Left Entorhinal Cortex Research Articles

The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease

AbstractIntroductionHippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78‐week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR‐SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non‐carriers over the 78‐week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non‐carriers who completed the 78‐week protocol.MethodsStructural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were analyzed for plasma biomarkers.ResultsTreatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR‐SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration.DiscussionThe HOPE4MCI study showed that APOE ε4 non‐carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non‐carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR‐SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non‐carriers treated with AGB101 before a clinical diagnosis of dementia.Highlights AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non‐carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline. Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain. AGB101 treatment reduces neurodegeneration in APOE ε4 non‐carriers with MCI due to AD.

Potential Biomarkers of Dysmenorrhea Relief: A MEG Study of Hinoki Aromatherapy and Working Memory.

Background/Objectives: This study explored the potential of Hinoki aromatherapy to induce biomarkers of dysmenorrhea relief through working memory. Structural magnetic resonance imaging and magnetoencephalography (MEG) were used to examine their effects on neurophysiological responses to a visual working memory (VWM) test. Behavioral performance was measured to understand its effects on the overall working memory. Methods: Twenty-four healthy participants completed the VWM task during nonmenstruation and menstruation. Behavioral (accuracy and reaction time) and neurophysiological (event-related fields, source estimation, and permutation t-test on source data) measures were assessed without and with Hinoki aromatherapy. Results: A significant difference in the ratio of accuracy to reaction time was found without and with aromatherapy in participants with dysmenorrhea, suggesting that aromatherapy may improve working memory performance in this population. MEG analysis revealed high temporal resolution of evoked latency and intensity during the VWM task. Source localization of the activation aimed to identify brain areas involved in dysmenorrhea. Aromatherapy reduced signals in these areas, which may also contribute to reducing dysmenorrhea-related visual signals. Conclusions: Based on these findings, Hinoki aromatherapy may be a promising treatment option for alleviating dysmenorrhea and improving related symptoms by reducing activity in brain pain processing regions. These regions include the left entorhinal cortex, inferior temporal gyrus, primary visual cortex, retrosplenial cortex, and presubiculum. Furthermore, decreased activity in these areas with aromatherapy suggests that they could be used as biomarkers of dysmenorrhea relief.

Altered structural node of default mode network mediated general cognitive ability in young adults with obesity

BackgroundObesity, characterized by excessive adiposity, is associated with brain structural abnormalities. Nevertheless, the relationships between altered structural nodes of default mode network (DMN), body mass index (BMI), general cognitive ability remained unclear in young adults. MethodsIn this study, we divided a large sample of young adults into three BMI-based groups. We then conducted one-way analyses of variance and post-hoc tests with Bonferroni corrections to investigate abnormal structural brain regions associated with obesity. Furthermore, mediation effects models were built to explore whether the structural alterations influenced the relationship between BMI and general cognitive ability. ResultsCompared to their lean and overweight counterparts, young adults with obesity exhibited significantly lower general cognitive ability, higher impulsivity traits, and worse sleep quality. Furthermore, compared with lean group, young adults with obesity exhibited altered cortical thickness of both the left temporal pole and right superior parietal lobule, and abnormal cortical surface area (CSA) of the left entorhinal cortex (EC), a hub within DMN. Moreover, CSA of the left EC mediated the relationship between BMI and general cognitive ability. ConclusionObesity was linked to altered structural node of DMN, which mediated general cognitive ability in young adults. These findings indicated the negative effect of obesity on DMN and general cognitive ability in young adults.

Tau pathology mediated the plasma biomarkers and cognitive function in patients with mild cognitive impairment

Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. Hence, this study aimed to demonstrate the relationship between plasma biomarkers (GFAP and NfL) and 18F-AV-1451 tau PET images, and to explore their effects on cognitive function. Ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 20 participants from the Shanghai Action of Prevention Dementia for the Elderly (SHAPE) cohort underwent plasma biomarker testing, 18F-AV-1451 tau PET scans and cognitive function assessments. Within the ADNI, there were 42 cognitively normal (CN) individuals and 49 with mild cognitive impairment (MCI). Similarly, in the SHAPE, we had 10 CN and 10 MCI participants. We calculated the standardized uptake value ratios (SUVRs) for the regions of interest (ROIs) in the 18F-AV-1451 PET scans. Using plasma biomarkers and regional SUVRs, we trained machine learning models to differentiate between MCI and CN subjects with ADNI database and validated in SHAPE.Results showed that eight selected variables (including left amygdala SUVR, right amygdala SUVR, left entorhinal cortex SUVR, age, education, plasma NfL, plasma GFAP, plasma GFAP/ NfL) identified by LASSO could differentiate between the MCI and CN individuals, with AUC ranging from 0.783 to 0.926. Additionally, cognitive function was negatively associated with the plasma biomarkers and tau deposition in amygdala and left entorhinal cortex. Increased tau deposition in amygdala and left entorhinal cortex were related to increased plasma biomarkers. Moreover, tau pathology mediated the effect of plasma biomarkers level on the cognitive decline. The present study provides valuable insights into the association among plasma markers (GFAP and NfL), regional tau deposition and cognitive function. This study reports the mediation effect of brain regions tau deposition on the plasma biomarkers level and cognitive function, indicating the significance of tau pathology in the MCI patients.

Associations of polygenic risk scores differentiating attention-deficit hyperactivity disorder from autism spectrum disorder with cognitive and cortical alterations in Schizophrenia patients.

Schizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. In this study, we investigated whether polygenic risk scores (PRSs) differentiating ASD from ADHD are associated with cognitive impairments and alterations in cortical structures in SCZ patients. Based on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n = 168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n = 145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n = 126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients. Among the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p = 0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta = 0.21, p = 8.29 × 10- 4), left entorhinal (beta = 0.21, p = 0.025), left postcentral (beta = 0.18, p = 7.52 × 10- 3), right fusiform (beta = 0.17, p = 6.64 × 10- 3), and left fusiform cortices (beta = 0.17, p = 7.77 × 10- 3) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p = 0.039; right, beta=-0.17, p = 0.045). Our study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.

Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent.

Patients with epilepsy are characterized by a dysregulation of excitation/inhibition balance (E/I). The assessment of E/I may inform clinicians during the diagnosis and therapy management, even though it is rarely performed. An accessible measure of the E/I of the brain represents a clinically relevant feature. Here, we exploited the exponent of the aperiodic component of the power spectrum of the electroencephalography (EEG) signal, as a non-invasive and cost-effective proxy of the E/I balance. We recorded resting-state activity with high-density EEG from 67 patients with temporal lobe epilepsy and 35 controls. We extracted the exponent of the aperiodic fit of the power spectrum from source-reconstructed EEG and tested differences between patients with epilepsy and controls. Spearman's correlation was performed between the exponent and clinical variables (age of onset, epilepsy duration and neuropsychology) and cortical expression of epilepsy-related genes derived from the Allen Human Brain Atlas. Patients with temporal lobe epilepsy showed a significantly larger exponent, corresponding to inhibition-directed E/I balance, in bilateral frontal and temporal regions. Lower E/I in the left entorhinal and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short-term verbal memory. Limited to patients with temporal lobe epilepsy, we detected a significant correlation between the exponent and the cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2 and PDYN genes. EEG aperiodic exponent maps the E/I balance non-invasively in patients with epilepsy and reveals a close relationship between altered E/I patterns, cognition and genetics.

Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults

BackgroundThe amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. MethodsWe studied healthy older adult participants (N = 21, ages 48–79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. ResultsSignificant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. ConclusionsThe results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.

Seeing beyond the symptoms: biomarkers and brain regions linked to cognitive decline in Alzheimer's disease.

