Journal of Alzheimer's Disease - Volume 94, issue 2

Authors: Qaisar, Rizwan | Karim, Asima | Iqbal, M. Shahid | Alkahtani, Shaea A. | Ahmad, Firdos | Kamli, Hossam

Article Type: Research Article

Abstract: Background: Hypertension and skeletal muscle decline are common findings in patients with Alzheimer’s disease (AD). Angiotensin-converting enzyme (ACE) inhibitors preserve skeletal muscle and physical capacity; however, the driving mechanisms are poorly understood. Objective: We investigated the effects of ACE inhibitors on the neuromuscular junction (NMJ) with relevance to skeletal muscle and physical capacity in AD patients and age-matched controls. Methods: We evaluated controls (n  = 59) and three groups of AD patients, including normotensive (n  = 51) and patients with hypertension taking ACE inhibitors (n  = 53) or other anti-hypertensive medications (n  = 49) at baseline and one year later. …We measure plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation, handgrip strength (HGS), and Short Physical Performance Battery (SPPB) as markers of physical capacity. Results: At baseline AD patients demonstrated lower HGS and SPPB scores and higher CAF22 levels than controls, irrespective of the hypertension status (all p  < 0.05). The use of ACE inhibitors was associated with higher HGS and relative maintenance of SPPB scores, gait speed, and plasma CAF22 levels. Conversely, other anti-hypertensive medications were associated with an unaltered HGS, reduced SPPB scores and elevated plasma CAF22 levels (both p  < 0.05). We also found dynamic associations of CAF22 with HGS, gait speed, and SPPB in AD patients taking ACE inhibitors (all p  < 0.05). These changes were associated with reduced oxidative stress in AD patients taking ACE inhibitors (p  < 0.05). Conclusion: Altogether, ACE inhibitors are associated with higher HGS, preserved physical capacity, and the prevention of NMJ degradation in hypertensive AD patients. Show more

Keywords: ACE inhibitors, Alzheimer’s disease, CAF22, handgrip strength, hypertension, short physical performance battery

DOI: 10.3233/JAD-230201

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 641-650, 2023

Authors: Zhu, Jing | Ji, Xin | Shi, Ruirui | He, Tianqi | Chen, Su-ying | Cong, Ruochen | He, Bosheng | Liu, Su | Xu, Hui | Gu, Jin-hua

Article Type: Research Article

Abstract: Background: At least one-third of Alzheimer’s disease (AD) patients have cerebrovascular abnormalities, micro- and macro-infarctions, and ischemic white matter alterations. Stroke prognosis impacts AD development due to vascular disease. Hyperglycemia can readily produce vascular lesions and atherosclerosis, increasing the risk of cerebral ischemia. Our previous research has demonstrated that protein O-GlcNAcylation, a dynamic and reversible post-translational modification, provides protection against ischemic stroke. However, the role of O-GlcNAcylation in the exacerbation of cerebral ischemia injury due to hyperglycemia remains to be elucidated. Objective: In this study, we explored the role and underlying mechanism of protein O-GlcNAcylation in the exacerbation …of cerebral ischemia injury caused by hyperglycemia. Methods: High glucose-cultured brain microvascular endothelial (bEnd3) cells were injured by oxygen-glucose deprivation. Cell viability was used as the assay result. Stroke outcomes and hemorrhagic transformation incidence were assessed in mice after middle cerebral artery occlusion under high glucose and streptozotocin-induced hyperglycemic conditions. Western blot estimated that O-GlcNAcylation influenced apoptosis levels in vitro and in vivo . Results: In in vitro analyses showed that Thiamet-G induces upregulation of protein O-GlcNAcylation, which attenuates oxygen-glucose deprivation/R-induce injury in bEnd3 cells cultured under normal glucose conditions, while aggravated it under high glucose conditions. In in vivo analyses, Thiamet-G exacerbated cerebral ischemic injury and induced hemorrhagic transformation, accompanied by increased apoptosis. While blocking protein O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine alleviated cerebral injury of ischemic stroke in different hyperglycemic mice. Conclusion: Overall, our study highlights the crucial role of O-GlcNAcylation in exacerbating cerebral ischemia injury under conditions of hyperglycemia. O-GlcNAcylation could potentially serve as a therapeutic target for ischemic stroke associated with AD. Show more

