Inferior Parietal Lobule Research Articles

Long-range connections damage in white matter hyperintensities affects information processing speed.

White matter hyperintensities, one of the major markers of cerebral small vessel disease, disrupt the integrity of neuronal networks and ultimately contribute to cognitive dysfunction. However, a deeper understanding of how white matter hyperintensities related to the connectivity patterns of brain hubs at the neural network level could provide valuable insights into the relationship between white matter hyperintensities and cognitive dysfunction. A total of 36 patients with moderate to severe white matter hyperintensities (Fazekas score ≥ 3) and 34 healthy controls underwent comprehensive neuropsychological assessments and resting-state functional MRI scans. The voxel-based graph-theory approach-functional connectivity strength was employed to systematically investigate the topological organization of the whole-brain networks. The white matter hyperintensities patients performed significantly worse than the healthy controls in episodic memory, executive function and information processing speed. Additionally, we found that white matter hyperintensities selectively affected highly connected hub regions, predominantly involving the medial and lateral prefrontal, precuneus, inferior parietal lobule, insula and thalamus. Intriguingly, this impairment was connectivity distance-dependent, with the most prominent disruptions observed in long-range connections (e.g. 100-150 mm). Finally, these disruptions of hub connectivity (e.g. the long-range functional connectivity strength in the left dorsolateral prefrontal cortex) positively correlated with the cognitive performance in white matter hyperintensities patients. Our findings emphasize that the disrupted hub connectivity patterns in white matter hyperintensities are dependent on connection distance, especially longer-distance connections, which in turn predispose white matter hyperintensities patients to worse cognitive function.

Genes Associated with Altered Brain Structure and Function in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) has been widely reported to cause abnormalities in brain structure and function, but the genetic mechanisms behind these changes remain largely unexplored. Our research aims to investigate the relationship between sleep characteristics, cognitive impairments, genetic factors, and brain structure and function in OSA. Using structural and resting-state functional magnetic resonance imaging data, we compared cortical morphology and spontaneous brain activity between 28 patients with moderate-to-severe OSA and 34 healthy controls (HCs) utilizing voxel-based morphology (VBM) and the amplitude of low-frequency fluctuations (ALFF) analyses. In conjunction with the Allen Human Brain Atlas, we used transcriptome-neuroimaging spatial correlation analyses to investigate gene expression patterns associated with changes in gray matter volume (GMV) and ALFF in OSA. Compared to the HCs, the OSA group exhibited increased ALFF values in the left hippocampus (t = 5.294), amygdala (t = 4.176), caudate (t = 4.659), cerebellum (t = 5.896), and decreased ALFF values in the left precuneus (t = -4.776). VBM analysis revealed increased GMV in the right inferior parietal lobe (t = 5.158) in OSA. Additionally, functional enrichment analysis revealed that genes associated with both ALFF and GMV cross-sampling were enriched in gated channel activity and synaptic transmission, glutamatergic synapse, and neuron.

Postoperative cerebellar mutism syndrome is an acquired autism-like network disturbance.

Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumor surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. In this study, we analyzed postoperative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and pediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n = 427). Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the pediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to the prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviors. Our findings indicate that CMS-associated lesions may result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

Cortical thickness of the inferior parietal lobule as a potential predictor of relapse in men with alcohol dependence.

Alcohol dependence is a disorder with a high recurrence rate that leads to a considerable public health burden. The risk of relapse appears to be related to a complex interplay of multiple factors. Herein, we aimed to explore the potential neural predictors of relapse in Chinese male patients with alcohol dependence.This study enrolled 58 male patients with alcohol dependence who had undergone acute detoxification. General demographic information and clinical features were collected. Magnetic resonance imaging data were used to measure cortical thickness across 34 regions of the brain. Patients were followed up at six months, and 51 patients completed the follow-up visit. These patients were divided into a relapser and an abstainer group. A binary logistic regression analysis was performed to investigate the potential risk factors of relapse.Compared to abstainers, relapsers showed higher inattention and non-planning impulsivity on the 11th version of the Barratt Impulsive Scale. The cortical thicknesses of the inferior-parietal lobules were significantly higher in abstainers compared with those in relapsers. Furthermore, binary logistic regression analysis showed that the thickness of the inferior parietal lobule predicted relapse, and lower non-planning impulse was a protective factor against relapse.Relapsers show poorer impulse control than abstainers, and structural magnetic resonance imaging revealed a decreased thickness of the inferior parietal lobule in relapsers. Our results indicate the thickness of the inferior parietal lobule as a potential relapse predictor in male patients with alcohol dependence.

