI in the Alzheimer’s disease continuum: Association with amyloid and tau burden in PE

Background and Hypothesis:This project assessed brain activation during a scene encoding task in 4 groups: older adults who were cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD). Associations between scene encoding related brain activation and tau, amyloid, and other biomarkers were analyzed. Our hypothesis was that higher levels of cerebral tau and amyloid would be associated with reduced scene encoding activation. In addition, we hypothesized that scene encoding activation would be significantly different between cognitively normal and cognitively impaired groups.&#x0D; Methods:234 individuals from the Indiana Memory and Aging Study (79 CN, 67 SCD, 70 MCI, and 18 AD) completed structural and functional MRI, clinical/cognitive assessment and biomarkers; 155 underwent amyloid ([18F]florbetapir/[18F]florbetaben) PET, while 111 also underwent [18F]flortaucipir PET. For the fMRI scene encoding task, participants were asked to view and remember a set of images. A one-way ANOVA test was used to analyze scene encoding related activation differences among the 4 groups. Regression was used to identify associations between scene encoding activation and tau and amyloid deposition.&#x0D; Results:Significant differences in activation were observed between the MCI and CN groups, including less activation in widespread regions during the task and reduced deactivation in the default mode network (DMN) in MCI participants relative to CN. Significant associations between higher amyloid and tau deposition and altered scene encoding activation were also observed.&#x0D; Conclusion and Potential Impact:Cognitive decline is associated with activation changes during scene encoding, as well as reduced deactivation in the DMN, especially in the posterior cingulate region. Higher cerebral amyloid and tau deposition predicted decreased scene encoding related activation. These findings are consistent with models linking cognitive status, functional brain activation during episodic encoding, and pathophysiological processes in the AD continuum.

A reappraisal of the default mode and frontoparietal networks in the common marmoset brain.

In recent years the common marmoset homolog of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates: Comp-A (which has been called both the DMN and FPN) and Comp-B. We performed GLM analysis on auditory task-fMRI and found Comp-B to be more appropriate as the DMN, and Comp-A as the FPN. Additionally, through fingerprint analysis, a DMN and FPN in the tasking human was closer to the resting common marmoset. The human DMN appears to have an advanced function that may be underdeveloped in the common marmoset brain.

The connectivity of the human frontal pole cortex, and a theory of its involvement in exploit versus explore.

The frontal pole is implicated in humans in whether to exploit resources versus explore alternatives. Effective connectivity, functional connectivity, and tractography were measured between six human frontal pole regions and for comparison 13 dorsolateral and dorsal prefrontal cortex regions, and the 360 cortical regions in the Human Connectome Project Multi-modal-parcellation atlas in 171 HCP participants. The frontal pole regions have effective connectivity with Dorsolateral Prefrontal Cortex regions, the Dorsal Prefrontal Cortex, both implicated in working memory; and with the orbitofrontal and anterior cingulate cortex reward/non-reward system. There is also connectivity with temporal lobe, inferior parietal, and posterior cingulate regions. Given this new connectivity evidence, and evidence from activations and damage, it is proposed that the frontal pole cortex contains autoassociation attractor networks that are normally stable in a short-term memory state, and maintain stability in the other prefrontal networks during stable exploitation of goals and strategies. However, if an input from the orbitofrontal or anterior cingulate cortex that expected reward, non-reward, or punishment is received, this destabilizes the frontal pole and thereby other prefrontal networks to enable exploration of competing alternative goals and strategies. The frontal pole connectivity with reward systems may be key in exploit versus explore.

Cortical gyrification pattern of depression in Parkinson's disease: a neuroimaging marker for disease severity?

