Current Alzheimer Research - Volume 19, Issue 6, 2022

Background: Alzheimer's disease (AD) is the most common form of dementia in the elderly population and places heavy burdens on medical care and nursing. Recently, the psychiatric and behavioral symptoms of prodromal AD, especially mild behavioral impairment (MBI), have attracted much attention. In 2012, Alzheimer's Association International Conference, MBI was proposed as a syndrome with psychiatric and behavioral disturbance before the onset of typical clinical cognitive symptoms in dementia. Increasing lines of evidence have indicated the link between MBI and early AD pathologies including Aβ and tau. Objective: This narrative review aims to summarize the advantages of MBI over other concept of psychiatric and behavioral symptoms associated with AD in the early prediction of AD dementia. We also discuss the possible common genetic basis and pathological mechanisms underlying the interactions between MBI and AD. Methods: Papers cited here were retrieved from PubMed up to February 2022. We selected a total of 95 articles for summary and discussion. Results: The occurrence of MBI is mainly due to the overlapped genetic and pathological risk factors with AD and is related to the brain's response to environmental stressors. MBI may be a warning sign for the early pathology of AD, and more attention should be paid on the number and duration of MBI symptoms. Conclusion: MBI may be an early sign and predictor of Alzheimer's disease dementia. Early intervention for MBI may have a positive effect on alleviating long-term cognitive decline.

Introduction: Alzheimer’s disease (AD) is a progressive, neurodegenerative disease that severely affects individuals' cognitive abilities, memory, and quality of life. It affects the elderly population, and there is no permanent prevention or cures available to date, treatments mainly aiming to alleviate the symptoms as and when they appear. Alternate therapeutic approaches are being researched constantly, and there is a growing focus on phytomedicine, herbal medicine, organic compounds, and ayurvedic compounds for the treatment of AD. Methods: The current study aims to provide an extensive review of these plants against AD from the currently existing literature. Most relevant keywords like Alzheimer’s Disease, phytomedicines, ethnic medicines, the role of phytomedicine in neuroprotection, common phytomedicines against AD, etc., were used to select the plants and their metabolites effective in treating AD. The study focuses on six plants: Panax ginseng, Ginkgo biloba, Bacopa monnieri, Withania somnifera, Curcuma longa, and Lavandula angustifolia. Their active components have been studied along with neuroprotective properties, and evidence of in-vitro, pre-clinical, and clinical studies conducted to prove their therapeutic potential against the disease have been presented. Results: All plants envisaged in the study show potential for fighting against AD to varying degrees. Their compounds have shown therapeutic effects by reversing the neurological changes such as clearing Aβ plaque and neurofibrillary tangle formation, and ameliorative effects against neurodegeneration through processes including improving concentration, memory, cognition and learning, higher working and cue memory, improved spatial memory, inhibition of NF-ΚB expression, inhibiting the release of pro-inflammatory cytokines, inhibition of AChE and lipid peroxidase enzymes, and reduction of interleukin levels and tumor necrosis factor-alpha. Conclusion: The present review is a comprehensive and up-to-date analysis supported by the evidentiary proofs from pre-clinical studies, meta-analyses, and review papers related to natural phytochemicals' impact on neurodegenerative disorders like AD.

Background: Learning and memory deficit has been reported to be correlated to oxidative mutilation in the hippocampus. Moreover, sleep deprivation (SD) mitigates memory via distressing oxidative stress balance. In the current report, the prospective neuroprotective role of oral sage (Salvia triloba) extract on cognitive impairment induced by chronic SD was investigated. Methods: The SD was induced in adult male Wistar rats employing a modified multiple platform (8 h/day; for six weeks). Simultaneously, S. triloba extract (375 mg/kg, orally) was administered for six weeks. Thereafter, the Radial Arm Water Maze test was utilized to evaluate spatial learning and memory. Moreover, activities of different hippocampal antioxidant parameters: glutathione peroxidase (GPx), oxidized glutathione (GSSG), reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and the thiobarbituric acid reactive substance (TBARS) were measured in rats’ hippocampus. Moreover, the level of brain derived neurotrophic factor (BDNF) was assessed. Results: Current results illustrate that chronic SD significantly compromised both memories, shortand long-term, while sage extract inhibited these consequences. Moreover, sage extract remarkably stabilized the antioxidant enzyme levels, which were decreased by SD, such as: SOD, catalase, and GPx (P < 0.05), and remarkably augmented the GSH/GSSG ratio in SD rats (P < 0.05). However, no substantial alterations of GSH, TBARS or BDNF levels (P > 0.05) were seen with sage extract administration. Conclusion: Chronic treatment with sage extract (S. Triloba) precluded SD-induced memory impairment by regularizing antioxidant parameters levels in rats’ hippocampus.

