Elderly Controls Research Articles

HnRNP K mislocalisation in neurons of the dentate nucleus is a novel neuropathological feature of neurodegenerative disease and ageing

Nuclear depletion and cytoplasmic mislocalisation of the RNA‐binding protein heterogeneous ribonucleoprotein K (hnRNP K) within pyramidal neurons of the frontal cortex have been shown to be a common neuropathological feature in frontotemporal lobar degeneration (FTLD) and elderly control brain. Here, we describe a second neuronal subtype vulnerable to mislocalisation within the dentate nucleus of the cerebellum. In contrast to neurons within the cerebellar cortex that typically exhibited normal, nuclear staining, many neurons of the dentate nucleus exhibited striking mislocalisation of hnRNP K to the cytoplasm within neurodegenerative disease brain. Mislocalisation frequency in this region was found to be significantly higher in both FTLD‐TDP A and Alzheimer's disease (AD) brain than in age‐matched controls. However, within control (but not disease) subjects, mislocalisation frequency was significantly associated with age‐at‐death with more elderly controls typically exhibiting greater levels of the pathology. This study provides further evidence for hnRNP K mislocalisation being a more anatomically diverse pathology than previously thought and suggests that potential dysfunction of the protein may be more broadly relevant to the fields of neurodegeneration and ageing.

Effective detection of abnormal gait patterns in Parkinson's disease patients using kinematics, nonlinear, and stability gait features.

Parkinson's disease (PD) is a neurodegenerative disease that produces movement disorders and it is the second most common neurodegenerative disease after Alzheimer's. Among other symptoms, PD affects gait patterns and produces bradykinesia, abnormal changes in posture, and shortened strides. In this study we present a comprehensive analysis of three different feature sets to model those abnormal gait patterns. The proposed approach is evaluated upon three groups of subjects: PD patients, young healthy controls (YHC), and elderly healthy controls (EHC). Three feature sets are created: (1) kinematic measures including those that allow modeling time, distance and velocity of the strides, (2) nonlinear dynamics including different measures extracted from embedded attractors resulting from the time-series of the gait signals, and (3) different stability measures extracted in the time and frequency-domains. Support Vector Machine, Random Forest and XGBoost classifiers are trained to automatically discriminate between PD patients and healthy subjects. Among the considered feature sets, three individual measures emerge as the ones that yield accurate detection of PD and could potentially be used in clinical practice. Accuracies of up to 87.0% and 90.0% are found for the classification between PD vs. YHC and PD vs. EHC, respectively, considering individual measures. This study contributes to a better understanding of abnormal gait patterns observed in PD patients. Particularly the introduced approach shows good results that could be potentially used in clinical practice as a tool to support the diagnosis and follow-up of the patients.

A comparative analysis of associated injuries in the elderly and youth for facial fractures

IntroductionHigh-velocity and high-impact forces can yield life-threatening injuries that are not only limited to the face but can involve other regions of the body. Associated injuries are more frequent in the elderly impacting management and outcomes. The primary objective was to study the association between associated injuries and age groups by identifying epidemiological trends and differences among the elderly and younger population. MethodsA retrospective review was conducted from January 2012 to January 2017 at the Royal Adelaide Hospital, Adelaide. A comparative analysis for elderly and younger controls was assessed for associated injuries, etiology, management, and length of stay. ResultsThere were 355 elderly and 1884 younger controls for the study. There were differences between gender, alcohol, socioeconomic status, type of facial fracture, mechanism of injury, and associated injuries (p<0.05). The elderly were 3.6 times more likely to have an associated injury compared to the younger cohort (p<0.05). Total limb injuries were 2.2 times more likely in the elderly compared to the younger cohort, and neurological related injuries were 2.7 times more likely (p<0.05). Neurological injuries were most frequent in fall-related injuries, limb injuries in RTA; and soft-tissue injuries for assault, sport, animal, and work (p<0.001). The elderly had longer hospital stays as compared with younger controls (p<0.05). ConclusionsAssociated injuries are more frequent in the elderly and impact other bodily systems leading to a longer length of stay. In the assessment and management of facial trauma, anatomical and disciplinary boundaries may cross requiring interdisciplinary care.

Cordycepin from Medicinal Fungi Cordyceps militaris Mitigates Inflammaging-Associated Testicular Damage via Regulating NF-κB/MAPKs Signaling in Naturally Aged Rats