Twelve weeks of physical exercise breaks with coordinative exercises at the workplace increase the sulcal depth and decrease gray matter volume in brain structures related to visuomotor processes

Physical exercise can evoke changes in the brain structure. Consequently, these can lead to positive impacts on brain health. However, physical exercise studies including coordinative exercises are rare. Therefore, in this study, we investigated how 12 weeks of physical exercise breaks (PEBs) with coordinative exercises, focusing mainly on juggling tasks, affected the brain structure. The participants were randomly allocated to an intervention group (IG, n = 16; 42.8 ± 10.2 years) and a control group (CG, n = 9; 44.2 ± 12.3 years). The IG performed the PEBs with coordinative exercises twice per week for 15–20 min per session. Before the intervention, after 6 weeks of the intervention, and after 12 weeks of the intervention, participants underwent a high-resolution 3T T1-weighted magnetic resonance imagining scan. Juggling performance was assessed by measuring the time taken to perform a three-ball cascade. A surface-based analysis revealed an increase in vertex-wise cortical depth in a cluster including the inferior parietal lobe after 6 and 12 weeks of training in the IG. After 12 weeks, the IG showed a decrease in gray matter (GM) volume in a cluster primarily involving the right insula and the right operculum. The changes in the GM volume were related to improvements in juggling performance. No significant changes were found for the CG. To conclude, the present study showed that regular engagement in PEBs with coordinative exercises led to changes in brain structures strongly implicated in visuomotor processes involving hand and arm movements.

Sex-specific grey matter abnormalities in individuals with chronic insomnia.

Previous studies have reported sex differences in altered brain function in patients with chronic insomnia (CI). However, sex-related alterations in brain morphology have rarely been investigated. This study aimed to investigate sex-specific grey matter (GM) alterations in patients with CI and to examine the relationship between GM alterations and neuropsychological assessments. Ninety-three (65 females and 28 males) patients and 78 healthy (50 females and 28 males) controls were recruited. Structural magnetic resonance imaging data were analysed using voxel-based morphometry to test for interactions between sex and diagnosis. Spearman's correlation was used to assess the associations among structure, disease duration, and sleep-, mood-, and cognition-related assessments. Males with CI showed reduced GM volume in the left inferior parietal lobe, left middle cingulate cortex, and right supramarginal gyrus. Females with CI showed increased GM volume in the right Rolandic operculum. Moreover, mood-related assessments were negatively correlated with GM volumes in the right supramarginal gyrus and left inferior parietal lobe in the male patients, and cognitive-related assessments were positively correlated with GM volumes in the Rolandic operculum in the female patients. Our findings indicate sex-specific alterations in brain morphology in CI, thereby broadening our understanding of sex differences in CI and potentially providing complementary evidence for the development of more effective therapies and individual treatments.

Altered brain activity and cognitive impairment in patients with psoriasis.

Patients with psoriasis may have cognitive impairment. However, there is limited information regarding intrinsic brain activity and cognitive function in patients with psoriasis. This study aim to assess alterations of intrinsic brain activity and its association with cognitive function in patients with psoriasis. A total of 222 patients with psoriasis aged 18-70 years and 144 age and gender-matched healthy controls (HCs) were enrolled into this study. All subjects underwent brain resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological testing. The rs-fMRI data were analysed for both intrinsic brain activity as indicated by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC). Correlative analysis of brain activity with cognitive assessment was performed. Compared with the HCs, patients with psoriasis had worse cognitive performance in the Trail Making Test, Digit Span Test and Stroop Color-Word Test (p < 0.05). Patients with psoriasis showed decreased ALFF in the left superior frontal gyrus, the left medial superior frontal gyrus and the right precuneus gyrus; as well as enhanced ALFF in the left paracentral lobule (pFWE < 0.05). Significant correlations were noted between the altered ALFF in the four brain regions and cognitive assessment (p < 0.05). Moreover, patients with psoriasis had increased FC between the four brain regions with altered ALFF (seeds) and the left prefrontal gyrus, the left anterior cingulate gyrus, left superior parietal lobule and default mode network (DMN) regions such as the right precuneus gyrus, left inferior parietal lobule, right angular gyrus and bilateral inferior temporal gyrus (pFWE < 0.05). Patients with psoriasis had altered brain activity and connectivity in the key brain areas within the DMN-prefrontal circuit. These brain changes may be the underlying neural correlates for cognitive functioning in patients with psoriasis.

