Bilateral Entorhinal Cortex Research Articles

Neural basis of false recognition in Alzheimer's disease and dementia with lewy bodies.

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease.

Structural Magnetic Resonance Imaging-Based Surface Morphometry Analysis of Pediatric Down Syndrome.

Down syndrome (DS) is a genetic disorder characterized by intellectual disability whose etiology includes an additional partial or full copy of chromosome 21. Brain surface morphometry analyses can potentially assist in providing a better understanding of structural brain differences, and may help characterize DS-specific neurodevelopment. We performed a retrospective surface morphometry study of 73 magnetic resonance imaging (MRI) examinations of DS patients (aged 1 day to 22 years) and compared them to a large cohort of 993 brain MRI examinations of neurotypical participants, aged 1 day to 32 years. Surface curvature measurements, absolute surface area measurements, and surface areas as a percentage of total brain surface area (%TBSA) were extracted from each brain region in each examination. Results demonstrate broad reductions in surface area and abnormalities of surface curvature measurements across the brain in DS. After adjusting our regional surface area measurements as %TBSA, abnormally increased presentation in DS relative to neurotypical controls was observed in the left precentral, bilateral entorhinal, left parahippocampal, and bilateral perirhinal cortices, as well as Brodmann's area 44 (left), and the right temporal pole. Findings suggest the presence of developmental abnormalities of regional %TBSA in DS that can be characterized from clinical MRI examinations.

Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline.

Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

Amygdala tau deposition best discriminates between stages of memory impairment

AbstractBackgroundThe recent development of positron emission tomography (PET) radiotracers for tau aggregates allows quantifying the regional tau burden in‐vivo. We aimed to investigate the associations between regional tauopathy and episodic memory outcomes in the AD spectrum from clinically normal to the dementia stage.MethodWe recruited 111 participants between 2019 and 2023 at the Memory Clinic of Saint‐Luc University Hospital. Each participant underwent [F18]‐MK6240 tau‐PET, 3DT1 MRI, cognitive assessment, and either lumbar puncture or [F18]‐Flutemetamol PET for amyloid status. Tau burden was quantified using Freesurfer by referring to the Desikan‐Kiliany lobe cortical parcellation, as well as in several medio‐temporal regions (MTL; i.e., entorhinal cortex, amygdala, hippocampus). Memory was assessed using three Z‐scores from the FCSRT: Sum of Free Recall (SFR), Sum of Total Recall (STR), and Sum of Delayed Free Recall (DFR). The average of these scores forms the Memory Composite Score (MCS). Participants were classified in three groups (Table 1): amyloid‐negative clinically normal participants (n = 44); non‐demented participants with AD pathology (early AD, n = 45); and AD dementia participants (n = 22). Based on their SFR and STR scores, subjects were also classified as having retrieval and/or encoding memory deficits according to a Stage of Objective Memory Impairment (SOMI) classification, inspired from Grober and colleagues (2018). Analyses were corrected for multiple comparisons.ResultIn early AD, SFR and DFR correlated with tauopathy in the bilateral entorhinal cortex (EC) and amygdala (Fig.1). MCS correlated with tauopathy in the bilateral amygdala, and the right frontal lobe. Tau levels did not correlate with STR in any regions. Moreover, MTL tauopathy differed between SOMI stages: Specifically, amygdala tauopathy gradually increased with retrieval deficits (SOMI1‐2) and encoding deficits (SOMI3‐4). In contrast, tauopathy in the EC, the temporal lobe, and the parietal lobe was elevated in all participants with memory deficits, but did not distinguish between retrieval and encoding deficits (Table 2).ConclusionTauopathy in the MTL ROIs is predictive of retrieval deficits in early stage of AD. SFR is a more sensitive measure of this early decline compared to STR. Amygdala tauopathy differs between patients with retrieval and encoding deficits.

Clinical Manifestations.

