GRK5 Deficiency Causes Mild Cognitive Impairment due to Alzheimer’s Disease

Prevention of Alzheimer’s disease (AD) is a high priority mission while searching for a disease modifying therapy for AD, a devastating major public health crisis. Clinical observations have identified a prodromal stage of AD for which the patients have mild cognitive impairment (MCI) though do not yet meet AD diagnostic criteria. As an identifiable transitional stage before the onset of AD, MCI should become the high priority target for AD prevention, assuming successful prevention of MCI and/or its conversion to AD also prevents the subsequent AD. By pulling this string, one demonstrated cause of amnestic MCI appears to be the deficiency of G protein-coupled receptor-5 (GRK5). The most compelling evidence is that GRK5 knockout (GRK5KO) mice naturally develop into aMCI during aging. Moreover, GRK5 deficiency was reported to occur during prodromal stage of AD in CRND8 transgenic mice. When a GRK5KO mouse was crossbred with Tg2576 Swedish amyloid precursor protein transgenic mouse, the resulted double transgenic GAP mice displayed exaggerated behavioral and pathological changes across the spectrum of AD pathogenesis. Therefore, the GRK5 deficiency possesses unique features and advantage to serve as a prophylactic therapeutic target for MCI due to AD.

Biomarker in Parkinson’s Disease: Clinical and Biochemical Biomarker

Parkinson’s disease is a neurodegenerative disease compromising progressive motor and non-motor features for a long disease course. Although many drugs controlling parkinsonian symptoms were discovered, treatment with disease-modifying or halting effect was not developed to date. The exploration of reliable biomarkers would be helpful for better predicting disease progression and thereby successful development of disease-modifying therapy. In this review, we will review the clinical biomarkers in the prodromal stage and biomarkers using biological tissue in Parkinson’s disease.

Psychotic Features Among Patients in the Prodromal Stage of Dementia with Lewy Bodies During Longitudinal Observation

Background: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described. Objective: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment. Methods: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through indicative and supportive biomarkers of scintigraphy. Results: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years. Conclusion: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis.

Humour: coping with travel bans during the COVID-19 pandemic

Purpose This study aims to extend the use of psychology in the field of tourism crisis and disaster management using coping theory. It examines how resident emotions change in the extended prodromal stage of the COVID-19 pandemic and how residents used humour to cope with stress from not being able to travel. Design/methodology/approach Early COVID-19 (March–April 2020) was characterised by negative media reports, lockdowns and travel restrictions but for Indonesia, no direct effects in terms of loss of life. This unusual context has led to phenomena not previously studied – humour as a coping strategy. This research consists of two studies: Study 1 used thematic analysis of interviews before and during the early lockdown period with a panel of 245 quarantined residents who had travelled in the prior two years. Study 2 followed up using a #hasthtag analysis of travel-related videos content posted on Instagram and TikTok. Findings The COVID-19 global pandemic is an unusual crisis which has resulted in high levels of stress and uncertainty. This study identified the unusual characteristics of the COVID-19 crises and changes of quarantined resident’s emotions during the pre-event and prodromal stages. In addition, this study found the use of humour as a coping mechanism during the lockdown period and the use of social media as the vehicle for humour. Research limitations/implications These findings may be generalisable only to a crises and disasters with an extended prodromal stage. Interestingly, climate change has some similar characteristics where warning signs are available, but the personal implications have not yet become apparent. Practical implications The emotions associated with crisis are dynamic and crisis managers may tailor communication to help deal with stress. Social implications This research provides an insight into how humorous content can be used to reduce negative emotions in the early stage of a stressful event associated with travel restrictions. This study may be suitable for use in integrated marketing communication in post-recovery messaging for the tourism industry and destination management organisation in the digital platform. Originality/value To the best of the authors’ knowledge, this study is the first to demonstrate “dark humour” during the early stages of COVID-19 and also the use of coping strategies to explain how humour can reduce stress.

Cognitive Function during the Prodromal Stage of Alzheimer’s Disease in Down Syndrome: Comparing Models

Accurate identification of the prodromal stage of Alzheimer’s disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40–82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.

Novel Plasma miRNAs as Biomarkers and Therapeutic Targets of Alzheimer’s Disease at the Prodromal Stage

Background: Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD) involving imbalanced beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). MicroRNAs (miRNAs) are associated with AD. Objective: This study aimed to investigated whether plasma miRNAs can predict prodromal AD or are associated with AD pathology. Methods: Participants in the discovery set (n = 10), analysis set (n = 30), and validation set (n = 80) were screened from the China Longitudinal Aging Study. RNA was extracted from the participants’ plasma. Microarray sequencing provided miRNA profiles and differentially expressed miRNAs (DEmiRNAs) in the discovery set included patients with 18F-Flutemetamol positron emission tomography scan-confirmed aMCI. Potential biomarkers were screened in the analysis set. The predict capability of candidate miRNAs was assessed in the validation set. Candidate miRNAs modulation of BACE1 expression was explored in rat and human hippocampal neurons in vitro. Results: We verified 46 significant DEmiRNAs between the aMCI and NC groups (p < 0.05), among which 33 were downregulated. In the analysis set, miR-1185-2-3p, miR-1909-3p, miR-22-5p, and miR-134-3p levels decreased significantly in the aMCI group. These miRNAs and previously identified miR-107 were selected as potential biomarkers. A prediction model comprising these five miRNAs showed outstanding accuracy (81.25%) to discriminate aMCI at cut-off value of 0.174. Except for miR-134-3p, the other four miRNAs significantly suppressed Bace1 expression in rat hippocampal neurons in vitro. BACE1 modulation of miR-1185-2-3p, miR-1909-3p, and miR-134-3p was confirmed in human hippocampal neurons in vitro. Conclusion: A predictive model consisting of five BACE1-related plasma miRNAs could be a novel biomarker for aMCI.

Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease

Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/−//SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of gba+/−//SNCAA53T (n = 8), SNCAA53T (n = 9), gba+/− (n = 10) and wildtype (n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old gba+/−//SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between gba+/−//SNCAA53T and SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.

Mild parkinsonian signs: the interface between aging and Parkinson’s disease

Mild Parkinsonian Signs (MPS) describe a spectrum that exists between the expected motor decline of normal aging and a more serious motor deterioration resulting from Parkinson’s disease (PD) and neurodegeneration. Although MPS are a feature of the prodromal stage of PD, their formal definition is unclear and still relies somewhat on conventional clinical criteria for PD. This review will summarise the early motor features of PD and methods of assessment, from conventional clinical scales to advances in quantitative measures. Finally, the boundaries of motor decline as part of normal aging and pathological neurodegeneration will be discussed.

Blood Cholesterol Decreases as Parkinson’s Disease Develops and Progresses

Background: Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson’s disease (PD); this finding has important ramifications, but its interpretation has been debated. Objective: To longitudinally examine how blood total cholesterol changes during the development of PD. Methods: In the Health, Aging and Body Composition study (n = 3,075, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. Results: Compared to the lowest tertile of baseline total cholesterol, the cumulative incident ratio of PD and 95%confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values∼4 years before disease diagnosis (observed-expected difference, –6.68 mg/dL (95%confidence interval: –13.14, –0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to –13.59 mg/dL (95%confidence interval: –22.12, –5.06), although the linear trend did not reach statistical significance (p = 0.10). Conclusion: Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD.