Journal of Alzheimer's Disease - Volume 76, issue 2

Authors: Lv, Ling-Li | Liu, Bo | Liu, Jing | Li, Li-Sheng | Jin, Feng | Xu, Yun-Yan | Wu, Qin | Liu, Jie | Shi, Jing-Shan

Article Type: Research Article

Abstract: Background: Dendrobium nobile is a well-known traditional Chinese herbal medicine used for age-related diseases. Dendrobium nobile Lindl. alkaloid (DNLA) is the active ingredient to improve learning and memory deficits in laboratory animals. Objective: The aim of the present study was to examine the anti-aging effects of long-term administration of DNLA and metformin during the aging process in senescence-accelerated mouse-prone 8 (SAMP8) mice. Methods: SAMP8 mice were orally given DNLA (20 and 40 mg/kg) or metformin (80 mg/kg) starting at 6 months of age until 12 months of age. Age-matched SAMR1 mice were used as controls. DNLA …and metformin treatments ameliorated behavioral deficits of 12-month-old SAMP8 mice, as determined by Rotarod, Y-maze, and Open-field tests. Results: DNLA and metformin treatments prevented brain atrophy and improved morphological changes in the hippocampus and cortex, as evidenced by Nissl and H&E staining for neuron damage and loss, and by SA-β-gal staining for aging cells. DNLA and metformin treatments decreased amyloid-β1–42 , AβPP, PS1, and BACE1, while increasing IDE and neprilysin for Aβ clearance. Furthermore, DNLA and metformin enhanced autophagy activity by increasing LC3-II, Beclin1, and Klotho, and by decreasing p62 in the hippocampus and cortex. Conclusion: The beneficial effects of DNLA were comparable to metformin in protecting against aging-related cognitive deficits, neuron aging, damage, and loss in SAMP8 mice. The mechanisms could be attributed to increased Aβ clearance, activation of autophagy activity, and upregulation of Klotho. Show more

Keywords: Aging, amyloid-β, autophagy, Dendrobium nobile Lindl. alkaloid (DNLA), metformin, senescence accelerated mouse prone 8 (SAMP8)

DOI: 10.3233/JAD-200308

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 657-669, 2020

Authors: Staekenborg, Salka S. | Kelly, Naomi | Schuur, Jacqueline | Koster, Pieter | Scherder, Erik | Tielkes, Caroline E.M. | Scheltens, Philip | Claus, Jules J.

Article Type: Research Article

Abstract: Background: The role of cognitive reserve (CR) to explain individual differences in cognitive functioning is unclear in memory clinic patients. Objective: To examine the cross-sectional effect of CR on cognition in relation to levels of neurodegeneration in a large elderly single-center memory clinic population. Methods: We included patients with subjective cognitive impairment (SCI, n  = 481), mild cognitive impairment (MCI, n  = 628) or Alzheimer’s disease (AD, n  = 1,099). Education was used as proxy for CR and visually rated medial temporal lobe atrophy (MTA) on CT was used as parameter of neurodegeneration. Relations between CR, cognition, and MTA …were analyzed with multiple linear regression adjusted for age, sex, and cerebral atrophy. In addition, we examined if education affects the relation between MTA and cognition using an interaction variable. Results: Education was significantly related to all measures of cognition including subtests with an explained variance of education as a determinant of cognition of 11%. More highly educated patients had more advanced levels of MTA at the same level of cognition. All these results were stronger or only present in demented compared to non-demented patients but appeared no longer significant in those with lowest overall cognition. The interaction effect was significant indicating that with more advanced MTA, less cognitive decline was shown in higher educated patients. Conclusion: Education is a very strong determinant of cognition in an elderly memory clinic population. The positive effect of education was stronger in demented than in non-demented patients but disappeared in those with the lowest cognitive scores indicating a “window of CR benefit”. Show more

Keywords: Cognitive reserve, dementia, education, medial temporal lobe atrophy, memory clinic

DOI: 10.3233/JAD-191332

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 671-679, 2020

Authors: Motta, Caterina | Finardi, Annamaria | Toniolo, Sofia | Di Lorenzo, Francesco | Scaricamazza, Eugenia | Loizzo, Stefano | Mercuri, Nicola Biagio | Furlan, Roberto | Koch, Giacomo | Martorana, Alessandro

