Journal of Alzheimer's Disease Reports - Volume 6, issue 1

Authors: Kim, Eun-Joo | Na, Duk L. | Kim, Hee-Jin | Park, Kyung Won | Lee, Jae-Hong | Roh, Jee Hoon | Kwon, Jay C. | Yoon, Soo Jin | Jung, Na-Yeon | Jeong, Jee Hyang | Jang, Jae-Won | Kim, Hee-Jin | Park, Kee Hyung | Choi, Seong Hye | Kim, SangYun | Park, Young Ho | Kim, Byeong C. | Youn, Young Chul | Ki, Chang-Seok | Kim, Seung Hyun | Seo, Sang Won | Kim, Young-Eun

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) syndrome is a genetically heterogeneous group of diseases. Pathogenic variants in the chromosome 9 open reading frame 72 (C9orf72 ), microtubule-associated protein tau (MAPT ), and progranulin (GRN ) genes are mainly associated with genetic FTD in Caucasian populations. Objective: To understand the genetic background of Korean patients with FTD syndrome. Methods: We searched for pathogenic variants of 52 genes related to FTD, amyotrophic lateral sclerosis, familial Alzheimer’s disease, and other dementias, and hexanucleotide repeats of the C9orf72 gene in 72 Korean patients with FTD using whole exome sequencing and the …repeat-primed polymerase chain reaction, respectively. Results: One likely pathogenic variant, p.G706R of MAPT , in a patient with behavioral variant FTD (bvFTD) and 13 variants of uncertain significance (VUSs) in nine patients with FTD were identified. Of these VUSs, M232R of the PRNP gene, whose role in pathogenicity is controversial, was also found in two patients with bvFTD. Conclusions: These results indicate that known pathogenic variants of the three main FTD genes (MAPT , GRN , and C9orf72 ) in Western countries are rare in Korean FTD patients. Show more

Keywords: Frontotemporal dementia, MAPT, next-generation sequencing, PRNP

DOI: 10.3233/ADR-220030

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 651-662, 2022

Authors: Taslima, Ferdous | Abdelhamid, Mona | Zhou, Chunyu | Chen, Yuxin | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: Tooth loss is closely associated with Alzheimer’s disease (AD). Previously, we reported that tooth loss induced memory impairment in amyloid precursor protein knock-in mice by decreasing neuronal activity and synaptic protein levels and increasing glial activation, neuroinflammation, and pyramidal neuronal cell loss without altering amyloid-β levels in the hippocampus. However, the effects of tooth loss in young wild-type mice have not been explored yet. Objective: We investigated the effects of tooth loss on memory impairment, neuronal activity, synaptic protein levels, glial activation, and pyramidal neuronal cell loss in young wild-type mice. Methods: Two-month-old wild-type mice …were randomly divided into control and tooth loss groups. In the tooth loss group, maxillary molar teeth on both sides were extracted, whereas no teeth were extracted in the control group. Two months after tooth extraction, we performed a novel object recognition test to evaluate memory function. Glial activation, neuronal activity, synaptic protein levels, and the number of pyramidal neurons were evaluated using immunofluorescence staining, immunohistochemistry, and western blotting. Results: The tooth loss group exhibited memory impairment and decreased neuronal activity and the levels of synaptic proteins in both the hippocampus and cortex. Moreover, tooth loss increased the activation of phosphorylated c-Jun N-terminal kinase (JNK), heat shock protein 90 (HSP90), and glial activation and reduced the number of pyramidal neurons in the hippocampus. Conclusion: Tooth loss in the young wild-type mice will attenuate neuronal activity, decrease synaptic protein levels, and induce pyramidal neuronal loss, and eventually lead to memory impairment. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, glial activation, neuronal cell loss, tooth loss, wild-type mice

DOI: 10.3233/ADR-220053

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 663-675, 2022

Authors: Vallés-Saiz, Laura | Ruiz-Gabarre, Daniel | García-Escudero, Vega | Perry, George | Avila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: Background: An increase in tau protein is believed to be necessary for tau aggregation. However, whether this is due to increased expression of the endogenous tau promoter or protein accumulation due to proteostasis failure remains uncertain. Objective: To analyze the expression of GFP protein under endogenous tau promoter across different ages and within different brain areas. Methods: We have measured direct expression of Mapt gene promotor by western blot and immunofluorescence, by means of a commercial tau knock-out mice generated by integrating GFP-encoding cDNA into exon 1 of the Mapt gene. Besides, we have …analyzed the MAPT gene expression in human samples. Results: Mapt expression is similar in the cortex, hippocampus, and cerebellum in mice and in human samples although some differences exist between dentate gyrus and CA1 hippocampal areas in mice. Besides, we have analyzed the murine Mapt gene expression during aging (at 2, 6, 12, and 18 moths) and no differences in endogenous tau promoter expression were observed. Conclusion: Our results suggest that Mapt promoter activity is similar in the brain areas studied and, therefore, tau accumulation due to aging is likely due to proteostasis failure rather than occurring at the transcriptional level. Show more