Early Alzheimer's disease (AD) diagnosis remains challenging, necessitating specific biomarkers for timely detection. This study aimed to identify such biomarkers and explore their associations with cognitive decline. A cohort of 1759 individuals across cognitive aging stages, including healthy controls (HC), mild cognitive impairment (MCI), and AD, was examined. Utilizing nine biomarkers from structural MRI (sMRI), diffusion tensor imaging (DTI), and positron emission tomography (PET), predictions were made for Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDRSB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS). Biomarkers included four sMRI (e.g., average thickness [ATH]), four DTI (e.g., mean diffusivity [MD]), and one PET Amyloid-β (Aβ) measure. Ensemble regression tree (ERT) technique with bagging and random forest approaches were applied in four groups (HC/MCI, HC/AD, MCI/AD, and HC/MCI/AD). Aβ emerged as a robust predictor of cognitive scores, particularly in late-stage AD. Volumetric measures, notably ATH, consistently correlated with cognitive scores across early and late disease stages. Additionally, ADAS demonstrated links to various neuroimaging biomarkers in all subject groups, highlighting its efficacy in monitoring brain changes throughout disease progression. ERT identified key brain regions associated with cognitive scores, such as the right transverse temporal region for Aβ, left and right entorhinal cortex, left inferior temporal gyrus, and left middle temporal gyrus for ATH, and the left uncinate fasciculus for MD. This study underscores the importance of an interdisciplinary approach in understanding AD mechanisms, offering potential contributions to early biomarker development.

Disentangling reference frames in the neural compass.

Abstract The neural system that encodes heading direction in humans can be found in the medial and superior parietal cortex and the entorhinal-retrosplenial circuit. However, it is still unclear whether heading direction in these different regions is represented within an allocentric or egocentric coordinate system. To investigate this problem, we first asked whether regions encoding (putatively) allocentric facing direction also encode (unambiguously) egocentric goal direction. Second, we assessed whether directional coding in these regions scaled with the preference for an allocentric perspective during everyday navigation. Before the experiment, participants learned different object maps in two geometrically similar rooms. In the MRI scanner, their task was to retrieve the egocentric position of a target object (e.g., Front, Left) relative to an imagined facing direction (e.g., North, West). Multivariate analyses showed, as predicted, that facing direction was encoded bilaterally in the superior parietal lobule (SPL), the retrosplenial complex (RSC), and the left entorhinal cortex (EC), a result that could be interpreted both allocentrically and egocentrically. Crucially, we found that the same voxels in the SPL and RSC also coded for egocentric goal direction but not for allocentric goal direction. Moreover, when facing directions were expressed as egocentric bearings relative to a reference vector, activities for facing direction and egocentric goal direction were correlated, suggesting a common reference frame. Besides, only the left EC coded allocentric goal direction as a function of the subject’s propensity to use allocentric strategies. Altogether, these results suggest that heading direction in the superior and medial parietal cortex is mediated by an egocentric code, whereas the entorhinal cortex encodes directions according to an allocentric reference frame.

Evidence for grid-cell-like activity in the time domain

The relation between the processing of space and time in the brain has been an enduring cross-disciplinary question. Grid cells have been recognized as a hallmark of the mammalian navigation system, with recent studies attesting to their involvement in the organization of conceptual knowledge in humans. To determine whether grid-cell-like representations support temporal processing, we asked subjects to mentally simulate changes in age and time-of-day, each constituting “trajectory” in an age-day space, while undergoing fMRI. We found that grid-cell-like representations supported trajecting across this age-day space. Furthermore, brain regions concurrently coding past-to-future orientation positively modulated the magnitude of grid-cell-like representation in the left entorhinal cortex. Finally, our findings suggest that temporal processing may be supported by spatially modulated systems, and that innate regularities of abstract domains may interface and alter grid-cell-like representations, similarly to spatial geometry.

Explainable machine learning radiomics model for Primary Progressive Aphasia classification.

Primary Progressive Aphasia (PPA) is a neurodegenerative disease characterized by linguistic impairment. The two main clinical subtypes are semantic (svPPA) and non-fluent/agrammatic (nfvPPA) variants. Diagnosing and classifying PPA patients represents a complex challenge that requires the integration of multimodal information, including clinical, biological, and radiological features. Structural neuroimaging can play a crucial role in aiding the differential diagnosis of PPA and constructing diagnostic support systems. In this study, we conducted a white matter texture analysis on T1-weighted images, including 56 patients with PPA (31 svPPA and 25 nfvPPA), and 53 age- and sex-matched controls. We trained a tree-based algorithm over combined clinical/radiomics measures and used Shapley Additive Explanations (SHAP) model to extract the greater impactful measures in distinguishing svPPA and nfvPPA patients from controls and each other. Radiomics-integrated classification models demonstrated an accuracy of 95% in distinguishing svPPA patients from controls and of 93.7% in distinguishing svPPA from nfvPPA. An accuracy of 93.7% was observed in differentiating nfvPPA patients from controls. Moreover, Shapley values showed the strong involvement of the white matter near left entorhinal cortex in patients classification models. Our study provides new evidence for the usefulness of radiomics features in classifying patients with svPPA and nfvPPA, demonstrating the effectiveness of an explainable machine learning approach in extracting the most impactful features for assessing PPA.

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

BackgroundEpileptic seizures are an established comorbidity of Alzheimer’s disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD.Aims1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls.2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD.3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters.MethodsSubjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs.ResultsWe found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher’s exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall–Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann–Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without.ConclusionWe confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes.Trial registrationClinicaltrials.gov, NCT04131491. 12/02/2020.

Exploring structural brain changes in children with neonatal brachial plexus palsy: a voxel-based morphometry analysis

BACKGROUND: Obstetric brachial plexus palsy (OBPP) is paralysis of the upper limb resulting from nerve injury during vaginal delivery. Although current treatment approaches frequently lead to complete reinnervation of the limb, some patients show long-term motor deficits. These impairments may result from upper limb disuse that causes structural brain changes. AIM: This study aimed to compare deep gray matter volumes between children with OBPP and healthy controls. METHODS: We analyzed the structural magnetic resonance imaging results of 46 children with OBPP (n=24, mean age — 10.20, of whom 12 were girls) and healthy age-matched controls (n=22, mean age — 9.63, of whom 10 were girls) using a voxel-based morphometry technique in SPM12 package (Statistical Parametric Mapping) in MATLAB R2019b. To minimize false discoveries, we used a stringent procedure to control the family-wise error rate. RESULTS: We found volumetric brain differences between children with OBPP and healthy controls (all FWE-corrected p 0.005). Children with OBPP had significantly lower gray matter volumes in the left amygdala, bilateral hippocampus, and right entorhinal cortex. CONCLUSION: Integrating our findings with previous work, we speculate that the amygdala–hippocampus–entorhinal cortex complex might play a significant role in motor disorders.

Does texture analysis classify semantic dementia from Alzheimer’s disease better than volumetric analysis?

AbstractBackgroundTexture analysis may capture subtle changes in the gray matter more sensitively than volumetric analysis. We aimed to investigate the patterns of neurodegeneration in semantic dementia (SD) and Alzheimer’s disease (AD) by comparing the temporal gray matter texture and volume between cognitively normal controls and older adults with SD and AD.MethodWe enrolled all participants from three national university hospitals in Korea. We obtained T1‐weighted magnetic resonance images and compared the gray matter texture and volume of regions of interest (ROIs) between the groups using analysis of variance with Bonferroni posthoc comparisons. We also developed models for classifying SD, AD and control groups using logistic regression analyses, and validated the models using receiver operator characteristics analysis.ResultCompared to the AD group, the SD group showed lower volumes in five ROIs (bilateral temporal poles, and the left inferior, middle, and superior temporal cortices) and higher texture in these five ROIs and two additional ROIs (right inferior temporal and left entorhinal cortices). The performances of both texture‐ and volume‐based models were good and comparable in classifying SD from NC (mean area under the curve [AUC] = 0.914 for texture; mean AUC = 0.894 for volume). However, only the texture‐based model achieved a good level of performance in classifying SD and AD (mean AUC = 0.775 for texture; mean AUC = 0.658 for volume).ConclusionTexture may be a useful neuroimaging marker for early detection of SD in older adults and its differentiation from AD.

Subjective cognitive impairment score associate with regional amyloid burden and brain atrophy in subjective cognitive decline subjects

