Hypotension with neurovascular changes and cognitive dysfunction: An epidemiological, pathobiological, and treatment review.

ABSTRACT: Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

Brain white matter changes and their associations with non-motor dysfunction in orthostatic hypotension in α-synucleinopathy: A NODDI study.

BACKGROUND: The specific non-motor symptoms associated with α-synucleinopathies, including orthostatic hypotension (OH), cognitive impairment, and emotional abnormalities, have been a subject of ongoing controversy over the mechanisms underlying the development of a vicious cycle among them. The distinct structural alterations in white matter (WM) in patients with α-synucleinopathies experiencing OH, alongside their association with other non-motor symptoms, remain unexplored. This study employs axial diffusivity and density imaging (NODDI) to investigate WM damage specific to α-synucleinopathies with concurrent OH, delivering fresh evidence to supplement our understanding of the pathogenic mechanisms and pathological rationales behind the occurrence of a spectrum of non-motor functional impairments in α-synucleinopathies. METHODS: This study recruited 49 individuals diagnosed with α-synucleinopathies, stratified into an α-OH group (n = 24) and an α-NOH group (without OH, n = 25). Additionally, 17 healthy controls were included for supine and standing blood pressure data collection, as well as neuropsychological assessments. Magnetic resonance imaging (MRI) was utilized for the calculation of NODDI parameters, and tract-based spatial statistics (TBSS) were employed to explore differential clusters. The fibers covered by these clusters were defined as regions of interest (ROI) for the extraction of NODDI parameter values and the analysis of their correlation with neuropsychological scores. RESULTS: The TBSS analysis unveiled specific cerebral regions exhibiting disparities within the α-OH group as compared to both the α-NOH group and the healthy controls. These differences were evident in clusters that indicated a decrease in the acquisition of the neurite density index (NDI), a reduction in the orientation dispersion index (ODI), and an increase in the isotropic volume fraction (FISO) (p < 0.05). The extracted values from these ROIs demonstrated significant correlations with clinically assessed differences in supine and standing blood pressure, overall cognitive scores, and anxiety-depression ratings (p < 0.05). CONCLUSION: Patients with α-synucleinopathies experiencing OH exhibit distinctive patterns of microstructural damage in the WM as revealed by the NODDI model, and there is a correlation with the onset and progression of non-motor functional impairments.

Aberrant microstructural integrity of white matter in mild and severe orthostatic hypotension: A NODDI study.

OBJECTIVE: Scarce evidence is available to elucidate the association between the abnormal microstructure of white matter (WM) and cognitive performance in patients with orthostatic hypotension (OH). This study investigated the microstructural integrity of WM in patients with mild OH (MOH) and severe OH (SOH) and evaluated the association of abnormal WM microstructure with the broad cognitive domains and cognition-related plasma biomarkers. METHODS: Our study included 72 non-OH (NOH), 17 MOH, and 11 SOH participants. Across the groups, the WM integrity was analyzed by neurite orientation dispersion and density imaging (NODDI), and differences in WM microstructure were evaluated by nonparametric tests and post hoc models. The correlations between WM microstructure and broad cognitive domains and cognition-related plasma biomarkers were assessed by Spearman's correlation analysis. RESULTS: The abnormal WM microstructure was localized to the WM fiber bundles in MOH patients but distributed widely in SOH cohorts (p < 0.05). Further analysis showed that the neurite density index of the left cingulate gyrus was negatively associated with amyloid ß-40, glial fibrillary acidic protein, neurofilament light chain, phospho-tau181 (p < 0.05) but positively with global cognitive function (MOCA, MMSE, AER-III), memory, attention, language, language fluency, visuospatial function and amyloid ß-40 / amyloid ß-42 (p < 0.05). Additionally, other abnormal WM microstructures of OH were associated with broad cognitive domains and cognition-related plasma biomarkers to varying degrees. CONCLUSION: The findings evidence that abnormal WM microstructures may present themselves as early as in the MOH phase and that these structural abnormalities are associated with cognitive functions and cognition-related plasma biomarkers.

Synchronous monitoring of brain-heart electrophysiology using heart rate variability coupled with rapid quantitative electroencephalography in orthostatic hypotension patients with α-synucleinopathies: Rapid prediction of orthostatic hypotension and preliminary exploration of brain stimulation therapy.