Elevated VCAM-1 levels in peripheral blood are associated with brain structural and functional alterations in major depressive disorder

BackgroundVascular cell adhesion molecule-1 (VCAM-1) is a well-known biomarker of endothelial activation. This study aimed to determine whether changes in peripheral VCAM-1 levels occurred in major depressive disorder (MDD) patients and explored immune-brain interactions based on neuroimaging. MethodsThis study included 165 subjects (80 healthy controls [HCs] and 85 MDD patients). Of them, 133 underwent magnetic resonance imaging. VCAM-1 was measured using a commercially available Enzyme-Linked Immunosorbent Assay kit following the manufacturer's instructions. The gray matter volume (GMV) and surface-based functional connectivity (FC) were calculated based on Schaefer parcellation 400 parcels. ResultsCompared with the HCs, MDD patients exhibited significantly higher level of VCAM-1. The correlation analysis showed that VCAM-1 had a significant negative correlation with GMV of the right medial frontal cortex (MFC) and postcentral (PostCG). The mediation analyses showed that VCAM-1 mediated the association between group and GMV of PostCG and the FC of left ventral prefrontal cortex (vPFC) with right inferior parietal lobe (IPL). ConclusionsThis study showed that a high level of VCAM-1 was associated to the decreased GMV in the right MFC and PostCG, and mediated the FC of the left vPFC with right IPL. These findings suggested that VCAM-1 might contribute to the etiology of MDD by influencing brain structure and function. LimitationsThe cross-sectional design makes it difficult to determine the causal relationship and dynamic effect among VCAM-1, brain structure/function features, and depressive symptoms.

Abnormal fractional amplitude of low-frequency fluctuations and regional homogeneity in major depressive disorder with non-suicidal self-injury

ObjectiveWe conducted this resting-state functional magnetic resonance imaging (rsfMRI) study to characterize changes in regional homogeneity (ReHo) or fractional amplitude of low-frequency fluctuations (fALFF) in young adult patients with major depressive disorder (MDD), with or without non-suicidal self-injury (NSSI). MethodsWe recruited 54 MDD patients with NSSI (MDD/NSSI), 68 MDD patients without NSSI, which is referred to as simple MDD (sMDD), and 66 matched healthy controls (HCs). A combination of fALFF and ReHo analyses was conducted. The effects of NSSI on the brain and their relationship to clinical variables were examined in this study. ResultsMDD/NSSI patients have decreased fALFF in the right superior frontal gyrus (SFG) and the right inferior parietal lobe (IPL), decreased ReHo in the right SFG and the right middle temporal gyrus (MTG) and the left middle occipital gyrus (MOG). fALFF and ReHo values of the right SFG are positively correlated. The ReHo values of the right SFG and the number of recent self-injuries are positively correlated; the fALFF values of the right SFG are negatively correlated with NSSI severity. ConclusionsThere is a difference in brain activity between MDD/NSSI and sMDD, which may serve as an important physiological marker to determine the risk of self-injury and suicide. SignificanceAbnormal brain activity in patients with NSSI may provide new perspectives and significant implications on the severity of MDD patients and the prevention of self-injury and suicide.

Enhancing learning outcomes through multisensory integration: A fMRI study of audio-visual training in virtual reality

The integration of information from different sensory modalities is a fundamental process that enhances perception and performance in real and virtual environments (VR). Understanding these mechanisms, especially during learning tasks that exploit novel multisensory cue combinations provides opportunities for the development of new rehabilitative interventions.This study aimed to investigate how functional brain changes support behavioural performance improvements during an audio-visual (AV) learning task. Twenty healthy participants underwent a 30 min daily VR training for four weeks. The task was an AV adaptation of a ‘scanning training’ paradigm that is commonly used in hemianopia rehabilitation. Functional magnetic resonance imaging (fMRI) and performance data were collected at baseline, after two and four weeks of training, and four weeks post-training.We show that behavioural performance, operationalised as mean reaction time reduction in VR, significantly improves. In separate tests in a controlled laboratory environment, we showed that the behavioural performance gains in the VR training environment transferred to a significant mean RT reduction for the trained AV voluntary task on a computer screen. Enhancements were observed in both the visual-only and AV conditions, with the latter demonstrating a faster response time supported by the presence of audio cues. The behavioural learning effect also transfers to two additional tasks that were tested: a visual search task and an involuntary visual task.Our fMRI results reveal an increase in functional activation (BOLD signal) in multisensory brain regions involved in early-stage AV processing: the thalamus, the caudal inferior parietal lobe and cerebellum. These functional changes were only observed for the trained, multisensory, task and not for unimodal visual stimulation. Functional activation changes in the thalamus were significantly correlated to behavioural performance improvements.This study demonstrates that incorporating spatial auditory cues to voluntary visual training in VR leads to augmented brain activation changes in multisensory integration, resulting in measurable performance gains across tasks. The findings highlight the potential of VR-based multisensory training as an effective method for enhancing cognitive function and as a potentially valuable tool in rehabilitative programmes.

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.

Transcranial Magnetic Stimulation based Network Integrity Assessment in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) has a relatively well‐characterized pathology of amyloid‐β and tau accumulation. Yet, disease progression from preclinical to clinical stage remains largely unpredictable at the individual level. Growing evidence shows disrupted synaptic signaling in functionally connected brain networks early in the preclinical stage, and suggests impaired network integrity, assessed with functional connectivity measures, as potential markers for disease symptomatology in AD.MethodHere propose a novel TMS‐induced causal connectivity measure reflecting integrity of multi‐synaptic signaling within the stimulated brain networks. In a preliminary sample of 9 cognitively normal older adults (Healthy Controls: HCs) and 11 patients with amnestic mild cognitive impairment or mild dementia (early AD), we applied 150 single pulses of TMS to inferior parietal lobule (IPL), a distinct brain region within the default mode network (DMN) showing decreased metabolism in early AD and recorded TMS evoked neural responses with simultaneous electroencephalography (TMS‐EEG). We also characterized spontaneous brain activity with resting‐state EEG (rsEEG) measurements. We performed source space spectral power analyses and seed‐based power envelope correlations (PEC) to estimate cortical distribution of relative alpha power and spontaneous IPL connectivity as rsEEG measurements. Network integrity was defined as the ratio of significantly activated vertices to the total number of vertices within the DMN following TMS of IPL.ResultAlthough relative alpha power (8‐12 Hz) was slightly lower and seed based connectivity was slightly higher within the IPL node in AD participants, no network specific differences was observed across the cortex for both rsEEG measures. On the other hand, DMN integrity was substantially lower in AD participants with an average ratio of 0.53 (0.79 in HC) indicating that almost half of the vertices within the DMN were not activated by TMS.ConclusionOverall, these preliminary analyses suggest that perturbation‐based (TMS‐EEG) measures may reveal neurophysiological signatures of brain network dysfunction that are not observable in spontaneous brain oscillations, and thus may characterize defining features of network failure in preclinical and mild AD.

Structural Correlates of Speech Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment

AbstractBackgroundIn the present study, we aimed to confirm the association between speech characteristics of individuals with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI) and brain regions, and to investigate the neurobiological basis of speech‐based AD detection.MethodIndividuals with MCI (n = 13, age = 78.3), mild‐to‐moderate AD (n = 12, age = 77.8) underwent a structural MRI scan and engaged in three speech tasks: an interview, sentence repetition, and paragraph recall. From the speech samples, we extracted frequency‐related, intensity‐related, and temporal features which were found to be altered in the course of AD and MCI pathology. We selected nine regions of interest (ROI) which were found to be involved in speech production and reduced in MCI and AD pathology; the Inferior Frontal Gyrus (IFG), the Medial Frontal Gyrus (MFG), the Precuneus, the Inferior Parietal Lobe (IPL), Inferior Temporal Gyrus (ITG), Medial Temporal Gyrus (MTG), the Superior Temporal Gyrus (STG), the Fusiform Gyrus (FFG), and the Cerebellum. The linear mixed‐effect analysis was used to identify the associations between speech features and regional brain volumes.ResultThe Left IPL (χ2 (1) = 7.69, corrected P = 0.033), the Right ITG (χ2 (1) = 11.5, corrected P = 0.0128) the Right FFG (χ2 (1) = 9.35, corrected P = 0.0198) reduced the pitch of voice by about 0.887 ± 0.292, 1.368 ± 0.329, and 1.69 ± 0.429 respectively. The associations between the Right FFG (χ2 (1) = 4.58, corrected P = 0.0900), Left FFG (χ2 (1) = 5.87, corrected P = 0.0675) and loudness were marginally significant, with the reduction of volumes in the Right FFG and Left FFG decreasing the loudness by 0.096 ± 0.041, and 0.1165 ± 0.0454. The marginally significant associations were observed between the Right IPL (χ2 (1) = 4.75, corrected P = 0.0900), the Left FFG (χ2 (1) = 0.39, corrected P = 0.53) and the speech rate, and the atrophy of brain regions decreased the speech rate by 0.0824 ± 0.0363, 0.0535 ± 0.0079.ConclusionThe present study identified the associations between speech biomarkers and regional brain volumes providing clinical validity for the speech‐based Alzheimer’s disease detection.

Enhanced arterial spin labeling in mild cognitive impairment phenotypes

AbstractBackgroundArterial spin labeling perfusion MRI is increasingly proving to be a promising tool for exploring neurovascular changes in neurodegenerative conditions. Using an advanced 3D pseudo‐continuous arterial spin labeling sequence with Hadamard‐encoded multiple post‐labeling delays (eASL), this study evaluated both cerebral blood flow (CBF) and arterial transit time (ATT) alterations in mild cognitive impairment (MCI) phenotypes.MethodMCI patients (N = 19;Mage = 74.63±5.65) and controls (N = 20;Mage = 70.04±7.06) underwent a 3T MR scan with the eASL sequence. ATT and CBF were simultaneously measured. Voxel‐wise group comparisons of CBF and ATT were performed. Results were thresholded at a cluster‐size corrected p&lt;0.001 (a&lt;0.05). A region of interest (ROI) was defined as the overlap of clusters showing a significant difference in CBF and ATT between MCI and controls. Independent t‐tests between MCI phenotypes (amnestic, non‐amnestic) and controls on CBF and ATT ROIs were conducted. Pearson correlations of ROIs with measures of cognition, including executive functioning, were calculated. Correlations informed regression analysis.ResultsVoxelwise analyses (Figure1) demonstrated decreased CBF in MCI compared to controls in the default mode network, middle and superior frontal gyri, inferior parietal lobule, and temporal lobe. Increased ATT was seen in similar regions, with clusters centered in inferior and middle temporal lobe and visual cortex. T‐tests using created ROIs (as described above) revealed group differences between controls and MCI phenotypes in both CBF and ATT (ps≤.01); there was a non‐significant trend for higher ATT in naMCI versus aMCI. The highest correlational values emerged between CBF and ATT ROIs with a measure of executive functioning (TrailsB). IVs in regression analysis were age (step 1) and ATT and CBF overlapping ROI values (step 2, stepwise); TrailsB = DV . Across the entire cohort, CBF (R2 change = .239, p&lt;.001), not ATT, was included in the model.ConclusionAdvanced 3D pCASL with Hadamard encoded multiple PLDs (eASL) can be used to simultaneously measure CBF and ATT in MCI and controls. MCI patients showed different patterns of reduced CBF and prolonged ATT. While CBF and ATT values were significantly correlated with TrailsB, regression analysis revealed that CBF was a more robust predictor of TrailsB. Future research should examine eASL as a biomarker for MCI phenotypes.

The interplay between White Matter Hyperintensities and regional β‐Amyloid on Defaults Mode Network

AbstractBackgroundCerebral small vessel ischemic disease (SVID) has been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Yet, the mechanistic role of SVID in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that axonal SVID influences amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults.MethodRegional Standard Uptake Value ratios (SUVr) from Aβ‐PET, and white matter hyperintensity (WMH) volumes from 3D MRI FLAIR images were analyzed across a sample of 72 clinically‐unimpaired (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ‐PET SUVr in the connected cortical DMN regions were analyzed using linear regression models adjusted for age, sex, ApoE and total brain volumes.ResultThe regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in the inferior parietal lobule (IPL) (p = 0.011).ConclusionThe findings suggest that the relation between Aβ parietal cortex is partially driven by SVID in downstream axonal pathways in pAD. The biological relationships and interplay between Aβ and white matter microstructure alterations that precede overt WMH development across the continuum of AD progression warrants further study.