Mild behavioral impairment (MBI) identifies a high-risk group for Alzheimer's disease and related dementias (ADRD), leveraging the risk associated with later-life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later-life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co-occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI. Seven-hundred-forty-two participants were included from the National Alzheimer's Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant-rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions-of-interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical-MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions. Participant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = -0.40, 95%CI:[-0.66, -0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI- participants, although not statistically significant (B = -0.13, 95%CI:[-0.35, -0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = -0.46, 95%CI:[-0.80, -0.12], p = .01) and entorhinal cortex (B = -0.42, 95%CI:[-0.76, -0.12], p = .009), and had greater progression-rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI. Our findings suggest that evaluating dementia-free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.

Neuroticism is associated with entorhinal cortex volume in cognitively unimpaired older adults

AbstractBackgroundNeuroticism, the tendency toward negative mood states, is associated with Alzheimer’s Disease (AD) and tau pathology within entorhinal cortex (EC) in mild cognitive impairment and healthy older adults. However, studies of the link between neuroticism and structural neurodegeneration of EC have been negative. This may result from failure to account for subsyndromal affective symptoms or previous psychiatric history, as neuroticism is closely related to mood conditions that in turn, affect similar brain regions vulnerable to AD. We examined the association between neuroticism and EC volume while accounting for cognition, affective symptoms, and other personality traits in cognitively unimpaired (CU) older adults without history of major psychiatric conditions.Method42 CU adults (age = 71.1 years, 27 females) with normal neuropsychological test performance and no known neurological conditions and current or past psychiatric disorders completed Geriatric Depression Scale, State‐Trait Anxiety Inventory, NEO Five‐Factor Inventory‐3 which assesses neuroticism, openness, conscientiousness, extraversion, and agreeableness, Montreal Cognitive Assessment (MoCA), and structural magnetic resonance imaging of whole brain at 3T. Regression analyses examined the unconditional ability of neuroticism to predict bilateral EC volume, and while considering the potential contribution of cognition (MoCA, California Verbal Learning Test Delayed Recall), affective state, other personality traits, and age, gender, and education. P&lt;.10 was set as the significance threshold for β estimates.ResultIn univariable modelling, neuroticism was predictive of left EC volume (β = ‐17.4, p = .025), explaining 9.8% of its variability [F(1, 40) = 5.45, p = .025]. Neuroticism remained a significant predictor of left EC volume (β = ‐1.9, p = .045) after factoring in demographic, cognitive and affective/personality variables. Additional left EC predictors were extraversion and state anxiety (β = ‐2.61, p = .01; β = 1.71, p = .045 respectively). Neuroticism was not predictive of right EC in univariable or multivariable modelling, but agreeableness emerged as a significant predictor (β = ‐1.68, p = .091).ConclusionNeuroticism was predictive of left EC volume in CU adults without current or past history of psychiatric disorders, independent of cognition, affect, and other personality traits. These findings, which have not been previously reported, extend previous epidemiological evidence of increased AD risk due to neuroticism and suggest the importance of considering the impact of mood symptoms and psychiatric history in this context.