Keywords: Aging, neurodegeneration, promotor expression, tau

DOI: 10.3233/ADR-220051

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 677-684, 2022

Authors: See, Yi Na | Khor, Pee Fen | Koh, Hui Ying | Leung, Phuong | Del-Pino-Casado, Rafael | Orgeta, Vasiliki

Article Type: Systematic Review

Abstract: Background: Anger is commonly experienced by family caregivers of people living with dementia yet its effect on caregivers’ physical health remains unknown. Objective: The primary aim of this study was to systematically review current evidence on the effects of anger and hostility on caregivers’ physical health. Methods: We searched Medline, EMBASE, PubMed, and PsycINFO up to January 2022. Two review authors independently extracted data on study characteristics, study quality, and effect sizes of associations of anger and hostility with caregiver health outcomes. Results: We found eight studies examining the effects of anger and hostility …on caregivers’ physical health reporting on a total of 937 participants, of which four were cross-sectional and four were longitudinal. Overall findings indicated that higher levels of anger and hostility exerted a negative effect on caregivers’ physical health. Higher anger control was longitudinally associated with increased weight gain (β = 1.13, p  < 0.001), whereas higher anger out predicted higher glucose dysregulation at long-term follow-up (r  = 0.27, p  < 0.05). Higher levels of caregiver hostility were associated with increased risk of chronic low-grade inflammation long-term (r  = 0.18, p  < 0.05), and increased risk of cognitive decline over time (r  = –0.16, p  < 0.05). Conclusion: Our review provides the first systematic synthesis of the evidence demonstrating the harmful effects of anger and hostility on dementia caregivers’ health and highlights the need for preventative interventions to support family caregivers experiencing high levels of anger. Show more

Keywords: Anger, dementia caregivers, disease, hostility, physical health

DOI: 10.3233/ADR-220040

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 685-698, 2022

Authors: Kandiah, Nagaendran | Choi, Seong Hye | Hu, Chaur-Jong | Ishii, Kenji | Kasuga, Kensaku | Mok, Vincent C.T.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) poses a substantial healthcare burden in the rapidly aging Asian population. Early diagnosis of AD, by means of biomarkers, can lead to interventions that might alter the course of the disease. The amyloid, tau, and neurodegeneration (AT[N]) framework, which classifies biomarkers by their core pathophysiological features, is a biomarker measure of amyloid plaques and neurofibrillary tangles. Our current AD biomarker armamentarium, comprising neuroimaging biomarkers and cerebrospinal fluid biomarkers, while clinically useful, may be invasive and expensive and hence not readily available to patients. Several studies have also investigated the use of blood-based measures of established core markers …for detection of AD, such as amyloid-β and phosphorylated tau. Furthermore, novel non-invasive peripheral biomarkers and digital biomarkers could potentially expand access to early AD diagnosis to patients in Asia. Despite the multiplicity of established and potential biomarkers in AD, a regional framework for their optimal use to guide early AD diagnosis remains lacking. A group of experts from five regions in Asia gathered at a meeting in March 2021 to review the current evidence on biomarkers in AD diagnosis and discuss best practice around their use, with the goal of developing practical guidance that can be implemented easily by clinicians in Asia to support the early diagnosis of AD. This article summarizes recent key evidence on AD biomarkers and consolidates the experts’ insights into the current and future use of these biomarkers for the screening and early diagnosis of AD in Asia. Show more

Keywords: Alzheimer’s disease, Asia, AT(N), biomarkers, dementia, early diagnosis

DOI: 10.3233/ADR-220059

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 699-710, 2022

Authors: Weigert, Hannah | Stuckenschneider, Tim | Pickert, Lena | Rossi, Andrea | Meyer, Anna M. | Nelles, Gereon | Schulz, Ralf-Joachim | Stahl, Wilhelm | Schneider, Stefan | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Preventive lifestyle strategies have shown promise to slow down or prevent age-related cognitive decline. However, evidence on the reciprocal longitudinal relationships between nutrition biomarkers and cognitive and physical performance is lacking. Studying nutritional, cognitive, and physical profiles over time may help to overcome this knowledge gap. Objective: To investigate the relationship of plasma levels of the robust nutritional- and antioxidant defense-related biomarkers carotenoids and tocopherols with both indicators of cognitive and physical performance in persons with mild cognitive impairment (MCI) participating in a structured exercise program. Methods: Data from 40 participants with MCI of the …NeuroExercise study were analyzed. Participants had undergone a blood withdrawal for the analysis of plasma concentrations of six carotenoids, two tocopherols and retinol prior to and after one-year of structured exercise. All participants had undergone a broad spectrum of cognitive and physical performance tests. Results: Significant associations between lipophilic micronutrients and cognitive/physical measures were observed that were previously found to play a role in cognitive and physical frailty. In particular, lutein, zeaxanthin, and lycopene are confirmed as robust, reliable, and stable indicators of nutritional defense. Importantly, these micronutrients were associated with cognitive measures prior to the physical training program and to a more prominent extent with indicators of motoric function after the physical exercise program. Conclusion: Specific profiles of lipophilic micronutrients are associated to cognitive performance measures and, especially after a structured exercise program, to indicators of physical performance. Show more