Article Type: Research Article

Abstract: Background: Neuroinflammatory cytokines can play a pivotal role in Alzheimer’s disease (AD) contributing to the evolution of degenerative processes. Objective: We aimed at evaluating the levels of cerebrospinal fluid (CSF) inflammatory cytokines, chemokines, and growth factors in subjects with diagnosis of amnestic mild cognitive impairment and mild AD. Methods: We evaluated CSF contents of inflammatory cytokines in 66 patients divided according to the NIA-AA research framework and the APOE genotype. CSF of a group of cognitively unimpaired individuals (n  = 23) was evaluated as control. All patients were evaluated for 24 months using Mini-Mental State Examination …(MMSE). Results: We found significant increased levels of IL-4, IL-6, IL-8, and G-CSF in the CSF of A+/T–APOE4 carriers, respect to A+/T–patients homozygous for APOE3 , respect to A+/T+ patients, regardless the APOE status, and respect to controls. Over a period of 24 months, A+/T–APOE4 carriers, with increased levels of cytokines, showed a preserved cognitive evaluation when compared to the other subgroups of patients (delta MMSE at 24 months respect to baseline: 0.10±0.35; p  < 0.05). Conclusion: Our data suggest that during early phases of AD, in APOE4 carriers, Aβ pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation. These data highlight the different role that neuroinflammation can play in AD pathology based on the presence of specific CSF biomarkers and on the APOE status. Show more

Keywords: Amyloid-β 42, APOE , cognitive decline, G-CSF, interleukins, tau

DOI: 10.3233/JAD-191250

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 681-689, 2020

Authors: Fowler, Mackenzie E. | Triebel, Kristen L. | Cutter, Gary R. | Schneider, Lon S. | Kennedy, Richard E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer’s disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies. Objective: To determine self-reported cancer history’s effect on longitudinal AD progression in an observational study. Methods: We utilized data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer’s …Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression. Results: Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53–0.85) after adjustment for covariates. Conclusion: Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD. Show more

Keywords: Alzheimer’s disease, cancer, cognitive impairment, disease progression, mild cognitive impairment

DOI: 10.3233/JAD-200108

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 691-701, 2020

Authors: Makino, Keitaro | Lee, Sangyoon | Bae, Seongryu | Shinkai, Yohei | Chiba, Ippei | Shimada, Hiroyuki

Article Type: Research Article

Abstract: Background: Both pain interference and depressive symptoms have certain effects on dementia, and these are reciprocally related. However, comorbid effects of pain interference and depressive symptoms on dementia have not been examined in detail. Objective: This longitudinal study aimed to examine the combined effects of pain interference and depressive symptoms on the incidence of dementia in community-dwelling elderly individuals. Methods: This prospective cohort study with a 36-month follow-up period included 4,326 community-dwelling elderly individuals without dementia at baseline. Pain interference and depressive symptoms were assessed for every participant at baseline. We collected medical records in the …Japanese public health insurance system to identify the incidence of dementia for 36 months. Results: The incidence rates of dementia during the follow-up period in the control, pain-interference, depressive-symptoms, and comorbid group were 3.2%, 6.2%, 7.9%, and 11.3%, respectively. A Cox regression analysis showed that the hazard ratios for the incidence of dementia were 1.85 (95% CI: 1.13–3.03) in the pain interference group, 1.87 (95% CI: 1.27–2.76) in the depressive symptoms group, and 2.20 (95% CI: 1.26–3.84) in the comorbid group, after adjusting for covariates. Conclusion: The coexistence of pain interference and depressive symptoms had a greater effect on the incidence of dementia than either condition alone in community-dwelling elderly individuals. Pain interference and depressive symptoms are known as common comorbid conditions and often form a negative cycle that accelerates the worsening of the individual symptoms of both. Thus, the comorbidity of these conditions may require monitoring for the prevention of dementia. Show more

Keywords: Activity limitation, community, dementia, depression, pain, prevention

DOI: 10.3233/JAD-191139

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 703-712, 2020

Authors: He, Yating | Zhang, Haihua | Wang, Tao | Han, Zhifa | Ni, Qing-bin | Wang, Kun | Wang, Longcai | Zhang, Yan | Hu, Yang | Jin, Shuilin | Sun, Bao-liang | Liu, Guiyou