1 Basal Forebrain Free Water Fraction is Associated with Cortical Cholinergic Levels in Idiopathic Parkinson’s Disease

Objective:Cognitive dysfunction is a common non-motor symptom of Parkinson’s disease (PD). Cognitive decline in PD is likely associated with dysfunction in the cholinergic system, which is affected by synuclein pathology early in the disease course. Recent studies have shown an association between reduced integrity of the basal forebrain (BF), which provides cholinergic innervation to most of cortex, and diminished cognitive functioning in PD. Specifically, those with PD and reduced cholinergic innervation also have higher rates of cognitive impairment. However, no study has directly investigated the relationship between basal forebrain integrity and cortical cholinergic levels. In the present study, we examined this relationship through measures of basal forebrain microstructural integrity and cholinergic nerve terminal density in cortical and subcortical gray matter.Participants and Methods:Participants included 92 non-demented individuals with idiopathic PD (M:F=64:28; Age=67.0±7.1 yrs) who underwent structural MRI, diffusion MRI, and [18F] fluoroethoxybenzovesamicol (FEOBV) cholinergic PET imaging. We used a basal forebrain and region of interest defined by AssemblyNet, which uses ensembles of pretrained convolutional neural networks to create a full brain segmentation. Bilateral putamen from this atlas was also included as a control region. We measured microstructural integrity using free water fraction (FWF), a diffusion MRI-derived metric of extracellular water that associates with cellular density and neuroinflammation. For PET data, we computed the distribution volume ratio (DVR) by regions as defined by FreeSurfer. A factor analysis of DVR in all 88 FreeSurfer ROIs resulted in seven clusters of ROIs covering 1) widespread bilateral cortical regions (PC1); 2) subcortical and limbic regions (PC2); 3) bilateral cingulate regions (PC3); 4) left frontal regions (PC4); 5) right frontal and temporal regions (PC5); 6) cerebellum (PC6); and 7) bilateral entorhinal cortex and left temporal cortex (PC7). We performed seven separate regression analyses per ROI (controlling for age and disease duration) to evaluate the association between BF FWF and cholinergic levels in these regions. To determine if these ROIs showed unique associations with BF FWF, we then entered ROIs with a significant association with BF FWF as independent variables in a stepwise regression with forward selection with BF FWF as the dependent variable.Results:BF FWF was significantly and negatively associated with cholinergic levels in PC1 (AR2=.042, ß=-0.208, p=.04), PC3 (AR2=.044, ß=-0.206, p=.03), PC4 (AR2=.056, ß=-0.239, p=.02), and PC7 (ß=-0.215, p=.04). BF FWF trended towards a negative association with cholinergic levels in PC5 (AR2=.045, ß=-0.168, p=.09) and PC6 (ß=-0.188, p=.09). Putamen FWF did not significantly associate with any of the ROIs. In the follow-up stepwise regression, only PC4 contributed significantly to the overall model (AR2=.061, ß=-0.261, p=.02).Conclusions:Basal forebrain FWF was inversely related to cholinergic levels in regions that are directly innervated by the basal forebrain (e.g., cingulate cortex, left frontal cortex, and bilateral entorhinal cortex). Future research should directly investigate the relationship between basal forebrain integrity, cortical cholinergic levels, and cognition. Separating the basal forebrain into specific nuclei would also be beneficial, as different nuclei may have differing associations with specific hemispheric cholinergic pathways and cognition.

11 Contributions of Cardiovascular Burden, Peripheral Inflammation, and Brain Integrity on Digital Clock Drawing Performance in Non-Demented Older Adults

Objective:Higher cardiovascular burden and peripheral inflammation are associated with small vessel vascular disease, a predominantly dysexecutive cognitive profile, and a higher likelihood of conversion to vascular dementia. The digital clock drawing test, a digitized version of a standard neuropsychological tool, is useful in identifying cognitive dysfunction related to vascular etiology. However, little is known about the specific cognitive implications of vascular risk, peripheral inflammation, and varying levels of overall brain integrity. The current study aimed to examine the role of cardiovascular burden, peripheral inflammation, and brain integrity on digitally acquired clock drawing latency and graphomotor metrics in non-demented older adults.Participants and Methods:The final prospectively recruited IRB-consented participant sample included 184 non-demented older adults (age: 69±6 years, education: 16±3 years, 46% female, 94% white) who completed digital clock drawing, vascular assessment, blood draw, and brain MRI. Digital clock drawing variables of interest included: total completion time (TCT), pre-first hand latency (PFHL), digit misplacement, hour hand distance from center, and clock face area (CFA). Cardiovascular burden was calculated using the revised version of the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation was operationalized using interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-a), and high sensitivity C-reactive protein (hsCRP). The brain integrity composite was comprised of bilateral entorhinal cortex volume, bilateral ventricular volume, and whole brain leukoaraiosis.Results:Over and above age and cognitive reserve, hierarchical regressions showed FSRP-10, inflammatory markers, and brain integrity explained an additional 13.3% of the variance in command TCT (p&lt; 0.001), with FSRP-10 (p=0.001), IL-10 (p= 0.019), and hsCRP (p= 0.019) as the main predictors in the model. FSRP-10, inflammatory markers, and brain integrity explained an additional 11.7% of the variance in command digit misplacement (p= 0.009), with findings largely driven by FSRP-10 (p&lt; 0.001).Conclusions:Overall, in non-demented older adults, subtle behavioral nuances seen in digital clock drawing metrics (i.e., total completion time and digit misplacement) are partly explained by cardiovascular burden, peripheral inflammation, and brain integrity over and above age and cognitive reserve. These nuanced behaviors on digitally acquired clock drawing may associate with an emergent disease process or overall vulnerability.Funding sources: Barber Fellowship; K07AG066813; R01 AG055337; R01 NR014810; American Psychological Foundation Dissertation Award; APA Dissertation Research Award