Keywords: Alzheimer’s disease, apoptosis, cerebral ischemia-reperfusion, hemorrhagic transformation, hyperglycemia, O-GlcNAcylation

DOI: 10.3233/JAD-230264

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 651-668, 2023

Authors: Melchior, Florian | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Assessing dementia knowledge is critical for developing and improving effective interventions. There are many different tools to assess dementia knowledge, but only one has been validated in German so far. Objective: To validate two tools for assessing dementia knowledge – the Dementia Knowledge Assessment Scale (DKAS-D) and the Knowledge in Dementia Scale (KIDE-D) for the German general population – and compare their psychometric properties with the Dementia Knowledge Assessment Tool 2 (DKAT2-D). Methods: A convenience sample of 272 participants completed online surveys. Analyses included internal consistency, structural validity, construct validity through the known-groups method, retest-reliability …with a subgroup of n  = 88, and floor and ceiling effects. This study used the STROBE checklist. Results: Internal consistency was acceptable for DKAT2-D (α = 0.780), very good for DKAS-D (α = 0.873), and poor for KIDE-D (α = 0.506). Construct validity was confirmed for all questionnaires. Retest-reliability was good for DKAT2-D (0.886; 0.825–0.926) and KIDE-D (0.813; 0.714–0.878), while it was great for DKAS-D (0.928; 0.891–0.953). Trends toward ceiling effects were observed for DKAT2-D and KIDE-D but not for DKAS-D. The principal component analysis did not reveal a coherent structure for DKAT2-D or KIDE-D, while the confirmatory factor analysis proposed the removal of 5 items for DKAS-D, resulting in the shortened DKAS20-D, which had nearly identical properties. Conclusion: Both DKAS-D and its shortened version, DKAS20-D, are reliable instruments for evaluating programs intended for the general population, as they were found to be convincing in all aspects. Show more

Keywords: Alzheimer’s disease, confirmatory factor analysis, dementia, knowledge, scale psychometrics, reliability, validity

DOI: 10.3233/JAD-230303

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 669-684, 2023

Authors: Nakamura, Yu | Omori, Takumi | Kim, Rei | Nishiyama, Kenichi | Kikuchi, Takashi | Ishikawa, Ichiro | Aoki, Hiroshi

Article Type: Research Article

Abstract: Background: In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer’s disease. Objective: To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer’s disease; and to evaluate safety on switching from donepezil hydrochloride tablets. Methods: This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study. Results: …A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer’s Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events. Conclusion: Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets. Show more

Keywords: Alzheimer’s disease, dementia, donepezil, open-label, patch

DOI: 10.3233/JAD-230387

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 685-693, 2023

Authors: Edwards, Lauren | Thomas, Kelsey R. | Weigand, Alexandra J. | Edmonds, Emily C. | Clark, Alexandra L. | Walker, Kayla S. | Brenner, Einat K. | Nation, Daniel A. | Maillard, Pauline | Bondi, Mark W. | Bangen, Katherine J.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. Objective: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. Methods: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-β (Aβ) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aβ-PET. Results: Adjusting …for tau-PET, the quadratic effect of WMH interacted with Aβ-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aβ-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. Conclusion: Results suggest that cerebrovascular lesions act synergistically with Aβ to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , executive function, memory, tau, white matter hyperintensities