Although the study of the neuroanatomical correlates of depression in Parkinson's Disease (PD) is gaining increasing interest, up to now the cortical gyrification pattern of PD-related depression has not been reported. This study was conducted to investigate the local gyrification index (LGI) in PD patients with depression, and its associations with the severity of depression. LGI values, as measured using FreeSurfer software, were compared between 59 depressed PD (dPD), 27 non-depressed PD (ndPD) patients and 43 healthy controls. The values were also compared between ndPD and mild-depressed PD (mi-dPD), moderate-depressed PD (mo-dPD) and severe-depressed PD (se-dPD) patients as sub-group analyses. Furthermore, we evaluated the correlation between LGI values and depressive symptom scores within dPD group. Compared to ndPD, the dPD patients exhibited decreased LGI in the left parietal, the right superior-frontal, posterior cingulate and paracentral regions, and the LGI values within these areas negatively correlated with the severity of depression. Specially, reduced gyrification was observed in mo-dPD and involving a larger region in se-dPD, but not in mi-dPD group. The present study demonstrated that cortical gyrification is decreased within specific brain regions among PD patients with versus without depression, and those changes were associated with the severity of depression. Our findings suggested that cortical gyrification might be a potential neuroimaging marker for the severity of depression in patients with PD.

RADT-32. USING NEUROANATOMICAL SUBSITE TO PREDICT PATTERNS OF GLIOBLASTOMA INFILTRATION: POTENTIAL FOR INDIVIDUALISING RADIATION THERAPY TARGET VOLUME DELINEATION OF THE PARIETAL AND POSTERIOR FRONTAL REGIONS

Abstract BACKGROUND Radiation therapy(IMRT) protocols for glioblastoma utilize isotropic margin expansion around neurosurgical cavities/residual contrast enhancing(T1gd) disease. However pathways of infiltration may be associated with white matter tract(WMT) involvement varying between neuroanatomical subsites. Posterior frontoparietal tumours involving posterior cingulate region (PostCing) may have extensive infiltration centrally. This study aims to quantify the PostCing infiltration pathway/relapse sites. METHODS Consecutive patients managed for GBMwt with IMRT between 1/2016-6/2022 were classified into 15 neuroanatomical subsites. Tumour segmentation on T1-gadolinium-enhanced(T1gd) and T2-weighted(T2) sequences was performed at diagnosis/relapse. Subsites of Frontal Lobe (Posterior) and Parietal Lobe (Superior/Posterior/Lateral) were identified. On both sequences involvement of adjacent/distant regions (cingulate gyrus, cingulum, splenium, ventricular trigone, parahippocampal-hippocampal gyrus) were identified; as were major WMT: cingulum-parahippocampal formation(CING-PHG), and arcuate fasciculus–inferior longitudinal fasciculus(AF-ILF). Survival was analysed in relation to pattern of infiltration and site of relapse. RESULTS Of 348 patients with glioblastoma, fifty-five(16%) involved PostCing region. Pre-IMRT features included near-total resection in 25%; impaired ECOG 2-3 in 47%; and 58% MGMT-methylated. Parietal lobe tumours(67%) were predominantly posterior(42%) with only 7% lateral parietal. WMT involvement was evident in 94% with T1gd(62%), and T2 alone(33%) abnormality. Infiltration to distal sites of cingulum/splenium/PHG was frequent and predictable; correlating to cingulum pathway involvement in 70% of patients. Median RFS and OS was 13.2 months(95%CI: 11.8-14.8) and 16.6 months(95%CI:14.8-18.5) respectively. Distant relapse was evident in 53% of relapses. In the forty-four Stupp60Gy patients, distant relapse occurred later and was associated with improved overall survival(p = 0.02). No difference in RFS(p = 0.82) or OS(p = 0.31) was noted if tract involvement was either T1gd or T2 alone abnormality. CONCLUSION For glioblastoma in posterior cingulate region, the infiltration and relapse pathways followed white matter tracts in a predictable distribution with high rate of distant disease at diagnosis and relapse. IMRT potentially may be individualised for neuroanatomical subsite and non-isotropic target volume expansion.

Alterations via inter-regional connective relationships in Alzheimer's disease.