Contributions of Cardiovascular Burden, Peripheral Inflammation, and Brain Integrity on Digital Clock Drawing Performance in Non-Demented Older Adults.

Greater cardiovascular burden and peripheral inflammation are associated with dysexecutive neuropsychological profiles and a higher likelihood of conversion to vascular dementia. The digital clock drawing test (dCDT) is useful in identifying neuropsychological dysfunction related to vascular etiology. However, the specific cognitive implications of the combination of cardiovascular risk, peripheral inflammation, and brain integrity remain unknown. We aimed to examine the role of cardiovascular burden, inflammation, and MRI-defined brain integrity on dCDT latency and graphomotor metrics in older adults. 184 non-demented older adults (age 69±6, 16±3 education years, 46% female, 94% white) completed dCDT, vascular assessment, blood draw, and brain MRI. dCDT variables of interest: total completion time (TCT), pre-first hand latency, digit misplacement, hour hand distance from center, and clock face area. Cardiovascular burden was calculated using the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation markers included interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha, and high sensitivity C-reactive protein. Brain integrity included bilateral entorhinal cortex volume, lateral ventricular volume, and whole brain leukoaraiosis. FSRP-10, peripheral inflammation, and brain integrity explained an additional 14.6% of the variance in command TCT, where FSRP-10 was the main predictor. FSRP-10, inflammatory markers, and brain integrity explained an additional 17.0% in command digit misplacement variance, with findings largely driven by FSRP-10. Subtle graphomotor behavior operationalized using dCDT metrics (i.e., TCT and digit misplacement) is partly explained by cardiovascular burden, peripheral inflammation, and brain integrity and may indicate vulnerability to a disease process.

Asymmetry of brain development in adolescent rats studied by 3.0 T magnetic resonance imaging.

To study the developmental patterns of brain structure in adolescent rats based on the registration with the SIGMA template by 3.0T MRI. Forty male Sprague-Dawley rats (180-220 g) were randomly divided into four groups. Rats in the four groups underwent 3.0 T MRI head scans at 7, 11, 15, and 19 weeks of age, respectively. The voxel-based morphological analysis of the rat brain was performed by coregistration with the SIGMA rat brain template. 3.0 T MRI can be used to study the anatomical structure of the rat brain by registration with the SIGMA template The gray matter volume of the bilateral hippocampus and bilateral entorhinal cortex increased significantly in the development of the rat from 7 to 19 weeks of age. In this period, the subtle structure of the rat brain is asymmetrically developed. The rat aged 7-19 weeks has asymmetrical gray matter volume development in the bilateral entorhinal cortex and hippocampus.

Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer’s disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.

Early tau detection in flortaucipir images: validation in autopsy-confirmed data and implications for disease progression

BackgroundThere is an increasing interest in utilizing tau PET to identify patients early in Alzheimer’s disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated.MethodsA total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (ADsignature) (Devous et al., J Nucl Med 59:937–43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944–51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/ADsignature+; Eτ+/ADsignature–; Eτ−/ADsignature−). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/ADsignature− group and B2 NFT scores were created for visual evaluation of uptake.ResultsSixty-four out of 390 analyzable subjects were identified as Eτ+/ADsignature–: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/ADsignature– status reflects an early stage of AD, Eτ+/ADsignature– subjects deteriorated significantly faster than Eτ–/ADsignature– subjects, but significantly slower than Eτ+/ADsignature+ subjects, on most measures (i.e., change in ADsignature SUVr, Eτ ROI cortical thickness, and MMSE). The ADsignature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/ADsignature–. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects.ConclusionThe Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/ADsignature–) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/ADsignature– subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ−/ADsignature− subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer’s disease.