DOI: 10.3233/JAD-221209

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 695-707, 2023

Authors: Singh, Neha Atulkumar | Graff-Radford, Jonathan | Machulda, Mary M. | Pham, Nha Trang Thu | Schwarz, Christopher G. | Reid, Robert I. | Lowe, Val J. | Petersen, Ronald C. | Jack Jr, Clifford R. | Josephs, Keith A. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are associated with characteristic patterns of structural network degeneration. Little is known about longitudinal patterns of white matter tract degeneration in these phenotypes. Objective: To assess longitudinal patterns of white matter degeneration and identify phenotype specific cross-sectional and longitudinal diffusion tensor imaging (DTI) biomarkers in PCA and LPA. Methods: Twenty-five PCA, 22 LPA and 25 cognitively unimpaired (CU) individuals were recruited and underwent structural MRI that included a DTI sequence with a follow-up one year later. Cross-sectional and longitudinal mixed effects models were fit to assess …the effects of diagnosis on baseline and annualized change in regional DTI metrics. Discriminatory power was investigated using the area under the receiver operating characteristic curves (AUROC). Results: PCA and LPA showed overlapping white matter degeneration profiles predominantly in the left occipital and temporal lobes, the posterior thalamic radiation and sagittal stratum at baseline, as well as the parietal lobe longitudinally. PCA showed degeneration in the occipital and parietal white matter, cross-sectionally and longitudinally, compared to CU, while LPA showed greater degeneration in the temporal and inferior parietal white matter and the inferior fronto-occipital fasciculus cross-sectionally, and in parietal white matter longitudinally compared to CU. Cross-sectionally, integrity of the inferior occipital white matter was best able to differentiate PCA from LPA, with an AUROC of 0.82. Conclusion: These findings contribute to our understanding of white matter degeneration and support usage of DTI as a useful additional diagnostic biomarker for PCA and LPA. Show more

Keywords: Atypical Alzheimer’s disease, diffusion tensor imaging, logopenic progressive aphasia, posterior cortical atrophy, white matter

DOI: 10.3233/JAD-221217

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 709-725, 2023

Authors: Vanninen, Aleksi | Lukkarinen, Heikki | Kokkola, Tarja | Koivisto, Anne M. | Kokki, Merja | Musialowicz, Tadeusz | Hiltunen, Mikko | Zetterberg, Henrik | Leinonen, Ville | Herukka, Sanna-Kaisa | Rauramaa, Tuomas

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. Objective: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. Methods: Our cohort included 222 …iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n  = 33) and patients with diagnosed AD and no iNPH (n  = 39). *-31pt Results: Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aβ1 - 42 , 0.779*t-Tau, and 0.610*P-Tau181 ) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aβ1 - 42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). Conclusion: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181 /Aβ1 - 42 ratio showed some utility in the diagnosis of AD in iNPH patients. Show more

Keywords: Alzheimer’s disease, brain, cerebrospinal fluid, needle biopsy, normal pressure hydrocephalus

DOI: 10.3233/JAD-230144

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 727-736, 2023

Authors: Hu, Dongjie | Dong, Xiangjun | Wang, Qunxian | Liu, Mingjing | Luo, Shuyue | Meng, Zijun | Feng, Zijuan | Zhou, Weihui | Song, Weihong

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer’s disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4 ), also known as brain-specific protein 19 , is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. Objective: To explore the role of PCP4 in amyloid-β protein precursor (AβPP) processing in AD. Methods: In this study, we …investigated the role of PCP4 in AD progression in vitro and in vivo . In vitro experiments, we overexpressed PCP4 in human Swedish mutant AβPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. Results: We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AβPP. The production of amyloid-β protein (Aβ) was also promoted by PCP4. The upregulation of endogenous AβPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aβ deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. Conclusion: Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AβPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aβ pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, Down’s syndrome, Purkinje cell protein 4

DOI: 10.3233/JAD-230192

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 737-750, 2023

Authors: Weidung, Bodil | Josefsson, Maria | Lyttkens, Peter | Olsson, Jan | Elgh, Fredrik | Lind, Lars | Kilander, Lena | Lövheim, Hugo

Article Type: Research Article

Abstract: Background: Herpesviruses have been proposed to be involved in Alzheimer’s disease development as potentially modifiable pathology triggers. Objective: To investigate associations of serum antibodies for herpes simplex virus (HSV)-1 and cytomegalovirus (CMV) and anti-herpesvirus treatment with cognitive outcomes in relation to interactions with APOE ɛ4. Methods: The study included 849 participants in the population-based Prospective Investigation of the Vasculature in Uppsala Seniors study. Cognitive performance at the ages of 75 and 80 years was assessed using the Mini-Mental State Examination (MMSE), trail-making test (TMT) A and B, and 7-minute screening test (7MS). Results: …Anti– HSV-1 IgG positivity was associated cross-sectionally with worse performance on the MMSE, TMT-A, TMT-B, 7MS, enhanced free recall, and verbal fluency tests (p  = 0.016, p  = 0.016, p  < 0.001, p  = 0.001, p  = 0.033, and p  < 0.001, respectively), but not orientation or clock drawing. Cognitive scores did not decline over time and longitudinal changes did not differ according to HSV-1 positivity. Anti– CMV IgG positivity was not associated cross-sectionally with cognition, but TMT-B scores declined more in anti– CMV IgG carriers. Anti– HSV-1 IgG interacted with APOE ɛ4 in association with worse TMT-A and better enhanced cued recall. Anti– HSV IgM interacted with APOE ɛ4 and anti-herpesvirus treatment in association with worse TMT-A and clock drawing, respectively. Conclusion: These findings indicate that HSV-1 is linked to poorer cognition in cognitively healthy elderly adults, including impairments in executive function, memory, and expressive language. Cognitive performance did not decline over time, nor was longitudinal decline associated with HSV-1. Show more

Keywords: Aged 80 and over, Alzheimer’s disease, Apolipoproteins E, cognition disorders, cohort studies, cytomegalovirus, dementia, Herpes simplex, herpesvirus 1 human, neurocognitive disorders

DOI: 10.3233/JAD-221116

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 751-762, 2023

Authors: Wang, Jie | Wang, Mengjie | Ren, Shuhua | Huang, Lin | He, Kun | Li, Junpeng | Hua, Fengchun | Guan, Yihui | Guo, Qihao | Huang, Qi | Xie, Fang

Article Type: Research Article

Abstract: Background: Gender, APOE ɛ4 status and age have different effects on brain amyloid deposition in patients with mild cognitively impaired (MCI). Objective: To investigate the effect of gender×APOE ɛ4 status interaction on Aβ deposition in the brains of individuals with MCI in different age groups by PET scanning. Methods: 204 individuals with MCI were classified into younger or older groups based on whether they were under or over 65 years of age. APOE genotyping, structural MRI, amyloid PET scans, and neuropsychological tests were performed. The effect of gender×APOE ɛ4 status interaction on …Aβ deposition was assessed in different age groups. Results: APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the whole group. Females with MCI had more amyloid deposition in the medial temporal lobe than males in the whole cohort and younger group. Older individuals with MCI had higher amyloid deposition than younger individuals. In stratified analysis by age, female APOE ɛ4 carriers had significantly increased amyloid deposition compared to their male counterparts only in the medial temporal lobe in the younger group. Amyloid deposition was increased in female APOE ɛ4 carriers compared to noncarriers in the younger group, whereas higher amyloid deposition was observed in male APOE ɛ4 carriers in the older group. Conclusion: Women in the younger group with MCI who were APOE ɛ4 carriers had more amyloid deposition in the brain, while men in the older group with MCI who were APOE ɛ4 carriers had higher amyloid deposition. Show more

Keywords: Alzheimer’s disease, amyloid deposition, APOE, gender, mild cognitive impairment, PET

DOI: 10.3233/JAD-221166

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 763-775, 2023