Inflammaging in male reproductive organs covers a wide variety of problems, including sexual dysfunction and infertility. In this study, the beneficial effects of cordycepin (COR), isolated from potential medicinal fungi Cordyceps militaris, in aging-associated testicular inflammation and serum biochemical changes in naturally aged rats were investigated. Male Sprague Dawley rats were divided into young control (YC), aged control (AC), and COR (5, 10, and 20 mg/kg) treated aged rat groups. Aging-associated serum biochemical changes and inflammatory parameters were analyzed by biochemical assay kits, Western blotting, and real-time RT-PCR. Results showed a significant (p < 0.05) alteration in the total blood cell count, lipid metabolism, and liver functional parameters in AC group when compared with YC group. However, COR-treated aged rats ameliorated the altered biochemical parameters significantly (p < 0.05 and p < 0.01 at 5, 10, and 20 mg/kg, respectively). Furthermore, the increase in the expression of inflammatory mediators (COX-2, interleukin (IL)-6, IL-1β, and tissue necrosis factor-alpha) in aged rat testis was significant (p < 0.05) when compared with YC group. Treatment with COR at 20 mg/kg to aged rats attenuated the increased expression of inflammatory mediators significantly (p < 0.05). Mechanistic studies revealed that the potential attenuating effects exhibited by COR in aged rats was mediated by regulation of NF-κB activation and MAPKs (c-Jun N-terminal kinase, extracellular signal-regulated kinase 1/2, and p38) signaling. In conclusion, COR restored the altered serum biochemical parameters in aged rats and ameliorated the aging-associated testicular inflammation proving the therapeutic benefits of COR targeting inflammaging-associated male sexual dysfunctions.

Wall shear stress and relative residence time as potential risk factors for abdominal aortic aneurysms in males: a 4D flow cardiovascular magnetic resonance case\u2013control study

BackgroundAbdominal aortic aneurysms (AAA) can lead to catastrophic events such as dissection or rupture, and are an expression of general aortic disease. Low wall shear stress (WSS), high oscillatory shear index (OSI), and high relative residence time (RRT) have been correlated against increased uptake of inflammatory markers in the vessel wall and may improve risk stratification of AAA. We sought to obtain a comprehensive view of WSS, OSI, and RRT in the whole aorta for patients with AAA and age-matched elderly controls and young normal controls.Methods4D Flow cardiovascular magnetic resonance images of the whole aorta were acquired in 18 AAA patients (70.8 ± 3.4 years), 22 age-matched controls (71.4 ± 3.4 years), and 23 young subjects (23.3 ± 3.1 years), all males. Three-dimensional segmentations of the whole aorta were created for all timeframes using a semi-automatic approach. The aorta was divided into five segments: ascending aorta, arch, descending aorta, suprarenal and infrarenal abdominal aorta. For each segment, average values of peak WSS, OSI, and RRT were computed. Student’s t-tests were used to compare values between the three cohorts (AAA patients vs elderly controls, and elderly controls vs young controls) where the data were normally distributed, and the non-parametric Wilcoxon rank sum tests were used otherwise.ResultsAAA patients had lower peak WSS in the descending aorta as well as in the abdominal aorta compared to elderly controls (p ≤ 0.001), similar OSI, but higher RRT in the descending and abdominal aorta (p ≤ 0.001). Elderly controls had lower peak WSS compared to young controls throughout the aorta (p < 0.001), higher OSI in all segments except for the infrarenal aorta (p < 0.001), and higher RRT throughout the aorta, except the infrarenal aorta (p < 0.001).ConclusionsThis study provides novel insights into WSS, OSI, and RRT in patients with AAA in relation to normal ageing, highlighting how AAA patients have markedly abnormal hemodynamic stresses not only in the infrarenal, but in the entire aorta. Moreover, we identified RRT as a marker for abnormal AAA hemodynamics. Further investigations are needed to explore if RRT or other measures of hemodynamics stresses best predict AAA growth and/or rupture.

Adapting UK Biobank imaging for use in a routine memory clinic setting: The Oxford Brain Health Clinic

The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB).In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) explored the alignment of measures from BHC patients to the largest brain MRI study in the world (ultimately 100,000 participants).Adaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences (i.e., additional imaging modalities) to improve patients’ tolerance for the MRI assessment. We adapted the UKB structural MRI analysis pipeline to take into account the characteristics of a memory clinic population (e.g., high amount of white matter hyperintensities and hippocampal atrophy). We then compared the imaging derived phenotypes (IDPs) extracted from the structural scans to visual ratings from radiology reports, non-imaging factors (age, cognition) and to reference distributions derived from UKB data.Of the first 108 BHC attendees (August 2020-November 2021), 92.5 % completed the clinical scans, 88.0 % consented to use of data for research, and 43.5 % completed the additional research sequences, demonstrating that the protocol is well tolerated. The high rates of consent to research makes this a valuable real-world quality research dataset routinely captured in a clinical service. Modified tissue-type segmentation with lesion masking greatly improved grey matter volume estimation. CSF-masking marginally improved hippocampal segmentation. The IDPs were in line with radiology reports and showed significant associations with age and cognitive performance, in line with the literature. Due to the age difference between memory clinic patients of the BHC (age range 65–101 years, average 78.3 years) and UKB participants (44–82 years, average 64 years), additional scans on elderly healthy controls are needed to improve reference distributions. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.