Assessment of gray matter microstructure and synaptic density in Alzheimer’s Disease: a multimodal imaging study with DWI and SV2A PET

AbstractBackgroundDiffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer’s Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.MethodThirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.ResultsAxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.ConclusionWe found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.

Assessment of gray matter microstructure and synaptic density in Alzheimer's Disease: a multimodal imaging study with DWI and SV2A PET

AbstractBackgroundDiffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer's Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.MethodThirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.ResultsAxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.ConclusionWe found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.

Association of Apathy with Amyloid‐β and Tau in Cognitively Unimpaired Older Adults: Findings from the Harvard Aging Brain Study

AbstractBackgroundApathy is one the most common neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) and is associated with elevated AD pathology in cognitively impaired individuals. However, it remains unclear if apathy is associated with AD pathology, specifically amyloid‐β and tau, in cognitively unimpaired (CU) older adults. Therefore, we examined cross‐sectional relationships between apathy and neuroimaging AD biomarkers in CU older adults from the Harvard Aging Brain Study (HABS).MethodHABS is a prospective cohort study that enrolled CU older adults. A random subset of HABS participants (n = 142, age: 80.53 ±6.0, 57% female) and their study partners (SP) completed the Apathy Evaluation Scale‐Self (AES‐S) and ‐Informant (AES‐I). The AES consists of 18 items rated on a 4‐point Likert‐type scale; lower scores indicate greater apathy. We used Pittsburgh Compound B (PiB) PET cortical composite distribution volume ratio to measure amyloid‐β (Aβ), and flortaucipir (FTP) PET standardized uptake value ratio in two regions (bilateral entorhinal (ER) cortex and inferior temporal (IT) cortex) to capture regional tau. We assessed the association of AES‐S or AES‐I (dependent variable) with Aβ, or each of the two regional tau values (independent variable), in linear models adjusting for age, sex, and education. We then explored Aβ‐independent associations between regional tau and AES‐I/AES‐S, by additionally adjusting for Aβ in each tau model.ResultElevated Aβ (β = ‐3.7, p = 0.015) and ER Tau (β = ‐6.0, p = 0.016) were associated with lower AES‐I, while IT tau was not (p = 0.14). None of the AD pathology measures were associated with AES‐S (all; p&gt;0.23). ER tau was no longer associated with AES‐I once Aβ was also adjusted for in the model (β = ‐4.4, p = 0.100).ConclusionGreater Aβ and tau levels were associated with higher apathy in CU older adults. Our findings imply that even in CU older adults, apathy is closely related to AD pathology may be more accurately measured by study partner report than self‐report, which may reflect a measurement property of this NPS. Further study of apathy in preclinical stages is needed to provide understanding of potential interventions to prevent or delay behavioral symptoms of AD.

Longitudinal medial temporal lobe gray matter volume and cognitive changes in late middle‐aged and older adults with treated and non‐treated obstructive sleep apnea