Disruptions in the inter-regional connective correlation within the brain are believed to contribute to memory impairment. To detect these corresponding correlation networks in Alzheimer's disease (AD), we conducted three types of inter-regional correlation analysis, including structural covariance, functional connectivity and group-level independent component analysis (group-ICA). The analyzed data were obtained from the Alzheimer's Disease Neuroimaging Initiative, comprising 52 cognitively normal (CN) participants without subjective memory concerns, 52 individuals with late mild cognitive impairment (LMCI) and 52 patients with AD. We firstly performed vertex-wise cortical thickness analysis to identify brain regions with cortical thinning in AD and LMCI patients using structural MRI data. These regions served as seeds to construct both structural covariance networks and functional connectivity networks for each subject. Additionally, group-ICA was performed on the functional data to identify intrinsic brain networks at the cohort level. Through a comparison of the structural covariance and functional connectivity networks with ICA networks, we identified several inter-regional correlation networks that consistently exhibited abnormal connectivity patterns among AD and LMCI patients. Our findings suggest that reduced inter-regional connectivity is predominantly observed within a subnetwork of the default mode network, which includes the posterior cingulate and precuneus regions, in both AD and LMCI patients. This disruption of connectivity between key nodes within the default mode network provides evidence supporting the hypothesis that impairments in brain networks may contribute to memory deficits in AD and LMCI.

The anterior medial hippocampus contributes to both recall and familiarity-based memory for scenes

The hippocampus is usually associated with recall memory, whereas its contribution to familiarity-based memory is debated. Growing evidence support the idea that this structure participates to any cognitive process performed on scene representations. In parallel, differences in functional specialisation and cortical connectivity were found across the longitudinal and transverse axes of the hippocampus. Here we reanalysed functional MRI data from 51 participants showing stronger engagement of the hippocampus in recall, familiarity-based recognition and rejection, and visual discrimination, of scenes compared to single objects. A conjunction analysis between these four tasks revealed a set of occipital, medial temporal, posterior cingulate, and parietal regions, matching the scene construction network described in the literature. Crucially, we found that the anterior medial part of the hippocampus was consistently involved in all tasks investigated for scene stimuli. These findings support that the hippocampus can contribute to both recall and familiarity-based memory, depending on stimulus type. More generally, this bolsters the recent proposal that circumscribed regions within the hippocampus may underpin specific cognitive mechanisms.

Causal evidence for the processing of bodily self in the anterior precuneus

To probe the causal importance of the human posteromedial cortex (PMC) in processing the sense of self, we studied a rare cohort of nine patients with electrodes implanted bilaterally in the precuneus, posterior cingulate, and retrosplenial regions with a combination of neuroimaging, intracranial recordings, and direct cortical stimulations. In all participants, the stimulation of specific sites within the anterior precuneus (aPCu) caused dissociative changes in physical and spatial domains. Using single-pulse electrical stimulations and neuroimaging, we present effective and resting-state connectivity of aPCu hot zone with the rest of the brain and show that they are located outside the boundaries of the default mode network (DMN) but connected reciprocally with it. We propose that the function of this subregion of the PMC is integral to a range of cognitive processes that require the self's physical point of reference, given its location within a spatial environment.

Diagnosis of autism spectrum disorder based on functional brain networks and machine learning

Autism is a multifaceted neurodevelopmental condition whose accurate diagnosis may be challenging because the associated symptoms and severity vary considerably. The wrong diagnosis can affect families and the educational system, raising the risk of depression, eating disorders, and self-harm. Recently, many works have proposed new methods for the diagnosis of autism based on machine learning and brain data. However, these works focus on only one pairwise statistical metric, ignoring the brain network organization. In this paper, we propose a method for the automatic diagnosis of autism based on functional brain imaging data recorded from 500 subjects, where 242 present autism spectrum disorder considering the regions of interest throughout Bootstrap Analysis of Stable Cluster map. Our method can distinguish the control group from autism spectrum disorder patients with high accuracy. Indeed the best performance provides an AUC near 1.0, which is higher than that found in the literature. We verify that the left ventral posterior cingulate cortex region is less connected to an area in the cerebellum of patients with this neurodevelopment disorder, which agrees with previous studies. The functional brain networks of autism spectrum disorder patients show more segregation, less distribution of information across the network, and less connectivity compared to the control cases. Our workflow provides medical interpretability and can be used on other fMRI and EEG data, including small data sets.