Clinical guidelines for prevention and treatment of type 2 diabetes mellitus in the elderly in China (2022 edition)

According to the data of seventh national census in China, the elderly population (≥60 years old) accounts for 18.7% (260.4 million) of the total population in 2020. Among them, 30% are diabetes (78.13 million, and more than 95% being type 2 diabetes). Diabetic complications caused by poor glycemic control are the main risk factors influencing the healthy and survival of the elderly, and thus, diabetes prevention and treatment has been to be one of the key actions of Healthy China (2019-2030). The present guideline-"Clinical guidelines for prevention and treatment of type 2 diabetes mellitus in the elderly in China (2022 edition)" is formulated on the basis of the " Expert consensus of the diagnosis and treatment measures for Chinese elderly patients with type 2 diabetes (2018 edition)" and summarizes the domestic and foreign related guidelines for elderly diabetes and research information. The aim of the guide is to optimize the elderly diabetes prevention and control concept, to promote the implementation of standardized clinical prevention, diagnosis and treatment strategy and to improve the level of overall management of diabetes in the elderly.

3T sodium MR imaging in Alzheimer’s disease shows stage-dependent sodium increase influenced by age and local brain volume

IntroductionApplication of MRI in clinical routine mainly addresses structural alterations. However, pathological changes at a cellular level are expected to precede the occurrence of brain atrophy clusters and of clinical symptoms. In this context, 23Na-MRI examines sodium changes in the brain as a potential metabolic parameter. Recently, we have shown that 23Na-MRI at ultra-high-field (7 T) was able to detect increased tissue sodium concentration (TSC) in Alzheimer’s disease (AD). In this work, we aimed at assessing AD-pathology with 23Na-MRI in a larger cohort and on a clinical 3T MR scanner. MethodsWe used a multimodal MRI protocol on 52 prodromal to mild AD patients and 34 cognitively healthy control subjects on a clinical 3T MR scanner. We examined the TSC, brain volume, and cortical thickness in association with clinical parameters. We further compared TSC with intra-individual normalized TSC for the reduction of inter-individual TSC variability resulting from physiological as well as experimental conditions. Normalized TSC maps were created by normalizing each voxel to the mean TSC inside the brain stem. ResultsWe found increased normalized TSC in the AD cohort compared to elderly control subjects both on global as well as on a region-of-interest-based level. We further confirmed a significant association of local brain volume as well as age with TSC. TSC increase in the left temporal lobe was further associated with the cognitive state, evaluated via the Montreal cognitive assessment (MoCA) screening test. An increase of normalized TSC depending on disease stage reflected by the Clinical Dementia Rating (CDR) was found in our AD patients in temporal lobe regions. In comparison to classical brain volume and cortical thickness assessments, normalized TSC had a higher discriminative power between controls and prodromal AD patients in several regions of the temporal lobe. DiscussionWe confirm the feasibility of 23Na-MRI at 3T and report an increase of TSC in AD in several regions of the brain, particularly in brain regions of the temporal lobe. Furthermore, to reduce inter-subject variability caused by physiological factors such as circadian rhythms and experimental conditions, we introduced normalized TSC maps. This showed a higher discriminative potential between different clinical groups in comparison to the classical TSC analysis. In conclusion, 23Na-MRI represents a potential translational imaging marker applicable e.g.for diagnostics and the assessment of intervention outcomes in AD even under clinically available field strengths such as 3T. Implication of 23Na-MRI in association with other metabolic imaging marker needs to be further elucidated.

Specific interactions between microglia and oligodendrocytes in white matter in continuous schizophrenia

To study the ultrastructure of microglia adjacent to oligodendrocytes in white matter of the prefrontal cortex in continuous schizophrenia (CSch) as compared to controls and attack-like schizophrenia (ASch) and to perform correlation analysis between the parameters of microglia and adjacent oligodendrocytes previously detected in both clinical types of schizophrenia. Electron microscopic morphometric study of microglia adjacent to oligodendrocytes was performed in postmortem white matter of the prefrontal cortex (BA10) in 9 cases of CSch, 8 cases of ASch and 20 healthy controls. Group comparisons were made by ANCOVA and Pearson correlation analyses. The reduction of volume fraction (Vv) and the number of mitochondria in microglia was found in elderly subjects (>50 y.o.) as compared to young controls (60%, p<0.05), and the increase in these parameters of lipofuscin granules were detected in elderly subjects as compared to elderly controls in CSch (470%, 606%, p<0.001). Vv and the number of mitochondria in microglia correlated negatively with area of heterochromatin in microglia (r≥-0.7, p<0.05), and area of lipofuscin correlated positively with area of heterochromatin in microglia (r=0.76, p<0.05) and with illness duration (r=0.7, p<0.05) only in the CSch group. The numerical density of microglia was not changed in both schizophrenia groups. Area of heterochromatin was increased in both groups as compared to controls (p<0.05) and correlated negatively with the numerical density of microglia in the CSch group. The number of mitochondria in oligodendrocytes (reduced in CSch) correlated positively with the number of mitochondria in microglia and negatively with Vv of lipofuscin granules in microglia and with area of microglial nucleus only in the CSch group. Specific features of CSch as compared to ASch might be associated with the disturbances of mitochondrial and lipid metabolism in microglia, dysfunction of nucleus and accelerated aging of microglia that might lead to alterations of mitochondrial metabolism in oligodendrocytes.

