Journal of Alzheimer's Disease - Volume 85, issue 3

Authors: Tadokoro, Koh | Yamashita, Toru | Sato, Junko | Omote, Yoshio | Takemoto, Mami | Morihara, Ryuta | Nishiura, Koichiro | Tani, Tomiko | Abe, Koji

Article Type: Research Article

Abstract: Background: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. Objective: To evaluate the therapeutic effect of makeup therapy. Methods: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n  = 16) or skin care plus makeup therapy (makeup therapy group, n  = 18) once every 2 weeks for 3 months were assessed. Results: Three months of makeup therapy significantly improved the Mini-Mental State …Examination (MMSE) score compared with control patients (* p  < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression (* p  < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r  = 0.43, * p  < 0.05). Conclusion: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software. Show more

Keywords: Artificial intelligence, dementia, facial appearance, makeup therapy

DOI: 10.3233/JAD-215385

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1189-1194, 2022

Authors: Fan, Fangcheng | Liu, Hua | Shi, Xiaojie | Ai, Yangwen | Liu, Qingshan | Cheng, Yong

Article Type: Research Article

Abstract: Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer’s disease (AD) are sparse. Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. Results: …Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, anti-Aβ agents, systematic review, umbrella review

DOI: 10.3233/JAD-215423

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1195-1204, 2022

Authors: Smith, C. Aaron | Smith, Haddon | Roberts, Lisa | Coward, Lori | Gorman, Gregory | Verma, Amrisha | Li, Qiuhong | Buford, Thomas W. | Carter, Christy S. | Jumbo-Lucioni, Patricia

Article Type: Research Article

Abstract: Background: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer’s disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Objective: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral …supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Methods: Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Results: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. Conclusion: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response. Show more

Keywords: Alzheimer’s disease, angiotensin (1-7), probiotic, Lactobacillus, tryptophan

DOI: 10.3233/JAD-210464

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1205-1217, 2022

Authors: Haverkamp, Rinske A. | Melis, René J.F. | Claassen, Jurgen A.H.R. | de Heus, Rianne A.A.

Article Type: Research Article

Abstract: Background: High day-to-day blood pressure variability (BPV) has been associated with an increased risk for cognitive decline and mortality in the general population. Whether BPV is associated with increased all-cause mortality in older people with cognitive impairment is unknown. Objective: To investigate the association between day-to-day home BPV and all-cause mortality in older patients attending a memory clinic. Methods: We included 279 patients attending a memory clinic, who measured home blood pressure (BP) for 7 consecutive days in the morning and evening. Within-subject BPV was defined as the variation independent of the mean (VIM). Time-to-death was …verified through the Dutch population registry. Cox proportional hazard regression was used. Separate analyses were performed for morning-to-morning and evening-to-evening BPV. Results: Mean age was 73±9 years, dementia and mild cognitive impairment were diagnosed in 35% and 34% respectively, and mean home BP was 139/79 mmHg. After a mean follow-up of 3.2 years, 52 patients had died. Neither day-to-day systolic nor diastolic VIM were associated with mortality (adjusted hazard ratio [HR] systolic VIM: 0.99, 95% -CI 0.92–1.06, p  = 0.770, HR diastolic VIM: 1.04, 95% -CI 0.93–1.17, p  = 0.517). When morning and evening measurements were analyzed separately, systolic morning-to-morning VIM was associated with mortality (adjusted HR: 1.09, 95% -CI 1.01–1.18, p  = 0.033). Conclusion: In this study, day-to-day BPV was not associated with all-cause mortality in patients attending a memory clinic. However, morning-to-morning BPV was. Due to the short assessment window, there is still a lack of clarity; hence future research is warranted to clarify the role of all BPV components in aging. Show more

Keywords: Alzheimer, cardiovascular risk management, dementia, geriatrics, home blood pressure monitoring, hypertension

DOI: 10.3233/JAD-215002

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1219-1231, 2022

Authors: Wang, Gang | Zhou, Wenju | Kong, Deping | Qu, Zongshuai | Ba, Maowen | Hao, Jinguang | Yao, Tao | Dong, Qunxi | Su, Yi | Reiman, Eric M. | Caselli, Richard J. | Chen, Kewei | Wang, Yalin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. Objective: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N  = 30), heterozygotes (HT, N  = 49) and …non-carriers (NC, N  = 61). Methods: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. Results: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. Conclusion: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals. Show more

Keywords: Effect size, magnetic resonance imaging, permutation t-test, radial distance, regions-of-interest, subspace decomposition

DOI: 10.3233/JAD-215149

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1233-1250, 2022

Authors: Chaudhary, Shefali | Zhornitsky, Simon | Chao, Herta H. | van Dyck, Christopher H. | Li, Chiang-Shan R.