The Sporadic Early‐Onset Alzheimer’s Disease Signature of Regional Atrophy

AbstractBackgroundIn EOAD, the localization of neurodegeneration is often more prominent in posterior lateral temporal, lateral and medial parietal, frontal, or occipital cortex relative to the medial and ventral temporal cortical localization of typical LOAD. Convergently, neuropathological investigations have identified a “hippocampal‐sparing” form of AD that is often present in younger patients. For these reasons, imaging biomarkers of neurodegeneration in EOAD, such as Magnetic Resonance Imaging (MRI) measures of atrophy, likely need to be different than those of neurodegeneration in typical LOAD. Although prior neuroimaging work has advanced our understanding of anatomical abnormalities in EOAD, these studies have included small samples, most composed of amnestic EOAD dementia and none focused on developing an MRI biomarker specific to EOAD. Such a disease‐signature MRI biomarker has been established and validated in LOAD dementia and has proven to be powerful in predicting progressive decline in people with MCI or who were cognitively unimpaired and in predicting molecular biomarker status. An a priori‐defined regional atrophy signature may also be helpful in constraining the analysis of MRI data in studies of putative disease‐modifying therapies.MethodLEADS is an observational study which includes annual MRI. In this analysis, we used FreeSurfer to define the sporadic EOAD atrophy signature in a small sample of MGH EOAD patients, and investigated its reproducibility in LEADS, as well as the magnitude of atrophy and its relationship to clinical measures.ResultThe EOAD signature is robustly reproducible across the two independent patient cohorts, with prominent atrophy in caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortex, with relative sparing of medial temporal lobe structures. Comparing patients to controls, Cohen’s d effect sizes within various regions ranged from 0.99 to 1.98.ConclusionThis study demonstrates the specific cortical regions with most prominent atrophy in patients with sporadic EOAD; this signature of regional atrophy will be used to examine longitudinal change.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology

AbstractBackgroundThe association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.MethodsSurvival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).ResultsHearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.ConclusionHearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.

Multimodal MRI and tau PET findings from the Autosomal Dominant Alzheimer’s disease cohort caused by the A431E PSEN1 Jalisco mutation

AbstractBackgroundThe A431E mutation in PSEN1 is a cause of Autosomal Dominant Alzheimer’s disease (ADAD) that represents a founder effect, apparently arising from the state of Jalisco, Mexico, with over 100 superficially distinct families being affected. The median age of symptom onset is 41 years, with about 40% of cases having an atypical presentation of substantial spastic paraparesis. This study aimed to identify the neuroimaging features associated with the A431E PSEN1 Jalisco mutation to elucidate its pathophysiology and to inform future clinical studies.MethodThirty‐one participants with or known to be at‐risk for the A431E PSEN1 mutation were enrolled in a comprehensive genetic, clinical, and imaging protocol including MRI and flortaucipir PET scans. Diffusion MRI and flortaucipir PET studies were conducted on sub‐samples of the cohort along with appropriate control participants.ResultPeak flortaucipir standard uptake value ratio (SUVR) among A431E mutation carriers was predominantly in the lateral parietal cortices relative to the medial temporal lobes with disproportionate signal in motor and sensory cortex relative to persons with late onset AD. Flortaucipir SUVR in 6 brain regions (i.e., medial orbitofrontal, caudal and rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were associated with neuropsychiatric symptoms in persons with or at risk for the A431E PSEN1 mutation. Among 21 A431E PSEN1 mutation carriers with available diffusion MRI images, the Ashworth score of spastic paraparesis correlated with mean diffusivity in several brain regions, particularly left inferior parietal, superior parietal, and paracentral lobules (r’s&gt;0.8, p’s&lt; 0.001). In a subset of 10 clinically impaired A431E PSEN1 mutation carriers, mean diffusivity in white matter tracts underlying multiple cortical areas was higher relative to 8 impaired persons with late onset AD or ADAD mutations that do not cause spastic paraparesis.ConclusionThe pattern of flortaucipir distribution was atypical with disproportionate involvement of sensorimotor areas and parietal cortex. Higher flortaucipir signal was associated with more neuropsychiatric symptoms. Microstructural changes in white matter were more pronounced in persons with the A431E PSEN1 mutation and likely underlie the associated spastic paraparesis. The distinct neuroimaging features and associated neuropsychiatric manifestations observed in this cohort highlight the importance of comprehensively characterizing heterogeneous AD subtypes.