Hyperbaric Oxygen Attenuates Aortic Vasoconstriction after Simulated Microgravity in Rats

Background The hindlimb suspended (HLS) rat model has been used in land-based research to evaluate effects of simulated microgravity. Previous research demonstrated that 2-4 weeks of HLS reduced vasoconstrictive responses of aortic, mesenteric, and femoral arterial rings to phenylephrine (PHE) while acute exposure to hyperoxia amplified constrictive responses to PHE. The purpose of this study was to determine if hyperbaric oxygen treatment (HBO) during HLS would reverse the attenuation of the vasoconstrictive response. Methods Five-month-old male Sprague Dawley rats were randomly divided into aging controls (AC), AC-HBO, HLS, and HLS-HBO. Groups receiving HBO (AC-HBO; HLS-HBO) were placed in a cage that was fitted for the animal hyperbaric chamber to maintain HLS. HBO groups received 24 treatments, once a day, 6 d/week using a wound care protocol. The chamber was flushed with 100% oxygen, compressed over 10 min to 2.5 atmospheres absolute (ATA) (22.5 psig), a 90-minute treatment, then a 10 min decompression. After 28 d of HLS, animals were sacrificed under isoflurane anesthesia and thoracic aorta segments isolated. Relaxation of aortic rings was measured in response to acetylcholine (ACh) and sodium nitroprusside (SNP) after pre-constriction with PHE (3×10-7). Constriction of aortic rings was also determined in response to increasing concentrations of PHE. All drugs were administered cumulatively in vessel baths at 10-10-10-4 M. Data were analyzed using four-parameter (i.e., minimum, maximum, EC50, slope) nonlinear regression, and groups compared using 2×2 ANOVA with HBO and HLS as main effects. Results Responses to ACh and SNP were not affected by HLS or HBO. However, in response to PHE, there was a decrease in maximum vasoconstriction in HLS compared to controls (44.7±7.3% vs 82.4±6.0%, respectively, p≤0.05) and in HBO compared to controls (48.5±6.5% vs 78.6±6.8%, p≤0.05). Conclusion These results indicate that PHE-induced constriction of thoracic aorta is decreased after HLS. HBO did not reverse HLS-induced reductions in contractile responses; instead, HBO independently reduced PHE-stimulated constriction of aortic segments. This suggests that HBO may be useful in conditions where constriction is enhanced, such as diabetes.

Human Brain Networks in Physiological and Pathological Aging: Reproducibility of Electroencephalogram Graph Theoretical Analysis in Cortical Connectivity.

Background: Physiological and pathological brain aging plays a central role in brain network modulation. The aim of the present article was to assess the stability of a proposed method for evaluation of small-world (SW) characteristics for the study of the human connectome. Subjects and Methods: Eighty subjects were recruited: 36 young healthy controls, 32 elderly healthy controls, and 12 patients affected by Alzheimer's disease (AD). Electroencephalograms (EEGs) were recorded during six separate sessions (480 recordings) at an average intersession interval of 3.8 ± 0.2 days. We applied graph theory functions to the weighted and undirected networks obtained by the lagged linear coherence estimated by exact low-resolution electromagnetic tomography (eLORETA). We explored the following frequency bands: delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Results: The proposed method for evaluation of SW characteristics exhibited good reproducibility and stability. Furthermore, results showed the pattern, Young>Elderly>AD, in low-frequency delta and theta bands and vice versa in the higher alpha band. Finally, a correlation with age was confirmed in healthy subjects, showing that the older the age, the higher the SW values for alpha 2. Discussion: Evidences from the present study confirm the stability of the SW index and suggest that the analysis of connectivity patterns evaluated from EEGs can be supported by the graph theory. The proposed method for evaluation of SW characteristics has shown good reproducibility and stability. This technique, applied to patient data, could provide more information on the pathophysiological processes underlying age-related brain disconnection, as well as on administration of rehabilitation treatments at the right time, which could allow patients to avoid unnecessary interventions. Impact statement The graph analysis tools described in this study represent an interesting approach to study the distinctive characteristics of physiological aging by focusing on functional connectivity networks. The proposed method for evaluation of small-world characteristics has shown good reproducibility and stability. This technique, applied to patient data, could provide more information on the pathophysiological processes underlying age-related brain disconnection, as well as on delivery of rehabilitation treatments at the right time, which could allow patients to avoid unnecessary interventions.

Spectral fundus autofluorescence peak emission wavelength in ageing and AMD.

To investigate the spectral characteristics of fundus autofluorescence (FAF) in AMD patients and controls. Fundus autofluorescence spectral characteristics was described by the peak emission wavelength (PEW) of the spectra. Peak emission wavelength (PEW) was derived from the ratio of FAF recordings in two spectral channels at 500-560 nm and 560-720 nm by fluorescence lifetime imaging ophthalmoscopy. The ratio of FAF intensity in both channels was related to PEW by a calibration procedure. Peak emission wavelength (PEW) measurements were done in 44 young (mean age: 24.0 ± 3.8 years) and 18 elderly (mean age: 67.5 ± 10.2 years) healthy subjects as well as 63 patients with AMD (mean age: 74.0 ± 7.3 years) in each pixel of a 30° imaging field. The values were averaged over the central area, the inner and the outer ring of the ETDRS grid. There was no significant difference between PEW in young and elderly controls. However, PEW was significantly shorter in AMD patients (ETDRS grid centre: 571 ± 26 nm versus 599 ± 17 nm for elderly controls, inner ring: 596 ± 17 nm versus 611 ± 11 nm, outer ring: 602 ± 16 nm versus 614 ± 11 nm). After a mean follow-up time of 50.8 ± 10.8 months, the PEW in the patients decreased significantly by 9 ± 19 nm in the inner ring of the grid. Patients, showing progression to atrophic AMD in the follow up, had significantly (p ≤ 0.018) shorter PEW at baseline than non-progressing patients. Peak emission wavelength (PEW) is related to AMD pathology and might be a diagnostic marker in AMD. Possibly, a short PEW can predict progression to retinal and/or pigment epithelium atrophy.

EEG slowing in predementia Alzheimer's disease is compatible with neuronal hyperactivity: A multiscale computational modeling study.

Evidence from animal models of Alzheimer's disease (AD) for neuronal hyperactivity and inhibitory dysfunction is accumulating, but the exact mechanism by which these microscale abnormalities lead to large-scale brain dysfunction and cognitive impairment in AD remains unclear. This study investigated empirically informed pathophysiological mechanisms of neuronal hyperactivity in a computational neurophysiological brain model and compared its output to EEG data of predementia AD patients. EEG-like oscillations were simulated by a computational brain network model of 78 neural masses, each representing regional activity of a large population of interconnected excitatory and inhibitory neurons, coupled according to human DTI-derived structural topology. Several scenarios of amyloid-β mediated neuronal hyperactivity were investigated, including excitatory hyperexcitability and inhibitory neuronal dysfunction. The model offered a direct readout of neuronal activity by showing excitatory neuron pulse density. Consequently, we performed spectral analysis and analyzed absolute power and relative power in relevant frequency bands and peak frequency on the model output of each simulated AD scenario as well as for resting state EEG of predementia AD patients with positive amyloid biomarkers (n = 196) and elderly controls (n = 180). Similarity in outcome measure changes between the modelled output of each scenario and human EEG resulted in a scenario compatibility score (range 0-6). Predementia AD patients showed increased relative theta power and decreased relative higher alpha power. The modeled scenarios involving 'inhibitory neuron hypoexcitability' and 'excessive neuronal excitation' were most compatible with the observed EEG changes in AD (score of 5), providing support for their presumed role. Other scenarios produced improbable physiologically parameter change combinations. Of the two best compatible scenarios, inhibitory hypoexcitability was the only scenario that led to neuronal hyperactivity in the model. We found that neuronal hyperactivity scenarios (i.e. increased pulse density) is compatible with large-scale oscillatory slowing of predementia AD patients. This study provides support for amyloid-driven neuronal disinhibition due to inhibitory hypoexcitability as most likely pathophysiological mechanism to explain oscillatory slowing in predementia AD.

Plasma total bilirubin in patients with Alzheimer’s disease: An observational study