Article Type: Research Article

Abstract: Background: Affecting nearly half of the patients with Alzheimer’s disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. Objective: To identify neuroanatomical correlates of AD-associated apathy. Methods: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 …healthy controls assessed with the Apathy Evaluation Scale. Results: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p  < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. Conclusion: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy. Show more

Keywords: Activation likelihood estimation, Alzheimer-type dementia, Alzheimer’s disease, emotional apathy, gray matter, inferior frontal gyrus, meta-analysis, middle temporal gyrus, striatum

DOI: 10.3233/JAD-215316

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1251-1265, 2022

Authors: Teipel, Stefan J. | Dyrba, Martin | Ballarini, Tommaso | Brosseron, Frederic | Bruno, Davide | Buerger, Katharina | Cosma, Nicoleta-Carmen | Dechent, Peter | Dobisch, Laura | Düzel, Emrah | Ewers, Michael | Fliessbach, Klaus | Haynes, John D. | Janowitz, Daniel | Kilimann, Ingo | Laske, Christoph | Maier, Franziska | Metzger, Coraline D. | Munk, Matthias H. | Peters, Oliver | Pomara, Nunzio | Preis, Lukas | Priller, Josef | Ramírez, Alfredo | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Schott, Björn H. | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Jessen, Frank | Heneka, Michael T.

Article Type: Research Article

Abstract: Background: Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of …cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42 /ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cholinergic system, neuroinflammation, MRI, plasma, sTREM2

DOI: 10.3233/JAD-215196

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1267-1282, 2022

Authors: von Linstow, Christian Ulrich | Waider, Jonas | Bergh, Marianne Skov-Skov | Anzalone, Marco | Madsen, Cecilie | Nicolau, Aina Battle | Wirenfeldt, Martin | Lesch, Klaus-Peter | Finsen, Bente

Article Type: Research Article

Abstract: Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe /presenilin 1 (PS1) ΔE9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/– , …and wildtype mice. Survival and weight were recorded. Levels of Aβ42/40/38 , soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ42 and Aβ40 in neocortex and hippocampus, and with only mild changes of soluble Aβ42 /Aβ40 . However, sAβPPα and sAβPPβ in hippocampus and Aβ38 and Aβ40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, APP/PS1, AβPP processing, cerebral amyloidosis, cerebrospinal fluid, 5-HT, neuroinflammation, tryptophan hydroxylase 2

DOI: 10.3233/JAD-210581

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1283-1300, 2022

Authors: Malone, Joseph | Jung, Jeah | Tran, Linh | Zhao, Chen

Article Type: Research Article

Abstract: Background: Periodontal disease and hepatitis C virus (HCV) represent chronic infectious states that are common in elderly adults. Both conditions have independently been associated with an increased risk for dementia. Chronic infections are thought to lead to neurodegenerative changes in the central nervous system possibly by promoting a proinflammatory state. This is consistent with growing literature on the etiological role of infections in dementia. Few studies have previously evaluated the association of periodontal disease with dementia in HCV patients. Objective: To examine whether periodontal disease increases the risk of developing Alzheimer’s disease and related dementias (ADRD) among HCV …patients in Medicare claims data. Methods: We used Medicare claims data for HCV patients to assess the incidence rate of ADRD with and without exposure to periodontal disease between 2014 and 2017. Cox multivariate regression was used to estimate the association between periodontal disease and development of ADRD, controlling for age, gender, race, ZIP-level income and education, and medical comorbidities. Results: Of 439,760 HCV patients, the incidence rate of ADRD was higher in patients with periodontal diseases compared to those without (10.84% versus 9.26%, p  < 0.001), and those with periodontal disease developed ADRD earlier compared to those without periodontal disease (13.99 versus 21.60 months, p  < 0.001). The hazard of developing ADRD was 1.35 times higher in those with periodontal disease (95% CI, 1.30 to 1.40, p  < 0.001) after adjusting for all covariates, including age. Conclusion: Periodontal disease increased the risk of developing ADRD among HCV patients in a national Medicare claims dataset. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementias, dementia, Hepatitis C virus, infection, periodontal disease

DOI: 10.3233/JAD-210666

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1301-1308, 2022

Authors: Salami, Alireza | Adolfsson, Rolf | Andersson, Micael | Blennow, Kaj | Lundquist, Anders | Adolfsson, Annelie Nordin | Schöll, Michael | Zetterberg, Henrik | Nyberg, Lars

Article Type: Research Article

Abstract: Background: The Apolipoprotein E (APOE ) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer’s disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers. Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up …to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity. Methods: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding. Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity. Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning. Show more

Keywords: Alzheimer’s disease, APOE, fMRI, hippocampus, longitudinal, magnetic resonance imaging, p-tau181, phosphorylated tau, population-based

DOI: 10.3233/JAD-210673

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1309-1320, 2022

Authors: Sun, Hao-Lun | Zhou, Fa-Ying | Chen, Dong-Wan | Tan, Cheng-Rong | Zeng, Gui-Hua | Liu, Yu-Hui | Wang, Jun | Bu, Xian-Le | Wang, Yan-Jiang | Li, Hui-Yun | Jin, Wang-Sheng

Article Type: Research Article

Abstract: Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD …patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain. Show more

Keywords: Alzheimer’s disease, monocytes, pathogenesis, tau

DOI: 10.3233/JAD-210692

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1321-1328, 2022

Authors: Chen, Jiu | Chen, Rong | Xue, Chen | Qi, Wenzhang | Hu, Guanjie | Xu, Wenwen | Chen, Shanshan | Rao, Jiang | Zhang, Fuquan | Zhang, Xiangrong

Article Type: Research Article

Abstract: Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated …with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, episodic memory, functional connectivity, grey matter, hippocampalsubregion, pattern classification, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210661

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1329-1342, 2022

Authors: Tropea, Maria Rosaria | Sanfilippo, Giulia | Giannino, Federico | Davì, Valentina | Gulisano, Walter | Puzzo, Daniela

Article Type: Research Article

Abstract: Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables. Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg. Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based …on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models. Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation. Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases. Show more

Keywords: Alzheimer’s mice, exploration, object preference, object recognition task

DOI: 10.3233/JAD-215209

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1343-1356, 2022

Authors: Kwak, Seyul | Oh, Dae Jong | Jeon, Yeong-Ju | Oh, Da Young | Park, Su Mi | Kim, Hairin | Lee, Jun-Young

Article Type: Research Article

Abstract: Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status. Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied. Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n  = 285), mild cognitive impairment (n  = 1,057), and Alzheimer’s …disease (n  = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes. Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n  > 500), especially when the model training is allowed to exploit complex patterns of the dataset. Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia. Show more

Keywords: Dementia, functional status, machine learning, neuropsychological tests

DOI: 10.3233/JAD-215244

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1357-1372, 2022

Authors: Yuen, Sze Chung | Lee, Simon Ming-Yuen | Leung, Siu-wai

Article Type: Research Article

Abstract: Background: Neuronal cell cycle re-entry (CCR) is a mechanism, along with amyloid-β (Aβ) oligomers and hyperphosphorylated tau proteins, contributing to toxicity in Alzheimer’s disease (AD). Objective: This study aimed to examine the putative factors in CCR based on evidence corroboration by combining meta-analysis and co-expression analysis of omic data. Methods: The differentially expressed genes (DEGs) and CCR-related modules were obtained through the differential analysis and co-expression of transcriptomic data, respectively. Differentially expressed microRNAs (DEmiRNAs) were extracted from the differential miRNA expression studies. The dysregulations of DEGs and DEmiRNAs as binary outcomes were independently …analyzed by meta-analysis based on a random-effects model. The CCR-related modules were mapped to human protein-protein interaction databases to construct a network. The importance score of each node within the network was determined by the PageRank algorithm, and nodes that fit the pre-defined criteria were treated as putative CCR-related factors. Results: The meta-analysis identified 18,261 DEGs and 36 DEmiRNAs, including genes in the ubiquitination proteasome system, mitochondrial homeostasis, and CCR, and miRNAs associated with AD pathologies. The co-expression analysis identified 156 CCR-related modules to construct a protein-protein interaction network. Five genes, UBC , ESR1 , EGFR , CUL3 , and KRAS , were selected as putative CCR-related factors. Their functions suggested that the combined effects of cellular dyshomeostasis and receptors mediating Aβ toxicity from impaired ubiquitination proteasome system are involved in CCR. Conclusion: This study identified five genes as putative factors and revealed the significance of cellular dyshomeostasis in the CCR of AD. Show more

Keywords: Alzheimer’s disease, cell cycle re-entry, co-expression analysis, meta-analysis, pagerank algorithm

DOI: 10.3233/JAD-215349

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1373-1398, 2022