Keywords: Carotenoids, cognitive performance, micronutrients, mild cognitive impairment, neuropsychological tests, nutrition, physical activity

DOI: 10.3233/ADR-220039

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 711-722, 2022

Authors: Velázquez, Esther | Le Baut Ayuso, Yannick | Blázquez, Enrique | Ruiz-Albusac, Juan Miguel

Article Type: Research Article

Abstract: Background: Glucagon-like peptide-2 (GLP-2) is an intestinal trophic factor that induces astrocyte proliferation through its own receptor (GLP-2R), but the control of its expression is not well known. Objective: To study the effects of glucose and of different mitogenic agents on the control of GLP-2R expression in cultured rat astrocytes. Methods: GLP-2R mRNA content was measured by quantitative RT-PCR. Results: GLP-2R expression was higher in proliferating than in resting cells. The expression was dependent of glucose concentration both in the absence and in the presence of GLP-2. In the presence of a high glucose …concentration, GLP-2, PDGF, and PDGF plus GLP-2 presented opposite effects depending on the incubation time. However, insulin, IGF-1, and EGF alone, and plus GLP-2 had no effect. IGF-2, but not IGF-2 plus GLP-2, increased the expression. On the contrary, NGF decreased the GLP-2R expression, but NGF plus GLP-2 increased it even until values similar to those obtained with GLP-2 alone. Interestingly, in the presence of a low glucose concentration, leptin and NPY produced a significant reduction of GLP-2R expression. Conclusion: Astrocytes are distributed throughout the brain, where GLP-2 appears to have important functions. Since these cells express the GLP-2R, the results of this study could be considered of interest to advance the knowledge of the role of GLP-2 signaling in the CNS, which should lead a better understanding of the events that occur under normal and pathophysiological conditions. Show more

Keywords: Astrocytes, GLP-2, GLP-2 receptor, glucose, growth factors, insulin, leptin, NPY

DOI: 10.3233/ADR-220043

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 723-732, 2022

Authors: Arthur, Paul | Li, Chih-Ying

Article Type: Short Communication

Abstract: Persons living with dementia and their caregivers are among society’s most vulnerable, a condition exacerbated by the COVID-19 pandemic. This national survey was conducted with dementia caregivers in the US. Primary outcomes targeted pandemic-related changes in cognitive, behavioral, and motors systems. 113 dementia caregivers from 30 US states completed the survey. The impact of the COVID-19 pandemic on persons living with dementia and their caregivers is substantial in comparison to society at large. A marked public health and preventative role signals opportunity for practitioners to fill the void and prepare for future public health emergencies.

Keywords: Alzheimer’s disease, behaviors, caregiving, COVID-19, dementia, neuropsychiatric symptoms, pandemic, public health emergency

DOI: 10.3233/ADR-220085

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 733-737, 2022

Authors: Santiago-Mujika, Estibaliz | Luthi-Carter, Ruth | Giorgini, Flaviano | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Vascular dementia (VaD) and Alzheimer’s disease (AD) are the two most common forms of dementia. Although these two types of dementia have different etiologies, they share some similarities in their pathophysiology, such as neuronal loss and decreased levels of tau protein. We hypothesize that these can have an impact upon the molecular changes in tubulin, precede the neuronal cell loss, and lead to changes in cytoskeletal associated proteins, as documented in both VaD and AD. Objective: We characterized different isotypes of tubulin together with their posttranslational modifications, as well as several microtubule associated proteins (MAPs), such as …tau protein, MAP2 and MAP6, all together known as the tubulin code. Methods: We performed western blotting in human brain homogenates of controls and AD and VaD subjects. Results: We report that the levels of different tubulin isotypes differ depending on the dementia type and the brain area being studied: whereas α-tubulin is increased in the temporal lobe of VaD patients, it is decreased in the frontal lobe of AD patients. In VaD patients, the frontal lobe had a decrease in tyrosinated tubulin, which was accompanied by a decrease in tau protein and a tendency for lower levels of MAP2. Conclusion: Our findings highlight distinct changes in the tubulin code in VaD and AD, suggesting a therapeutic opportunity for different dementia subtypes in the future. Show more

Keywords: Alzheimer’s disease, human brain samples, posttranslational modifications, tubulin, vascular dementia

DOI: 10.3233/ADR-220068

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 739-748, 2022

Authors: Mozdbar, Sima | Petersen, Melissa | Zhang, Fan | Johnson, Leigh | Tolman, Alex | Nyalakonda, Ramyashree | Gutierrez, Alejandra | O’Bryant, Sid

Article Type: Research Article

Abstract: Background: Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer’s disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. Objective: This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting. Methods: Participants were recruited from Alzheimer’s Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus …imaging was performed. Results: Data were examined on n  = 91 participants. The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer, and the inferior quadrant of the macular retinal nerve fiber layer. Conclusion: The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, optical coherence tomography, retinal biomarkers

DOI: 10.3233/ADR-220070

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 749-755, 2022