AbstractBackgroundBilirubin, the primary end product of the heme cleavage pathway, is currently regarded as a major physiologic antioxidant with important cytoprotective properties. Oxidative stress is a well established contributing factor in the development of Alzheimer's disease (AD). In the present study, we aimed to compare serum bilirubin levels in patients with AD and healthy elderly controls, and to analyze the potential relationship between serum total bilirubin levels and dementia severity in AD patients.MethodMeasures of fasting serum total bilirubin levels were studied in 68 patients with AD (34 women; mean age 71.4±5.8 years; range 60‐82) (DSM‐IV; NINCDS‐ADRDA criteria) from a private ambulatory of neurology, recruited in a community elderly in Skikda‐Algeria (2017‐2020); and in 68 elderly controls (34 women; mean age 70.4±6.3 years; range 58‐82). Dementia severity was assessed by the clinical dementia rating scale‐CDR global score.ResultThe mean (±SD) plasma total bilirubin level was 0.72±0.13 (Range 0.49–1.08) among AD group and 0.66±0.11 (range 0.48–1.02) mg/dL among control group; (p= 0.0029). By gender, plasma total bilirubin level was higher in cases compared to controls both in men 0.75±0.14 vs. 0.67±0.13 mg/dL respectively, (p= 0.027); and in women 0.70±0.12 vs. 0.64±0.10 mg/dL; (p= 0.040). Patients with mild AD (Mean age 68±3.7 years) showed significantly higher levels of plasma total bilirubin compared with patients with moderate AD (Mean age 77.4±3.6 years): 0.77±0.13 vs. 0.64±0.09 mg/dL respectively (one way ANOVA, p= 0.0001). Plasma total bilirubin level was significantly negatively correlated with dementia severity, r= ‐0.4503; (95% CI for rho: ‐0.621; ‐0.238), p= 0.0001. By gender r= ‐3564; (p= 0.038) for men; and r= ‐0.5481, (p= 0.0007) for women.ConclusionThese data indicate that plasma total bilirubin level is increased in AD compared to controls, and inversely correlates with dementia severity. Patients with mild AD have higher total bilirubin levels (Within clinical normal range) than patients with moderate AD. These results suggest that serum total bilirubin level may provide additional information for predicting development of AD. We speculate that a possible beneficial physiologic antioxidant role for bilirubin could be operating during earlier stages of AD and gradually fades with disease progression.

Klotho‐VS heterozygosity modifies amyloid‐dependent tau accumulation and memory impairment in Alzheimer’s disease

Klotho-VS heterozygosity (KL-VShet ) is associated with reduced risk of developing Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, the key AD pathology driving cognitive decline, is unknown. Here, we tested the interaction between KL-VShet and beta-amyloid, the key driver of tau pathology, on PET-assessed neurofibrillary tau in elderly controls and patients across the AD continuum. In the ADNI cohort, we identified 144 KL-VShet carriers (55-90y, 53% women, 38% ApoE4+, 24% MCI) and 407 KL-VShet non-carriers (55-90y, 51% women, 37% ApoE4+, 29% MCI) with tau-sensitive ([18F]flortaucipir) and Aβ-sensitive ([18F]florbetapir or [18F]florbetaben) PET acquisitions as well as genetic and clinical information available. A subgroup of 200 participants (52 KL-VShet carriers) underwent a second tau-PET after 1.63 years on average. We assessed the KL-VShet x amyloid-PET interaction effect on tau-PET SUVR levels or annual change rates derived from an inferior temporal and global cortical ROI. Mediation analysis was used to determine whether KL-VShet was associated with better memory performance (ADNI-MEM), and whether this association was mediated by reduced tau-PET levels. All analyses were controlled for age, sex, diagnosis, education and ApoE4. We found a significant interaction effect indicating that KL-VShet carriers compared to non-carriers had lower inferior temporal (β=-0.12, P=0.009, effect size (Cohen's f)=0.112) and global (β=-0.13, P=0.008, effect size=0.114) tau-PET levels per centiloid (CL) unit increase in amyloid-PET (Fig 1a,b). Longitudinally assessed annual change rates of inferior temporal tau-PET were also lower in KL-VShet carriers per unit increase in baseline amyloid-PET (β =-0.22, P=0.039, effect size=0.148; Fig 1c,d). Post-hoc correlation analysis revealed that the KL-VShet effect on tau-PET was stronger in Klotho mRNA-expressing brain regions (Fig. 2). Importantly, KL-VShet was associated with better memory performance (β=0.13, p=0.040, effect size=0.104) in amyloid-positive participants and this association was significantly mediated by lower tau-PET levels. Our findings provide evidence for a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly individuals at risk of AD dementia. Hence, Klotho may be an attractive treatment target to slow the progression of AD.

Alzheimer’s disease resemblance atrophy index in the identification of Alzheimer's disease with mild dementia

AbstractBackgroundAlzheimer’s disease (AD) resemblance atrophy index (AD‐RAI) is an MRI‐based biomarker that was developed using a machine learning technology that combines multi‐region MRI features to reflect the characteristic atrophy pattern of AD. It was validated to be accurate in predicting conversion from mild cognitive impairment to dementia (1) and in identifying AD patients with moderate dementia. We aimed to compare the performance of AD‐RAI with various MRI‐based quantitative medial temporal lobe atrophy (MTA) measures in identifying AD with mild dementia.MethodWe reviewed 3489 subjects in 3 datasets, i.e., ADNI (n=1529), AIBL (n=862), and OASIS 3 (n=1098). We selected subjects aged 65 to 85 years with clinical dementia rating scale of 1. Among potential eligible AD subjects with mild dementia who also had amyloid data based on either cerebrospinal fluid analysis or positron emission tomography (n=73), we further excluded those who were amyloid negative (n=5). A total of 121 AD subjects with mild dementia and 691 age‐matched elderly normal controls (NC) were eventually recruited. An automated computational tool, AccuBrain, was used to generate the following imaging biomarkers: hippocampal volume (HV), hippocampal fraction (HF), quantitative MTA (QMTA) and AD‐RAI. We compared the following performance metrics in identifying AD with mild dementia for each of the imaging biomarkers: area under curve (AUC) of receiver operating characteristic (ROC) curve, sensitivity, specificity and balanced accuracy.ResultRegarding the ROC analysis, the AD‐RAI performed the best in identifying mild AD from NC (AUC=0.92, sensitivity=0.88 and balanced accuracy=0.83), followed by QMTA and HV/ HF (Table 1 and Figure 1).ConclusionAD‐RAI outperformed other MRI‐based quantitative MTA measures in identifying AD with mild dementia. Since majority of AD patients when they first presented to memory clinic are at the stage of mild dementia, AD‐RAI may aid accurate diagnosis of AD in clinical practice. Reference: 1) Zhao L, Luo Y, Lew D, Liu W, Au L, Mok V, et al. Risk estimation before progression to mild cognitive impairment and Alzheimer's disease: an AD resemblance atrophy index. Aging (Albany NY). 2019;11(16):6217‐36.