AbstractBackgroundSubjective cognitive decline (SCD) is now regarded as the first preclinical stage of Alzheimer’s disease (AD) spectrum disorders. It is important to predict which patients would progress to dementia, and screening tools might be helpful. In this study, we aimed to investigate the possible correlations between AD biomarkers‐regional amyloid burden and volume changes‐and Korean Dementia Screening Questionnaire‐Cognition (KDSQ‐C) score in SCD.MethodThis study analyzed SCD data from prospective population cohort study from July 2018 to December 2020. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid Positron Emission Tomography (PET) were performed. Demographics, physical data, social and physiological functions were also obtained.KDSQ‐C was administered to SCD subjects as part of the clinical evaluation at the 36 month follow‐up visit. KDSQ‐C included 15 questions that assess 3 dimensions: memory impairment (items 1‐5), other cognitive impairments including language impairments (items 6‐10), and the ability to perform complex tasks in daily life (items 11‐15).ResultPrevalence of subjective cognitive impairment (KDSQ‐C ≧6) among 86 subjects was 73.3%.. No significant difference was observed between groups in terms of demographic characteristics including age, sex and APOE Ɛ4 status and neuropsychological test. However, regional SUVR (amygdala, inferior temporal gyrus and precuneus) and global SUVR were significantly higher in subjectively cognitive impaired group(p<0.05). There were no brain volume differences between groups.For volumetry and KDSQ‐C correlation analysis, partial correlation analysis controlled for age, sex and APOE Ɛ4 status showed significant negative correlation between left entorhinal cortex, right hippocampal volume and KDSQ‐C (r = ‐0.230, p = 0.046; r = ‐0.226, p = 0.049). Similar association was also found between KDSQ‐C memory domain score and brain volume.ConclusionKDSQ‐C can be a useful tool for screening SCD patients at a higher risk with higher amyloid deposition and brain atrophy.This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530

Effects of β‐amyloid deposition, dopaminergic depletion, and perfusion on clinical features in cognitively impaired patients

AbstractBackgroundAlthough mixed pathologies are common in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), effects of β‐amyloid and dopaminergic depletion on brain perfusion and clinical features have not been elucidated.MethodIn 99 patients with cognitive impairment due to AD and/or DLB and 32 control participants, 18F‐Florbetaben (FBB) PET, dual‐phase dopamine transporter (DAT) PET, and brain MRI were performed to measure β‐amyloid standardized uptake value ratio (SUVR), dopaminergic depletion in the ventral striatum, caudate, and putamen, and regional brain perfusion. Cognitive score, visual hallucination (VH), cognitive fluctuation (CF), and rapid eye movement sleep behavior disorder (RBD) were evaluated. Relationship among global FBB‐SUVR, striatal DAT uptakes, regional brain perfusion, clinical symptoms, and cognitive scores were evaluated using general linear or logistic regression models as appropriate.ResultGlobal and mean lobar FBB SUVRs negatively correlated with DAT uptakes in the ventral striatum and caudate but not with putamen DAT uptake. Lower ventral striatal DAT uptake was associated with right temporo‐parietal hypoperfusion and hyper‐perfusion in the anterior cingulate cortex, vermis, motor cortex, and hippocampus, while higher FBB SUVR was associated with hypoperfusion in the left entorhinal cortex and temporo‐parietal cortex. Lower ventral striatal DAT uptake increased the risks of VH and RBD directly and indirectly through the mediation of hippocampal hyper‐perfusion, while hippocampal hyper‐perfusion fully mediated the effect of lower ventral striatal DAT uptake on the risk of CF. Higher FBB SUVR and lower DAT uptake were associated with language, memory, and executive dysfunction directly and indirectly through the mediation of regional perfusion, while regional perfusion fully mediated their effects on visuospatial dysfunction.Conclusionβ‐amyloid deposition and striatal dopaminergic depletion reflecting AD‐ and DLB‐related neurodegenerations are inter‐correlated but differently contribute to regional perfusion changes and cognitive dysfunction.

Hub brain regions for the remote spatial association between tau and Amyloid‐β proteins