Multimodal MRI and tau PET findings from the Autosomal Dominant Alzheimer’s disease cohort caused by the A431E PSEN1 Jalisco mutation

AbstractBackgroundThe A431E mutation in PSEN1 is a cause of Autosomal Dominant Alzheimer’s disease (ADAD) that represents a founder effect, apparently arising from the state of Jalisco, Mexico, with over 100 superficially distinct families being affected. The median age of symptom onset is 41 years, with about 40% of cases having an atypical presentation of substantial spastic paraparesis. This study aimed to identify the neuroimaging features associated with the A431E PSEN1 Jalisco mutation to elucidate its pathophysiology and to inform future clinical studies.MethodThirty‐one participants with or known to be at‐risk for the A431E PSEN1 mutation were enrolled in a comprehensive genetic, clinical, and imaging protocol including MRI and flortaucipir PET scans. Diffusion MRI and flortaucipir PET studies were conducted on sub‐samples of the cohort along with appropriate control participants.ResultPeak flortaucipir standard uptake value ratio (SUVR) among A431E mutation carriers was predominantly in the lateral parietal cortices relative to the medial temporal lobes with disproportionate signal in motor and sensory cortex relative to persons with late onset AD. Flortaucipir SUVR in 6 brain regions (i.e., medial orbitofrontal, caudal and rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were associated with neuropsychiatric symptoms in persons with or at risk for the A431E PSEN1 mutation. Among 21 A431E PSEN1 mutation carriers with available diffusion MRI images, the Ashworth score of spastic paraparesis correlated with mean diffusivity in several brain regions, particularly left inferior parietal, superior parietal, and paracentral lobules (r’s&gt;0.8, p’s&lt; 0.001). In a subset of 10 clinically impaired A431E PSEN1 mutation carriers, mean diffusivity in white matter tracts underlying multiple cortical areas was higher relative to 8 impaired persons with late onset AD or ADAD mutations that do not cause spastic paraparesis.ConclusionThe pattern of flortaucipir distribution was atypical with disproportionate involvement of sensorimotor areas and parietal cortex. Higher flortaucipir signal was associated with more neuropsychiatric symptoms. Microstructural changes in white matter were more pronounced in persons with the A431E PSEN1 mutation and likely underlie the associated spastic paraparesis. The distinct neuroimaging features and associated neuropsychiatric manifestations observed in this cohort highlight the importance of comprehensively characterizing heterogeneous AD subtypes.

Lower Endogenous Estrogens in APOE4‐Positive Postmenopausal Women Associated with Lower Regional Brain Volumes

AbstractBackgroundDuring the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers.MethodsParticipants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Cross‐sectional associations of interest were analyzed with APOE4 genotype (carrier versus noncarrier; excluding APOE2)ormone levels, and their interaction, as predictors and regional brain volumes (33 regions per hemisphere) as outcome measures using lme4 Package in R. Models controlled for, years of education, and body mass index.ResultsNeither APOE4 carrier status nor hormone levels were associated with brain volumes . However, significant interactions were observed between APOE4 carrier status and E2 levels in relation to volume of the right (p&lt;.05) and left isthmus cingulate (p&lt;.01), right and left middle temporal lobe (p&lt;.05), and the left posterior cingulate (p&lt;.05), such that the positive association between E2 and regional brain volumes was more positive among APOE4 carriers (Figure 1). Further, there was a significant interaction between APOE4 carrier status and E1 levels in relation to volumes of the right and left inferior parietal lobe (p&lt;.05), right (p&lt;.05) and left isthmus cingulate (p&lt;.05), left cuneus (p&lt;.05), left precuneus (p&lt;.05), and left lingual gyrus (p&lt;.05)(Figure 2).ConclusionAlthough some of these findings would be expected by chance, results suggest that lower levels of endogenous estrogens may be a risk factor for regional brain volume loss in female APOE4 carriers compared to non‐carriers.Supported by NIH RF1AG053504 and R01AG053504 (Thurston &amp; Maki)