AbstractBackgroundNeuroimaging studies in obstructive sleep apnea (OSA) have found both gray matter atrophy and hypertrophy in medial temporal lobe subregions, the latter probably reflecting edema. Whether and how these changes progress over time when OSA is treated or untreated remains unclear. Here, we investigated gray matter volume changes in medial temporal lobe subregions in treated OSA, untreated OSA and control participants aged &gt; 55 years. We also explored whether the medial temporal lobe volume at baseline could predict cognitive decline.MethodTwenty‐three non‐treated OSA participants (65.8 ±5.4 years) and twenty controls (64.0 ±6.4 years) were evaluated with overnight polysomnography, MRI session and neuropsychological assessment. Twelve OSA participants then started continuous positive airway pressure (CPAP) therapy and used it at least 4 hours per night, 4 nights per week. Eleven participants refused treatment. Participants were evaluated again with MRI and neuropsychology after 18 months. We extracted the entorhinal, hippocampal and parahippocampal volumes using FreeSurfer 7.1. We performed repeated‐measure ANOVAs with Group (treated OSA, untreated OSA and controls) and Time (baseline and follow‐up) on bilateral volumes. We also performed partial correlations between bilateral medial temporal volumes at baseline and changes in cognition (Montreal Cognitive Assessment, score at follow‐up – baseline) in each group separately. Analyses were corrected for age, sex, and total intracranial volume.ResultWe found a significant Group X Time interaction for bilateral parahippocampal volumes (F = 7.2; p = 0.002) where treated OSA participants showed a decreased volume over time (p tukey&lt;0.001), while no changes occurred in the two other groups. Regarding the predictive value of medial temporal lobe volume, in untreated participants, higher bilateral hippocampal volume at baseline was associated with more severe cognitive decline over time (r = ‐0.77; p = 0.01). In treated participants, higher bilateral entorhinal cortex volume at baseline was associated with more cognitive decline (r = ‐0.74; p = 0.035). No associations were found in controls.ConclusionThese preliminary results showed that presenting hypertrophy of the medial temporal lobe subregions at baseline is associated with worse cognitive outcome at 18‐month follow‐up in OSA participants. In the CPAP group, the decrease in parahippocampal volume might represent a reduction in hypertrophy, possibly by limiting edema.

Possible Role of Endocannabinoids in Olfactory and Taste Dysfunctions in COVID-19 Patients and Volumetric Changes in the Brain.

IntroductionCOVID-19 infection develops neurologic symptoms such as smell and taste loss. We aimed to determine the volumetric changes in the brain and correlation of possible related biochemical parameters and endocannabinoid levels after COVID-19 recovery.MethodsBrain magnetic resonance images of recovered COVID-19 patients and healthy volunteers, whose olfactory and gustatory scores were obtained through a questionnaire, were taken, and the volumes of the brain regions associated with taste and smell were measured by automatic and semiautomatic methods. Endocannabinoids (EC), which are critical in the olfactory system, and vitamin B12, zinc, iron, ferritin, thyroid-stimulating hormone (TSH), and thyroxine (T4) levels, which are reported to have possible roles in olfactory disorders, were measured in peripheral blood.ResultsTaste and smell disorder scores and EC levels were found to be higher in recovered COVID-19 patients compared to controls. EC levels were negatively correlated with bilateral entorhinal cortex (ENT) volumes in the COVID-19 group. Subgenual anterior cingulate cortex volumes showed correlations with gustatory complaints and ferritin in recovered COVID-19 patients.ConclusionsThe critical finding of our study is the high EC levels and negative correlation between EC levels and left ENT volumes in recovered COVID-19 patients.ImplicationsIt is possible that ECs are potential neuromodulators in many conditions leading to olfactory disorders, including COVID-19.

Dynamic network model reveals distinct tau spreading patterns in early- and late-onset Alzheimer disease

BackgroundThe clinical features of Alzheimer’s disease (AD) vary substantially depending on whether the onset of cognitive deficits is early or late. The amount and distribution patterns of tau pathology are thought to play a key role in the clinical characteristics of AD, which spreads throughout the large-scale brain network. Here, we describe the differences between tau-spreading processes in early- and late-onset symptomatic individuals on the AD spectrum.MethodsWe divided 74 cognitively unimpaired (CU) and 68 cognitively impaired (CI) patients receiving 18F-flortaucipir positron emission tomography scans into two groups by age and age at onset. Members of each group were arranged in a pseudo-longitudinal order based on baseline tau pathology severity, and potential interregional tau-spreading pathways were defined following the order using longitudinal tau uptake. We detected a multilayer community structure through consecutive tau-spreading networks to identify spatio-temporal changes in the propagation hubs.ResultsIn each group, ordered tau-spreading networks revealed the stage-dependent dynamics of tau propagation, supporting distinct tau accumulation patterns. In the young CU/early-onset CI group, tau appears to spread through a combination of three independent communities with partially overlapped territories, whose specific driving regions were the basal temporal regions, left medial and lateral temporal regions, and left parietal regions. For the old CU/late-onset CI group, however, continuation of major communities occurs in line with the appearance of hub regions in the order of bilateral entorhinal cortices, parahippocampal and fusiform gyri, and lateral temporal regions.ConclusionLongitudinal tau propagation depicts distinct spreading pathways of the early- and late-onset AD spectrum characterized by the specific location and appearance period of several hub regions that dominantly provide tau.

Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer\u2019s disease dementia

BackgroundCholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer’s disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood.MethodsThis study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer’s disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4β2 nicotinic cholinergic receptor binding (VT/fp) was measured using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest.ResultsSPM analysis showed the group VT/fp binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p < .05, FWE-corrected). Pairwise comparisons revealed lower binding in the AD group compared to the CU group in similar regions. Binding in the entorhinal cortex was lower in the MCI group than in the CU group; binding in the hippocampus was lower in the AD group than in the MCI group. AD participants taking cholinesterase inhibitor medication had lower 2FA binding in the bilateral hippocampus and thalamus compared to those not taking medication. In the CU group, age was negatively associated with 2FA binding in each region of interest (rs = − .33 to − .59, p < .05 for each, uncorrected). Attention, immediate recall, and delayed recall scores were inversely associated with 2FA binding in most regions across the full sample. In the combined group of CU and MCI participants, attention was inversely associated with 2FA binding in most regions, beyond the effect of hippocampal volume.ConclusionsNicotinic cholinergic receptor binding in specific limbic and subcortical regions is lower in MCI and further reduced in AD dementia, compared to CU older adults, and is related to cognitive deficits. Cognitive decline with age may be a consequence of reduced cholinergic receptor density or binding affinity that may also promote vulnerability to other Alzheimer’s processes. Contemporary modification of the “cholinergic deficit” of aging and AD may reveal opportunities to prevent or improve clinical symptoms.

Brain activation during episodic scene encoding is associated with amyloid and tau levels in amyloid‐positive older adults

AbstractBackgroundThe relationship between amyloid and tau deposition and episodic memory‐related brain activity is understudied. Our goal was to determine the association between brain activation on fMRI during encoding of complex scenes and amyloid and tau deposition on PET.Methods91 individuals from the Indiana Memory and Aging Study (36 cognitively normal (CN), 27 subjective cognitive decline (SCD), 28 mild cognitive impairment (MCI)) underwent amyloid ([18F]florbetapir or [18F]florbetaben) and [18F]flortaucipir PET, structural and functional MRI, and clinical and cognitive testing. The fMRI task was a scene encoding paradigm in which the participant is asked to try to remember a set of complex scenes relative to viewing a scrambled control image. Amyloid Centiloid (CL) and tau SUVR images were generated using standard methods. Amyloid positivity was defined as global cortical CL≥21. Areas activated during the task (“main effect” (ME)) across all participants were determined (Figure 1A). Mean BOLD signals from ME regions, the entorhinal cortex (EC), and the inferior parietal lobule (IPL) were extracted. Mean cortical amyloid CL and tau SUVR from the bilateral EC, IPL, and lateral temporal lobe (LTL) were also extracted. Tau and amyloid were non‐normally distributed, so Spearman correlation models were used to evaluate the relationship of scene encoding activation and PET. Age, diagnosis, and sex were evaluated as covariates but did not change the observed pattern of results.ResultsSignificant association between tau and scene encoding activation was observed (Figure 1B). When limited to amyloid‐positive individuals only (n=28), the observed associations were considerably stronger between scene encoding activation and both amyloid CL level and tau deposition (Figure 1C‐E). Similar results were observed when limiting to the CN and SCD groups.ConclusionAmyloid and tau deposition are associated with reduced brain activity during episodic memory encoding in older adults at risk for AD. These findings suggest that brain function is another important biomarker to consider in both the temporal sequencing of biomarkers (Jack et al. 2013) and the A/T/N framework. Future studies in larger samples are warranted. Reference: Jack et al. (2013) Lancet Neurology.