BACKGROUND: In α-synucleinopathies, the dysfunction of the autonomic nervous system which typically manifests as orthostatic hypotension (OH) often leads to severe consequences and poses therapeutic challenges. This study aims to discover the brain-cardiac electrophysiological changes in OH patients with α-synucleinopathies using the rapid quantitative electroencephalography (qEEG) coupled with heart rate variability (HRV) technique to identify rapid, noninvasive biomarkers for early warning and diagnosis, as well as shed new light on complementary treatment approaches such as brain stimulation targets. METHODS: In this study, 26 subjects of α-synucleinopathies with OH (α-OH group), 21 subjects of α-synucleinopathies without OH (α-NOH group), and 34 healthy controls (control group) were included from September 2021 to August 2023 (NCT05527067). The heart rate-blood pressure variations in supine and standing positions were monitored, and synchronization parameters of seated resting-state HRV coupled with qEEG were collected. Time-domain and frequency-domain of HRV measures as well as peak frequency and power of the brainwaves were extracted. Differences between these three groups were compared, and correlations between brain-heart parameters were analyzed. RESULTS: The research results showed that the time-domain parameters such as MxDMn, pNN50, RMSSD, and SDSD of seated resting-state HRV exhibited a significant decrease only in the α-OH group compared to the healthy control group (p < 0.05), while there was no significant difference between the α-NOH group and the healthy control group. Several time-domain and frequency-domain parameters of seated resting-state HRV were found to be correlated with the blood pressure changes within the first 5 min of transitioning from supine to standing position (p < 0.05). Differences were observed in the power of beta1 waves (F4 and Fp2) and beta2 waves (Fp2 and F4) in the seated resting-state qEEG between the α-OH and α-NOH groups (p < 0.05). The peak frequency of theta waves in the Cz region also showed a difference (p < 0.05). The power of beta2 waves in the Fp2 and F4 brain regions correlated with frequency-domain parameters of HRV (p < 0.05). Additionally, abnormal electrical activity in the alpha, theta, and beta1 waves was associated with changes in heart rate and blood pressure within the first 5 min of transitioning from supine to standing position (p < 0.05). CONCLUSION: Rapid resting-state HRV with certain time-domain parameters below normal levels may serve as a predictive indicator for the occurrence of orthostatic hypotension (OH) in patients with α-synucleinopathies. Additionally, the deterioration of HRV parameters correlates with synchronous abnormal qEEG patterns, which can provide insights into the brain stimulation target areas for OH in α-synucleinopathy patients.

Efficacy analysis of three brain stimulation techniques for Alzheimer's disease: a meta-analysis of repeated transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation.

INTRODUCTION: This systematic review and meta-analysis study investigates the efficacy of repeated transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS) using neuropsychological assessments as a potential treatment option for Alzheimer's disease (AD). METHODS: PubMed, Embase, and the Cochrane Library were searched for studies on rTMS, tDCS, and DBS for the treatment of patients with AD between April 1970 and October 2022. The mini-Mental State Examination (MMSE) and AD Assessment Scale - Cognitive Subscale (ADAS-Cog) were adopted as the efficacy index. RESULTS: The analysis yielded 17 eligible studies. rTMS greatly improved the cognition of patients with AD (immediate post-treatment WMD of MMSE score: 2.06, p < 0.00001; short-term follow-up WMD of MMSE score: 2.12, p = 0.006; WMD of ADAS-Cog score in single-arm studies: -4.97, p = 0.001). DBS did not reverse the progression of cognitive decline (WMD of ADAS-Cog score in single-arm studies: 7.40, p < 0.00001). Furthermore, tDCS demonstrated no significant efficacy in improving cognition in random clinical trials or single-arm studies. CONCLUSION: rTMS is a promising non-medicinal alternative for cognitive improvement inpatients with AD.

Dendrobine rescues cognitive dysfunction in diabetic encephalopathy by inhibiting ferroptosis via activating Nrf2/GPX4 axis.

BACKGROUND: Ferroptosis playsa crucial role in the development of dementia and dendrobine (Den)possesseshypoglycemic and neuroprotective effects. However, the character of ferroptosis in diabetic encephalopathy (DE) and Den's therapeutic effect remains unclear. PURPOSE: This study aimed to verify the effects of Den on ferroptosis in treating DE and underlying mechanisms. STUDY DESIGN: Den's therapeutic effect was assessed in db/db mice and advanced glycation end products (AGEs)-induced HT22 cells. METHODS: After oral administration with Den orMetformin for 8-week, behavioral tests were used to assess cognitive capacity. Then, biochemical analysis was preformed to detect glucose and lipid metabolism levels; histological analysis and transmission electron microscope were applied to evaluate pathological injuries. Meanwhile, EdU staining and flow cytometry were applied to test cell apoptosis. Furthermore, mitochondrial dynamics, iron transport, and Nrf2/GPX4 axis related proteins were detected by western blot or immunofluorescence. RESULTS: Our results demonstrated that Den remarkably alleviated glucose and lipid metabolism disorders, as well as ameliorated mnemonic deficits of db/db mice. Meanwhile, Den could protect AGEs-induced HT22 cells from death and apoptosis. In addition, we noted that Den inhibited lipid peroxidation by restoring mitochondrial function and reducing reactive oxygen species production. Furthermore, ferroptosis was proven to exist in db/db mice brain and Den could inhibit it via activating Nrf2/GPX4 axis. CONCLUSION: These findings indicated that Den could rescue cognitive dysfunction in DE by inhibiting ferroptosis via activating Nrf2/GPX4 axis.

Relationship of 24-Hour Movement Behaviors with Weight Status and Body Composition in Chinese Primary School Children: A Cross-Sectional Study.

24 h movement behaviors, specifically physical activity (PA), sedentary behavior, and sleep, play a crucial role in the prevention and intervention of childhood obesity. This study aimed to examine the association of 24 h movement behaviors with weight status and body composition among Chinese primary school children. Using a random stratified sampling, 978 eligible participants (9.1 ± 1.4 years, 53.2% boys) were recruited from 1 May to 15 July 2021. Demographics included children's age, gender, grade, parents' education level, and household income. Movement behaviors were measured by validated self-reported scales. Weight status and body composition (percent of body fat, PBF; fat-free mass, FFM; skeletal muscle mass, SMM) were measured objectively. Results indicated that participants who were younger, boys, and at lower grade showed higher guidelines adherence. PA was inversely associated with PBF, while screen time (ST) was positively associated with overweight/obesity risk and FFM. Sleep showed no association with any health indicators. Meeting the behavioral guidelines was associated with better weight status and lower PBF, yet not with FFM and SMM. Interventions to improve the Children's weight status and PBF should involve enhancing their overall movement behaviors and considering their demographic differences. More research on examining the association of movement guidelines adherence with body composition indicators is needed.

Genetic Effects of NDUFAF6 rs6982393 and APOE on Alzheimer's Disease in Chinese Rural Elderly: A Cross-Sectional Population-Based Study.

PURPOSE: To investigate the associations of genotypes of NDUFAF6 rs6982393 and APOE and their combined genotypes with the risk of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in Chinese rural elderly. METHODS: This cross-sectional population-based study included 5096 older adults (age ≥60 years, 57.1% female). Genotypes of NDUFAF6 rs6982393 and APOE were detected using the multiple-polymerase chain reaction amplification. We diagnosed AD following the criteria of Diagnostic and Statistical Manual of Mental Disorders, the fourth edition and diagnosed MCI following the Petersen's criteria MCI. Data were analyzed using the logistic regression model. RESULTS: The overall prevalence of AD and MCI was 3.57% (95% confidence interval [CI]: 0.040, 0.053) and 22.65% (95% CI: 0.223, 0.247), separately. The TT versus CC/CT genotype of NDUFAF6 rs6982393 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 1.61 (1.02, 2.54) in the total sample, 3.36 (1.48, 7.60) in those aged 60-69, and 1.24 (0.71, 2.17) in those aged 70 years and above. The interaction between genotype of NDUFAF6 rs6982393 with age groups (60-69 versus ≥70 years) was significant on the risk of AD. The presence of APOE ε4 was not significantly associated with the risk of AD. Carrying both NDUFAF6 TT and APOE ε4 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 2.69 (1.10, 2.56). In addition, there was no significant association between the above genotypes and MCI. CONCLUSION: In Chinese rural elderly, the TT versus CT/CC genotype of NDUFAF6 rs6982393 was associated with an increased likelihood of AD; such an association only existed among young-old adults. Carrying both NDUFAF6 rs6982393-TT and APOE ε4 was related to a higher risk of AD. This finding highlights the importance of considering age and combined genotype in studying the genetic profiles of AD.

Association and interaction of TOMM40 and PVRL2 with plasma amyloid-ß and Alzheimer's disease among Chinese older adults: a population-based study.

Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aß40, Aß42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73-22.48) for TOMM40GG, 1.47 (0.89-2.42) for PVRL2AA, and 12.87 (3.97-41.73) for having both risk alleles (Pinteraction = 0.0003). Among APOEε3/ε3 carriers, the multiadjusted odds ratio of AD associated with TOMM40AG was 2.90(1.15-7.31). In biomarker subsample, TOMM40GG was significantly associated with lower plasma Aß42 and the Aß42-to-Aß40 ratio (p < 0.05). TOMM40 genotype is differentially associated with AD risk depending on APOE genotype. TOMM40 and PVRL2 genes could interact to substantially increase AD risk, possibly through influencing Aß metabolism.