Comparison of neuronal activity profiles in Alzheimer’s disease and frontotemporal dementia measured by resting‐state fMRI

AbstractBackgroundNeuronal activity (NA) and metabolism are impaired in the early stages of Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) leading to specific patterns of cognitive decline. Detailed disease models elucidating how and where in brain these NA disturbances commence and how they gradually progress remain incomplete. Recently, we introduced several NA metrics quantified based on fluctuations of the resting‐state fMRI (rs‐fMRI) signal. NA was significantly lower in AD and mild cognitive impairment compared to normal elderly controls (NEC). Here we extend this work using the most sensitive metric to examine NA profile differences between people with AD and FTD.Method3T MRI rs‐fMRI data (TR=∼2.4 Sec, 250 volumes) were obtained from the Ontario Neurodegenerative Disease Research Initiative (AD group: N=40, aged 71.8 ± 8.1, 42% female; and FTD group: N=50, aged 67.8 ± 7.3, 36% female), and Gait and Brain Study (NEC group: N=46, aged 71.0 ± 5.5, 33% female). The rs‐fMRI signal was pre‐processed and decomposed into independent components (ICs) using IC analysis. The ICs were classified into neuronal and non‐neuronal sources using a support vector machine classifier. Voxelwise NA was quantified based on the magnitude of neuronal ICs in the rs‐fMRI signal composition. This metric was utilized to create resting‐state NA maps in each subject, which were compared between groups voxel by voxel using a multiple comparisons permutation test (MCPT) with 1000 permutations.ResultGroup average NA maps are provided in Fig. 1. Average NA was lower in FTD (24%) and AD (40%) compared to NEC. There was a significant difference (adjusted p‐values from MCPT) between NEC and FTD (p&lt;0.001), NEC and AD (p&lt;0.001), and FTD and AD (p&lt;0.05). Difference NA maps comparing the groups and associated significance maps are shown in Fig. 2. The FTD group had significantly higher NA compared to AD in ∼53% of brain voxels (Fig. 2).ConclusionSignificantly lower NA was detected in AD and FTD compared to NEC. Localized significant NA differences between AD and FTD were detected emerging mostly as clusters in occipital and subcortical areas that are known to be less affected by FTD.

Impairment of recognition of facial expressions in different types of dementia

AbstractBackgroundImpairment of facial expression recognition in dementia is one of the cognitive deficits that could affect the social life of dementia patients. The severity of the facial expression recognition in different types of dementia has not been fully addressed. Previous studies showed that EEG event‐related oscillation (ERO) studies could reveal the brain dynamics during successful facial expression recognition. Furthermore, the impairment of facial recognition in Alzheimer's disease patients were represented with abnormal EROs (Güntekin et al., 2019). The present study aims to compare the impaired facial expression recognition between different types of dementia by analysis of event‐related delta responses. The role of delta responses in facial expression and emotional paradigms was reported previously by several researchers (Güntekin and Başar, 2014).Method25 Healthy elderly controls (HC), 25 Mild Cognitive Impairment patients (MCI), 25 patients with Alzheimer's disease (AD), 15 patients with Parkinson's disease with Mild Cognitive Impairment (PDMCI) and 16 patients with Parkinson's disease Dementia (PDD) were included in the study. The electroencephalographic activity was recorded during the perception of the facial expression recognition task (Angry, Happy, Neutral). Delta power and phase‐locking were computed for each facial recognition stimuli and compared among the groups (ANOVA, p&lt;0.05).ResultBoth delta power and delta phase locking were lower in dementia groups than healthy controls being worst in PDD. Figure 1 shows the grand average of delta power in all groups for the right occipital location. PDD (p&lt;0.0001) and AD (p&lt;0.05) had lower delta power than the healthy controls, the reduction of delta responses in PDD and AD were especially found over occipital locations. MCI and PDMCI subjects were found less impaired facial expression recognition compared to AD and PDMCI.ConclusionThe present study showed that dementia patients had severe facial recognition deficits that increased cognitive impairment. Event‐related delta responses successfully showed the impaired recognition of facial expression in different types of dementia groups. Among all dementia subjects, PDD patients had the most reduced delta responses that could be an electrophysiological biomarker of impaired facial expression recognition. Acknowledgments: This work (grant number 218S314) was supported by TUBITAK.

