Current Alzheimer Research - Volume 17, Issue 6, 2020

Neurodegenerative Diseases (NDD) are the major contributors to age-related causes of mental disability on a global scale. Most NDDs, like Alzheimer’s Disease (AD), are complex in nature - implying that they are multi-parametric both in terms of heterogeneous clinical outcomes and underlying molecular paradigms. Emerging evidence from high throughput genomic, transcriptomic and small RNA sequencing experiments hint at the roles of long non-coding RNAs (lncRNAs) in AD. X-inactive Specific Transcript (XIST), a component of the Xic, the X-chromosome inactivation centre, is an RNA gene on the X chromosome of the placental mammals indispensable for the X inactivation process. An extensive literature survey shows that aberrations in Xist expression and in some cases, a disruption of the Xchromosome inactivation as a whole play a significant role in AD. Considering the enormous potential of Xist as an endogenous silencing molecule, the idea of using Xist as a non-conventional chromosome silencer to treat diseases harboring chromosomal alterations is also being implemented. Comprehensive knowledge about how Xist could play such a role in AD is still elusive. In this review, we have collated the available knowledge on the possible Xist involvement and deregulation from the perspective of molecular mechanisms governing NDDs with a primary focus on Alzheimer’s disease. Possibilities of XIST mediated therapeutic intervention and linkages between XIC and preferential predisposition of females to AD have also been discussed.

Aims: Unlike autobiographical memory (i.e., memory for personal information) in Alzheimer’s Disease (AD), little is known about Self-Defining Memories (SDM) (i.e., memories of highly significant personal events) in AD. Methods: The characteristics of self-defining memories in AD were evaluated by analyzing their specificity, emotional valence, and integration, as well as their centrality and contribution to self-continuity. Results demonstrated fewer specific SDM in AD participants than in controls. Results: No significant differences were observed between AD participants and controls regarding the production of positive or integrated SDM. Furthermore, no significant differences were observed between AD participants and controls regarding the rating of the centrality of SDM and their contribution to self-continuity. These results demonstrate that, although AD participants produce fewer specific SDM than controls, both populations have similar levels of emotional valence, integration, centrality, and selfcontinuity of these memories. Conclusion: It is concluded that patients with AD, at least those in the mild stages of the disease, can build on significant personal events and experiences (i.e., SDM) to reflect on how these events have changed the way they see themselves.

Background: Identifying and classifying individuals with Cognitive Impairment-No Dementia (CIND) has further challenged diagnostic methods, since varying the cutoffs for objective impairment as well as the neuropsychological tests considered can significantly affect diagnosis. Therefore, we investigated the applicability of an actuarial neuropsychological approach for clinical subdivision of CIND and quantified the variability in diagnostic outcomes that results from diverse neuropsychologically derived definition of objective cognitive impairment. Methods: 1459 non-demented, clinic-based individuals were recruited from a monocentric memory clinic from 1/1/2016/ to 1/1/2018 and classified as Cognitively Normal (NC), Slight Cognitive Symptom (SCS), SSubtle Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) via different diagnostic strategies, which varied the composition of objective cognitive assessments involved in the diagnostic process. Results: We compared two methods of criteria proposed by Jak/Bondi and Petersen/Winblad to classify individuals with CIND. A substantial range of differences in the percentages recognized as NC, SCS, SCD, and MCI was presented, depending on the classification criteria adopted. Our data revealed that the application of a set of six neuropsychological scores dividing CIND into 4 subgroups (NC, SCS, SCD, and MCI) was able to classify all non-demented individuals without overlap or omission. Conclusion: Our study provided clinical support for an operational framework of the CIND classification system and underlined the value of applying comprehensive neuropsychological assessments for definition. The concept of SCS, considered appropriate for a preclinical stage, was proposed as the symptomatic definition for early intervention.

Background: Utilisation of intervention programmes and services for Persons with Dementia (PWD) has been generally modest despite the growing numbers. One reason has been the lack of knowledge about dementia and information on such services. Objective: We sought to close this gap by providing caregivers with an information session about dementia and the importance and availability of related services. We explored the uptake of intervention programmes and services and reasons for non-uptake thereafter. Methods: Two hundred and seventy-five PWD and caregiver dyads attended the Dyad Education and Empowerment Programme (DEEP). At the DEEP, while caregivers underwent an information session, PWD were assessed by a multidisciplinary team on their need and suitability for programmes and services such as daycare, cognitive engagement programmes and physical rehabilitation. The dyads then received individualized recommendations on the appropriate services, if any. Follow-up through medical records review and phone calls was conducted one month after DEEP to ascertain if the dyads had acted upon the recommendations and if not, what difficulties they encountered. Results: One hundred and eleven PWD received recommendations, of which 40 (36.0%) agreed and enrolled in the services while 71 (64%) declined. Thematic analysis of the reasons for non-uptake revealed 3 themes: PWD-related factors (e.g., refusal, functional improvement or decline), caregiverrelated factors (adequacy of care at home, other care arrangements), and service-related factors (e.g., cost, timing). Conclusion: Despite adequate information, there are other reasons for non-uptake of dementia- related services, some of which should be addressed to improve service updates and to provide better care for PWD.

Aims: The purpose of the study was to evaluate the reliability of our new visual scale for a quick atrophy assessment of parietal lobes on brain Magnetic Resonance Imaging (MRI) among different professionals. A good agreement would justify its use for differential diagnosis of neurodegenerative dementias, especially early-onset Alzheimer’s Disease (AD), in clinical settings. Methods: The visual scale named the Parietal Atrophy Score (PAS) is based on a semi-quantitative assessment ranging from 0 (no atrophy) to 2 (prominent atrophy) in three parietal structures (sulcus cingularis posterior, precuneus, parietal gyri) on T1-weighted MRI coronal slices through the whole parietal lobes. We used kappa statistics to evaluate intra-rater and inter-rater agreement among four raters who independently scored parietal atrophy using PAS. Rater 1 was a neuroanatomist (JM), rater 2 was an expert in MRI acquisition and analysis (II), rater 3 was a medical student (OP) and rater 4 was a neurologist (DS) who evaluated parietal atrophy twice in a 3-month interval to assess intra-rater agreement. All raters evaluated the same 50 parietal lobes on brain MRI of 25 cognitively normal individuals with even distribution across all atrophy degrees from none to prominent according to the neurologist’s rating. Results: Intra-rater agreement was almost perfect with the kappa value of 0.90. Inter-rater agreement was moderate to substantial with kappa values ranging from 0.43-0.86. Conclusion: The Parietal Atrophy Score is the reliable visual scale among raters of different professions for a quick evaluation of parietal lobes on brain MRI within 1-2 minutes. We believe it could be used as an adjunct measure in differential diagnosis of dementias, especially early-onset AD.

Background: Early-Onset Familial Alzheimer’s Disease (EOFAD) has been reported to be associated with Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated. Objective: To investigate the spectrum of mutations in patients with EOFAD in Chinese population. Methods: We performed whole-exome sequencing and described relevant clinical features in a total of 67 subjects from 3 families with EOFAD. Results: A splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified. Conclusion: The variant p. S290C (c.869-2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotypes when compared with that of Europeans.

Background: White matter lesions are frequently found in mild cognitive impairments and Alzheimer’s disease. Matrix metalloproteinases and the tissue inhibitor of metalloproteinases are implicated in amyloid-β catabolism and blood brain barrier permeability. However, it remains unclear whether they are associated with white matter lesions in Alzheimer’s disease. Objective: The aim of this study was to examine the association of matrix metalloproteinases and tissue inhibitor of metalloproteinases with white matter degeneration in subjects with amyloid-positive mild cognitive impairment. Methods: Thirty subjects with amnestic mild cognitive impairment (14 men and 16 women; mean age, 75.6 ± 5.8 years) underwent magnetic resonance imaging, ¹¹C-Pittsburgh Compound B positron emission tomography, and ¹⁸F-fluorodeoxyglucose positron emission tomography. Levels of plasma matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured using multiplex assays. All subjects had an abnormal brain amyloid burden. Subjects were divided into two groups according to the presence of white matter lesions using the Fazekas scale. Cognitive function testing results i.e., mean ¹¹C-Pittsburgh Compound B and ¹⁸F-fluorodeoxyglucose uptake, concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases, and matrix metalloproteinases/tissue inhibitor of metalloproteinases ratios were compared between the groups. Correlation analysis was conducted to investigate the association between Fazekas scale score and clinical and neuroimaging variables as well as concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Results: Matrix metalloproteinases-2, -8, and -9 levels, matrix metalloproteinases-2/ tissue inhibitor of metalloproteinases-2, matrix metalloproteinases-8/ tissue inhibitor of metalloproteinases-1, and matrix metalloproteinases-9/tissue inhibitor of metalloproteinases-1 significantly increased and tissue inhibitor of metalloproteinases-1 and-2 levels significantly decreased in the group with white matter lesions compared with the group without white matter lesions. Matrix metalloproteinases-2, -8, and -9 levels correlated positively and tissue inhibitor of metalloproteinases-1 and -2 levels correlated negatively with Fazekas scale score. Conclusion: Plasma matrix metalloproteinases-2, -8, -9 and tissue inhibitor of metalloproteinases-1 and -2 levels are associated with white matter lesions in the mild cognitive impairment stage of Alzheimer’s disease.

Background: The present study was designed to examine the association of circulating cholesterol with cognitive function in non-demented community aging adults. Methods: This was a cross-sectional study including 1754 Chinese adults aged 55-80 years. The association between serum cholesterol levels and cognitive function was examined. Participants were categorized into four groups according to the quartile of circulating TC (total cholesterol), High Density Lipoprotein Cholesterol (HDL-c), Low Density Lipoprotein Cholesterol (LDL-c) levels and HDLc/ LDL-c ratio. The difference in cognitive performance among the groups was compared. Logistic regression model was used to determine the association of circulating cholesterol level with the risk of Mild Cognitive Impairment (MCI). Results: Mild increase of serum LDL-c level correlated with better visual and executive, language, memory and delayed recall abilities. Higher circulating TC and HDL-c levels were found to be associated with poorer cognitive function, especially in aging female subjects. Higher circulating TC, HDL-c and HDL/LDL ratio indicated an increased risk of MCI, especially in female subjects. Conclusion: Slight increase in circulating LDL-c level might benefit cognitive function in aging adults. However, higher circulating TC and HDL-c levels might indicate a decline of cognitive function, especially in aging female subjects.

Background: Alzheimer’s Disease (AD) and Type 2 Diabetes Mellitus (T2DM) have an increased incidence in modern society. Although increasing evidence has supported the close linkage between these two disorders, the inter-relational mechanisms remain to be fully elucidated. Objective: The primary purpose of this study is to explore the shared pathophysiological mechanisms of AD and T2DM. Methods: We downloaded the microarray data of AD and T2DM from the Gene Expression Omnibus (GEO) database and constructed co-expression networks by Weighted Gene Co-Expression Network Analysis (WGCNA) to identify gene network modules related to AD and T2DM. Then, Gene Ontology (GO) and pathway enrichment analysis were performed on the common genes existing in the AD and T2DM related modules by clusterProfiler and DOSE package. Finally, we utilized the STRING database to construct the protein-protein interaction network and found out the hub genes in the network. Results: Our findings indicated that seven and four modules were the most significant with AD and T2DM, respectively. Functional enrichment analysis showed that AD and T2DM common genes were mainly enriched in signaling pathways such as circadian entrainment, phagosome, glutathione metabolism and synaptic vesicle cycle. Protein-protein interaction network construction identified 10 hub genes (CALM1, LRRK2, RBX1, SLC6A1, TXN, SNRPF, GJA1, VWF, LPL, AGT) in AD and T2DM shared genes. Conclusion: Our work identified common pathogenesis of AD and T2DM. These shared pathways might provide a novel idea for further mechanistic studies and hub genes that may serve as novel therapeutic targets for diagnosis and treatment of AD and T2DM.

Background: The accumulation and aggregation of Aβ as amyloid plaques, the hallmark pathology of the Alzheimer's disease, has been found in other neurological disorders, such as traumatic brain injury. The axonal injury may contribute to the formation of Aβ plaques. Studies to date have focused on the brain, with no investigations of spinal cord, although brain and cord share the same cellular components. Objective: We utilized a spinal cord transection model to examine whether spinal cord injury acutely induced the onset or promote the progression of Aβ plaque 3 days after injury in TgCRND8 transgenic model of AD. Methods: Spinal cord transection was performed in TgCRND8 mice and its littermate control wild type mice at the age of 3 and 20 months. Immunohistochemical reactions/ELISA assay were used to determine the extent of axonal damage and occurrence/alteration of Aβ plaques or levels of Aβ at different ages in the spinal cord of TgCRND8 mice. Results: After injury, widespread axonal pathology indicated by intra-axonal co-accumulations of APP and its product, Aβ, was observed in perilesional region of the spinal cord in the TgCRND8 mice at the age of 3 and 20 months, as compared to age-matched non-TgCRND8 mice. However, no Aβ plaques were found in the TgCRND8 mice at the age of 3 months. The 20-month-old TgCRND8 mice with established amyloidosis in spinal cord had a reduction rather than increase in plaque burden at the lesion site compared to the tissue adjacent to the injured area and corresponding area in sham mice following spinal cord transection. The lesion site of spinal cord area was occupied by CD68 positive macrophages/ activated microglia in injured mice compared to sham animals. These results indicate that spinal cord injury does not induce the acute onset and progression of Aβ plaque deposition in the spinal cord of TgCRND8 mice. Conversely, it induces the regression of Aβ plaque deposition in TgCRND8 mice. Conclusion: The findings underscore the dependence of traumatic axonal injury in governing acute Aβ plaque formation and provide evidence that Aβ plaque pathology may not play a role in secondary injury cascades following spinal cord injury.