Background: Vascular lesions may be a common finding also in Alzheimer's dementia, but their role on cognitive status is uncertain. Objective: The study aims to investigate their distribution in patients with Alzheimer's, vascular or mixed dementia and detect any distinctive neuroradiological profiles. Methods: Seventy-six subjects received a diagnosis of Alzheimer’s (AD=32), vascular (VD=26) and mixed (MD=18) dementia. Three independent raters assessed the brain images acquired with an optimized 3T MRI protocol (including (3D FLAIR, T1, SWI, and 2D coronal T2 sequences) using semiquantitative scales for vascular lesions (periventricular lesions (PVL), deep white matter lesions (DWML), deep grey matter lesions (DGML), enlarged perivascular spaces (PVS), and microbleeds (MB)) and brain atrophy (medial temporal atrophy (MTA), posterior atrophy (PA), global cortical atrophy- frontal (GCA-F) and Evans’ index). Results: Raters reached a good-to-excellent agreement for all scales (ICC ranging from 0.78-0.96). A greater number of PVL (p<0.001), DWML (p<0.001), DGML (p=0.010), and PVS (p=0.001) was observed in VD compared to AD, while MD showed a significant greater number of PVL (p=0.001), DWML (p=0.002), DGML (p=0.018), and deep and juxtacortical MB (p=0.006 and p<0.001, respectively). Comparing VD and MD, VD showed a higher number of PVS in basal ganglia and centrum semiovale (p=0.040), while MD showed more deep and juxtacortical MB (p=0.042 and p=0.022, respectively). No significant difference was observed in scores of cortical atrophy scales and Evans’ index among the three groups. Conclusion: The proposed MRI protocol represents a useful advancement in the diagnostic assessment of patients with cognitive impairment by more accurately detecting vascular lesions, mainly microbleeds, without a significant increase in time and resource expenditure. Our findings confirm that white and grey matter lesions predominate in vascular and mixed dementia, whereas deep and juxtacortical microbleeds predominate in mixed dementia, suggesting that cerebral amyloid angiopathy could be the main underlying pathology.

Background: No previous study has examined the effect of dual-task training using changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) as an outcome. Objective: This study aimed to examine the effects of simultaneous dual-task training of exercise and cognitive tasks on rCBF using SPECT in older adults with amnestic mild cognitive impairment (aMCI). Methods: In this non-randomized control trial, 40 older adults with aMCI participated from May 2016 to April 2018. Outpatients in the intervention group (n = 22) underwent 24 sessions (12 months) of dualtask training twice a month for 60 mins per session. Participants in the control group (n = 18) continued to have regular outpatient visits. The primary outcome was rCBF at baseline and after 12 months, which was compared in each group using the two-sample t-test. The secondary outcomes were the rate of reversion and conversion from aMCI after 12 months. Results: Of the 22 participants in the intervention group, six dropped out; therefore, 16 were included in the analysis. The intervention group showed more significant increases in rCBF in multiple regions, including the bilateral frontal lobes, compared with the control group. However, the rates of reversion or conversion from mild cognitive impairment (MCI) were not significantly different. Conclusion: Dual-task training for older adults with aMCI increased rCBF in the frontal gyrus but did not promote reversion from MCI to normal cognition. Future intervention studies, such as follow-up examinations after the intervention, are warranted to consider long-term prognosis.

Background: Neuroimaging suggests that white matter microstructure is severely affected in Alzheimer's disease (AD) progression. However, whether alterations in white matter microstructure are confined to specific regions and whether they can be used as potential biomarkers to distinguish normal control (NC) from AD are unknown. Methods: In this cross-sectional study, 33 cases of AD and 25 cases of NC were recruited for automatic fiber quantification (AFQ). A total of 20 fiber bundles were equally divided into 100 segments for quantitative assessment of fractional anisotropy (FA), mean diffusivity (MD), volume and curvature. In order to further evaluate the diagnostic value, the maximum redundancy minimum (mRMR) and LASSO algorithms were used to select features, calculate the Radscore of each subject, establish logistic regression models, and draw ROC curves, respectively, to assess the predictive power of four different models. Results: There was a significant increase in the MD values in AD patients compared with healthy subjects. The differences were mainly located in the left cingulum hippocampus (HCC), left uncinate fasciculus (UF) and superior longitudinal fasciculus (SLF). The point-wise level of 20 fiber bundles was used as a classification feature, and the MD index exhibited the best performance to distinguish NC from AD. Conclusion: These findings contribute to the understanding of the pathogenesis of AD and suggest that abnormal white matter based on DTI-based AFQ analysis is helpful to explore the pathogenesis of AD.

Background: Rapidly progressive dementias (RPDs) are dementias that progress subacutely over a time period of weeks to months. Primary Sjögren’s syndrome (pSS) is an autoimmune disease that can affect any organ system and may present with a wide range of clinical features that may mimic a plethora of medical conditions and, in rare cases, may manifest as RPD. We describe a unique case of pSS, in which rapidly progressive dementia (RPD) was the first disease manifestation, and the patient’s radiological and electroencephalogram findings were compatible with Creutzfeldt- Jakob disease (CJD). Case Presentation: Here, we report a 58-year-old woman who presented with cognitive impairment rapidly deteriorating over the last 6 months prior to admission. Brain MRI and EEG were indicative of CJD. However, CSF 14-3-3 and tau/phospho tau ratio were within normal limits and therefore alternative diagnoses were considered. Blood tests were significant for positive antinuclear antibodies, anti-ENA, and anti-SSA and a lip biopsy was consistent with pSS. The patient was started on intravenous steroids followed by oral prednisone taper, which prevented further deterioration. Conclusion: This rare case expands the spectrum of neurological manifestations in pSS and highlights the importance of considering pSS in the differential diagnosis of RPDs in order to avoid misdiagnosis and provide appropriate treatment in a timely fashion.