Copy number variation (CNV) identification and association study on 3,928 Alzheimer's disease whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Estimation of heritability of Alzheimer's Disease (AD) ranges from 49-79%, but the conventional single nucleotide variants (SNVs) identified to date account for <50% of the AD heritability. The involvement of genetic variants, such as SNVs and copy number variations (CNVs), has been proposed to explain part of the missing heritability. To accelerate AD genetic discovery, the Alzheimer's Disease Sequencing Project (ADSP) sequenced cases and cognitively normal elder controls from multiple ethnic groups. Leveraging this large-scale Whole Genome Sequence (WGS) collection, we could detect and conduct AD genetic analyses in full-spectrum of CNVs (small or large, common or rare, and coding or non-coding in genomic regions). We developed a bioinformatics pipeline consisting of four steps. First, we applied three calling algorithms, CNVnator, JAX-CNV, and Smoove, on each sample. Results of each tool were then merged by Svimmer. Second, we employed GraphTyper for genotyping. GraphTyper is a graph-pangenome-based method that may mitigate bias of human references. Finally, we resolved issues of multiple CNVs overlapping in a region by bedtools. Once the CNV callset was obtained, we conducted an association study to identify CNV regions that contribute to AD. We consider conventional association methods as well as a new developed CNV-curve-centric strategy which models CNVs as piecewise constant curves to assess the CNV effect on AD. For each sample, we identified an average of 7,959 CNVs by three algorithms. After merging CNVs of all samples, we obtained 56,316 deletions and 16,390 duplications for GraphTyper joint genotyping. The preliminary results of PLINK permutation-based test on the chromosome 19 indicated significant CNVs (p-value < 0.05 after adjusting for multiple tests) on genes UNC13A, IGSF23, KMT2B, LIN37, PSENEN, IGFLR1, and U2AF1L4. UNC13A, KMT2B, and PSENEN have been discovered to be associated in frontotemporal dementia, dystonia, and AD. Further validations of those CNVs are necessary. We developed a scalable CNV detection pipeline and applied it to 3,928 ADSP WGS samples. The preliminary results of the association study validate some known AD, dementia, and dystonia genes. To the best of our knowledge, this is the first large-scale CNV investigation of AD using WGS data.

Impairment of EEG functional connectivity in dementia during recognition of emotional facial expression

AbstractBackgroundThe performance of facial expression recognition is affected both in neurocognitive disorders and in healthy elderly. Emotional content processing is expected to be adversely affected in dementia and as well in Parkinson's disease patients. The present study aims to compare the impaired facial expression recognition between different types of dementia patients, functional connectivity changes in patients with mild cognitive impairment, and patients with dementia were investigated by event‐related EEG‐coherence.Method25 Healthy elderly controls (HC), 25 Mild Cognitive Impairment patients (MCI), 25 patients with Alzheimer's disease (AD), 15 patients with Parkinson's disease with Mild Cognitive Impairment (PDMCI), and 16 patients with Parkinson's disease Dementia (PDD) were included in the study. EEG was recorded while angry, happy, and neutral facial expressions were presented. The artifacts were rejected by using Independent‐Component‐Analysis and Current‐Source‐Density. Magnitude‐squared coherence values of theta (4‐7Hz, 50‐400ms) responses were calculated. Inter‐hemispheric and intra‐hemispheric (frontal and central centered) pairs of F3, F4, C3, C4, T7, T8, Tp7, Tp8, P3, P4, O1, O2 channels were used. Two separate inter and intra hemispheric repeated‐measures‐ANOVA models were used for group comparisons.ResultThere were no group differences for intra‐hemispheric comparisons, but GroupXLocation comparison (p=.040) was significant, HE and MCI groups had higher coherence values in central‐ temporal, central‐ temporoparietal, and central‐ occipital connections compared to PDMCI, PDD, and AD patient groups (Figure 1). FaceXGroup (p=.009) interaction was significant for inter‐hemispheric coherence values, HC and MCI groups had higher interhemispheric coherence values than the PDMCI, PDD, and AD, especially during recognition of "angry" facial expression.ConclusionThe connectivity between the central and posterior regions increased with emotional face content; this increase seems to be preserved in MCI. On the other hand, it wasn't maintained in patients with more severe neurocognitive impairment; PDMCI, PDD, and AD groups had reduced central‐posterior connectivity and interhemispheric connectivity during the facial expression recognition paradigm. The decrease in inter and intra‐connectivity in the posterior regions is consistent with behavioral scores and may indicate neural losses as a phenomenon.