Article Type: Research Article

Abstract: Background: Altered calcium homeostasis is hypothesized to underlie Alzheimer’s disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. Objective: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. Methods: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 …controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. Results: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35–0.95, p  = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. Conclusion: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study, inverse-variance weighted, Mendelian randomization, serum calcium

DOI: 10.3233/JAD-191249

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 713-724, 2020

Authors: Piamonte, Bernadeth Lyn C. | Espiritu, Adrian I. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: A critical strategy in the management of Alzheimer’s disease (AD) is optimizing the effects of currently available pharmacologic therapies such as citicoline (CC). Objective: The purpose of this study was to determine the effects of CC as adjunct therapy to cholinesterase inhibitors (AChEI) in the treatment of AD. Methods: We identified relevant studies by electronic search until April 2020. We considered studies with a comparator group that enrolled elderly patients with a diagnosis of AD and employed CC as an adjunct therapy to AChEIs compared to AChEI monotherapy or comparisons of different AChEIs combined with …CC. Methodological quality assessment was done using the Newcastle-Ottawa Scale. Results: Out of 149 articles identified, two retrospective cohort studies involving 563 elderly patients affected with AD were included. After 3 months and 9 months, better Mini-Mental Status Examination scores were observed in the “AChEIs + CC” group versus “AChEIs alone” group. CC combined with donepezil may be better in improving cognition than when combined with rivastigmine. No significant difference was noted in terms of activities of daily living (ADL) and instrumental-ADL. Neuropsychiatric Inventory and Geriatric Depression Scale-short form scores appeared to be lower in the combination treatment versus monotherapy. The adverse events of combined treatment were self-limiting and included occasional excitability, gastric intolerance, and headache. Conclusion: Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, citicoline, systematic review

DOI: 10.3233/JAD-200378

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 725-732, 2020

Authors: Rajji, Tarek K. | Bowie, Christopher R. | Herrmann, Nathan | Pollock, Bruce G. | Bikson, Marom | Blumberger, Daniel M. | Butters, Meryl A. | Daskalakis, Zafiris J. | Fischer, Corinne E. | Flint, Alastair J. | Golas, Angela C. | Graff-Guerrero, Ariel | Kumar, Sanjeev | Lourenco, Lillian | Mah, Linda | Ovaysikia, Shima | Thorpe, Kevin E. | Voineskos, Aristotle N. | Mulsant, Benoit H. | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: By the time Alzheimer’s disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer’s dementia with Cognitive …remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive remediation, major depressive disorder, mild cognitive disorder, PACt-MD, prevention, transcranial direct current stimulation, NCT02386670

DOI: 10.3233/JAD-200141

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 733-751, 2020

Authors: Cuttler, Katelyn | Bignoux, Monique J. | Otgaar, Tyrone C. | Chigumba, Stephanie | Ferreira, Eloise | Weiss, Stefan F.T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently, it has been demonstrated that the 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Since both LRP/LR and telomerase are known to play a role in the Aβ facet of AD, we hypothesized that they might also play a role in tauopathy. Objective: This study aimed …to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins. Methods: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-SY5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting. Results: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. LRP::FLAG overexpression also resulted in increased hTERT levels. Conclusion: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels. Show more

Keywords: Alzheimer’s disease, 37 kDa/67 kDa laminin receptor (LRP/LR), PrPc , tau, telomerase

DOI: 10.3233/JAD-200244

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 753-768, 2020

Authors: Takemoto, Mami | Ohta, Yasuyuki | Hishikawa, Nozomi | Yamashita, Toru | Nomura, Emi | Tsunoda, Keiichiro | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Omote, Yoshio | Abe, Koji

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer’s disease (AD) are associated with a lower quality of life. Objective: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. Methods: In the present study, we evaluated the efficacy of sertraline (n  = 11; average dose = 31.8 mg), escitalopram (n  = 13; average dose = 7.3 mg), and nicergoline (n  = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) …(>5) or a high Apathy Scale (AS) (>16) scores. Results: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p  = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p  = 0.05); however, no significant changes were noted in patients receiving nicergoline. Conclusion: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD. Show more

Keywords: Alzheimer’s disease, apathy, depression, escitalopram, nicergoline, sertraline

DOI: 10.3233/JAD-200247

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 769-772, 2020