Association of Cognition and Brain Reserve in Aging and Glymphatic Function Using Diffusion Tensor Image-along the Perivascular Space (DTI-ALPS)

The glymphatic system is a fluid-clearance pathway that clears cerebral waste products, and its dysfunction has been associated with protein aggregation diseases such as Alzheimer’s disease. To understand how the glymphatic system changes with aging, we enrolled 433 cognitive unimpaired participants (236 women and 197 men, 13–88 years) and evaluated the glymphatic function by calculating diffusion tensor imaging analysis along the perivascular space (ALPS) index and explored how the ALPS index is associated with cortical atrophy and cognitive decline in older people. We found a significant inverse correlation between ALPS index and age (ρ = −0.45, p < 0.001), with a peak value in people in their thirties. A higher ALPS index indicated a better cortical reserve in regions coincided with the default mode network. Declines in mental manipulation and short-term memory performance in the older participants were associated with a lower ALPS index and cortical atrophy in the amygdala, anterior and posterior cingulate, thalamus and middle frontal regions. Our findings highlight that the ALPS index could be used to evaluate brain reserve and cognitive reserve in older people.

Posterior Cingulate Epilepsy: A Systematic Review.

In this review, authors discuss epilepsy originating from posterior cingulate regions, a challenging entity to diagnose and most likely underrecognized. A systematic review of posterior middle and posterior cingulate epilepsy cases was conducted to present a summary of current knowledge about this localization-based type of epilepsy. The literature search identified 32 articles, for a total of 69 patients (34 with posterior middle cingulate epilepsy [pMCE] and 35 with posterior cingulate epilepsy [PCE]). Most patients were children and young adults with drug-resistant lesional epilepsy with high seizure burden. In both groups, most patients reported auras, mainly sensory, but various types were reported, including autonomic, behavioral, and cognitive manifestations. Most pMCE and PCE showed motor manifestations (mainly respectively asymmetric tonic posturing and automotor features). Impaired awareness during seizures was more frequently reported in PCE than in pMCE. As for ictal scalp EEG, epileptogenic abnormalities were poorly lateralized and did not localize the seizure onset zone. An ictal temporal involvement was only observed in PCE. Interictal EEG findings were nonspecific. As for other presurgical noninvasive investigations, data are limited, and no studies have adequately assessed their value. Partly explained by our inclusion criteria, most patients underwent a surgical procedure (either lesionectomy or resection of epileptogenic zone as defined by intracranial EEG study results), which overall yielded good outcomes.

Diagnostic potential of magnetic resonance spectroscopy in cognitive impairment in the elderly

To explore the potential use of magnetic resonance spectroscopy (MRS) in the diagnosis of pre-dementia cognitive disorders in elderly people. A total of 65 elderly individuals (37 individuals with mild cognitive impairment (MCI) according to NIA-AA criteria, mean age 67.2 years; 28 controls, mean age 65.2 years) underwent MRS (3.0 T) with posterior cingulate cortex as the region of interest. Absolute concentrations of metabolites (tCr, NAA, Glx, mI, Cho, NAA) were calculated based on their signal intensities. Statistical analysis was performed to assess intergroup differences and correlations. Statistically significant differences were observed between the clinical and control groups in the absolute concentrations of metabolites: mI (MCI 4.97±0.13; controls 4.76±0.15; p=0.04) and NAA/mI (MCI 1.61±0.04; controls 1.73±0.04; p=0.04), as well as in the intensities of the choline-containing compounds signal (MCI 0.215±0.015; controls 0.205±0.005; p=0.04) in the posterior cingulate cortex region. No significant correlations between these changes and age were observed, suggesting the predominant role of neurodegeneration in the pathological process under investigation. The findings highlight the promising nature of MRS as a tool to find the neurodegeneration biomarker.

Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.

Amyloid Negative, Highly Tau Positive: Clinical Characterization of a Rare Biomarker Profile

AbstractBackgroundThe majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).MethodWe searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) &gt; 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold &gt; 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).ResultAmong A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).ConclusionA‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.