AbstractBackgroundThe pathology of Alzheimer’s disease (AD) is characterized by two types of proteins: intracellular neurofibrillary tau tangles and extracellular β‐amyloid (Aβ) plaques. In the present observational studies, spatial discrepancies between these two proteins across the brain regions are well‐documented. However, the association between these two proteins remains elusive in different stages of depositions.MethodsWe aimed to investigate the remote association between tau and Aβ uptakes by using 572 elderlies 67.11 ± 6.08 (476 healthy control (HC) and 96 mild cognitive impairments (MCI)) Aβ and tau positron emission tomography (PET) scans. We leveraged 47 tau‐PET and 97 Aβ‐PET scans of healthy young individuals (aged 20‐40) to find the regional cut‐points for 68 cortical regions in the brain. Then by using these cut‐points and tau PET scans of all elderly individuals, we identified four groups of individuals (no tau phase, pre‐acceleration phase, acceleration phase, and post‐acceleration phase) (Table 1). Finally, a regional multiple linear regression model is performed for each group to detect the hubs region based on the remote association between each target region of tau and all other regions Aβ in the different phases of tau accumulations (controlling for gender, age, intracranial volume, and each target region Aβ).ResultsFirst, we show that the left and right entorhinal cortex, and right parahippocampal tau are the hubs of remote association with Aβ in several cortical regions (especially temporal regions) in the early stage of aggregation (Figure 1). Second, we identify tau in the same regions, continuing to demonstrate the highest remote associations with cortical Aβ (Figure 2) in the acceleration phase.ConclusionThe remote association appears in medial temporal lobe (MTL) tau during the early stage, as well as the later stage of tau accumulation (pre‐acceleration and acceleration phases). While the cellular mechanism of remote association is still elusive, in vivo studies have demonstrated that the Aβ triggers tau deposition indirectly in distal regions. Understanding the association between tau and Aβ at the preclinical stage of AD is critically important for a better consideration of tau spreading, especially in disease‐related brain regions.

Hub vulnerability and short path length to entorhinal cortex are associated with tau binding in Alzheimer’s disease: a combined MEG/PET study

AbstractBackgroundBrain network studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer’s disease (AD) pathology. Additionally, the ‘‘transneuronal spread” hypothesis proposes that a toxic agent (tau) propagates along shortest paths through functionally connected neurons, driven by aberrant neuronal activity. We investigate whether network characteristics as determined using magnetoencephalography (MEG) are correlated to tau pathology in the different stages of AD.MethodWe analysed source‐reconstructed MEG data and dynamic 100‐minutes [18F]flortaucipir PET from 57 subjects positive for amyloid‐beta (Aβ)‐pathology (preclinical AD (n = 16)), mild cognitive impairment (MCI (n = 16)) and AD dementia (n = 25)). Cognitively healthy subjects without Aβ‐pathology were included as controls (n = 25). For each subject, we obtained a network based on the alpha band amplitude envelope correlation (AEC‐c, 8‐13Hz), and theta band phase lag index (PLI, 4‐8Hz), based on the Brainnettome atlas. For each node in the network, we obtained the following measures: weighted degree, degree, betweenness centrality, eccentricity (as measures of hubness); distance to left entorhinal cortex (measure of shortest path/transneuronal spread); hub disruption index for all previous hubness measures (selective hub damage) and [18F]flortaucipir BPND. Pearson’s correlations were calculated between group averages of network measures and tau‐PET binding (FDR‐corrected). Furthermore, we analysed whether network measures of the previous disease stage correlated with [18F]flortaucipir retention in the subsequent disease stage.ResultHub regions were predominantly found in the temporal areas (Fig‐1). Higher ‘hubness’ and shorter neuronal distance to epicentre were associated to higher tau binding in all stages of the AD continuum (Fig‐2a). Disproportional disruption to hub regions in the AEC‐c alpha band was associated with increased tau binding, but the opposite effect was found for the PLI theta band (Fig‐2b). Finally, high weighted degree, degree, and betweenness centrality in the preceding disease stage were correlated with increased tau binding in subsequent disease stages (Fig‐2c).ConclusionHub regions and transneuronal spreading are key mechanisms in the propagation of tau pathology across the AD brain. Furthermore, hubs are particularly vulnerable to tau. The insight that high neuronal activity might play a causal role in Alzheimer’s disease can have implications for early detection and interventional strategies.

42 Cognitive and Neuroanatomic Correlates of Olfactory Function in Cognitively Unimpaired and Impaired Older Adults

Objective:Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults.Participants and Methods:We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements.Results:In the unimpaired group, SS-OIT significantly associated with language (p<.05). In the impaired group, SS-OIT significantly associated with language and memory (p<.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p<.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p<.05) and left hippocampal mean thickness (p<.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p<.05) and mean thickness (p<.05).Conclusions:This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.