Journal of Alzheimer's Disease Reports - Volume 4, issue 1

Authors: Gaitán, Julian M. | Boots, Elizabeth A. | Dougherty, Ryan J. | Ma, Yue | Edwards, Dorothy F. | Mitchell, Carol C. | Christian, Bradley T. | Cook, Dane B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: A growing body of evidence supports that aerobic exercise can decrease the risk of future cognitive impairment and Alzheimer’s disease (AD). There is a pressing need to rigorously determine whether cognitively normal yet at-risk individuals stand to benefit from the protective effects of exercise. The present study will test the feasibility of an aerobic exercise intervention in such a population and inform the design of a larger-scale randomized, controlled trial examining the effect of aerobic exercise on biomarkers of AD in late-middle-aged, at-risk individuals. This was a single-site, 1 : 1 block-randomized, parallel, two-arm trial. Cognitively normal participants aged 45–80 with documentation …of familial and genetic AD risk factors were randomly assigned to one of two interventions. The Usual Physical Activity group was provided educational materials about exercise. The Enhanced Physical Activity intervention delivered 26 weeks of individualized and supervised aerobic exercise. Exercise duration and intensity were incrementally increased to 150 min/week and 70–80% of heart rate reserve, respectively. Retention and adherence were measured to assess study feasibility. In addition, pre- and post- intervention differences between the two arms were evaluated for cardiorespiratory fitness, physical activity, brain glucose metabolism, cerebral structure, vascular health, memory, executive function, and mood. Data from randomized controlled trials of exercise training are needed to identify the proper exercise prescription for reducing accumulation of AD biomarkers in cognitively normal individuals. The current trial will contribute to filling that gap while informing the design of large-scale trials. Show more

Keywords: Cardiorespiratory fitness, exercise, magnetic resonance imaging, physical activity, positron emission tomography, preclinical Alzheimer’s disease

DOI: 10.3233/ADR-200180

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 107-121, 2020

Authors: Barthelson, Karissa | Newman, Morgan | Lardelli, Michael

Article Type: Review Article

Abstract: Sortilin-related receptor 1 (SORL1) encodes a large, multi-domain containing, membrane-bound receptor involved in endosomal sorting of proteins between the trans-Golgi network, endosomes and the plasma membrane. It is genetically associated with Alzheimer’s disease (AD), the most common form of dementia. SORL1 is a unique gene in AD, as it appears to show strong associations with the common, late-onset, sporadic form of AD and the rare, early-onset familial form of AD. Here, we review the genetics of SORL1 in AD and discuss potential roles it could play in AD pathogenesis.

Keywords: Alzheimer’s disease, amyloid, amyloid-beta protein precursor, endocytosis, endosomes, protein transport

DOI: 10.3233/ADR-200177

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 123-140, 2020

Authors: Niklasson, Bo | Lindquist, Lars | Klitz, William | Netherlands Brain Bank | Englund, Elisabet

Article Type: Research Article

Abstract: We investigated formalin-fixed postmortem brain tissue from the hippocampus region of 18 AD cases and 11 age-matched controls using a polyclonal antibody against Ljungan virus (LV) capsid protein 1. Evidence of a LV antigen was found in all AD cases but in none of the control specimens (p  < 0.0001). The antibodies reacted with neurons and astrocytes and also showed distinct positive reaction in the amyloid/neuritic plaques. The possible role of an incompletely characterized picornavirus as the etiologic agent in AD open up the possibility of treatment with antiviral therapy directed against picornaviruses. The positive result of such treatment in a …small number of patients is presented separately back to back to this report. Show more

Keywords: Alzheimer’s disease, immunohistochemistry, Ljungan virus, neurodegenerative disease, picornavirus

DOI: 10.3233/ADR-200174

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 141-146, 2020

Authors: Wada-Isoe, Kenji | Kikuchi, Takashi | Umeda-Kameyama, Yumi | Mori, Takahiro | Akishita, Masahiro | Nakamura, Yu

Article Type: Research Article

Abstract: Background: The Neuropsychiatric Inventory (NPI) is a widely used scale for the assessment of the behavioral and psychological symptoms of dementia (BPSD). We previously developed a novel dementia scale, the ABC dementia scale, in the TRIAD1412 trial and we compared the BPSD domain scores with the NPI scores. We, therefore, considered that we should investigate the quality of the NPI items using statistical approaches. Objective: We investigated the statistical characteristics of the 12 questions or items in the Japanese version of the NPI using the item response theory. This theory is the standard approach for the development of …a new assessment scale and we used it to evaluate the quality of the items in the NPI. Methods: First, we performed factor analysis with Promax rotation to identify latent constructs in the data from 312 patients obtained in TRIAD1412. Second, following the result of the factor analysis, we divided the 12 items into domains and then investigated the characteristics of the sub-syndromes in each domain using item response category characteristic curves. Results: We found three latent constructs or domains: “hyperactivity,” “psychosis and apathy,” and “affect” (Cronbach’s α = 0.68) in the 12 items. Further, the items on euphoria, apathy, and appetite and eating abnormalities did not provide sufficient information to estimate BPSD severity. Conclusion: The NPI item characteristics indicate that while the scale can distinguish whether patients have severe BPSD or not, it cannot estimate the degree of severity in a suspected case with a mild or unknown level of BPSD. Show more

Keywords: Factor analysis, item characteristic curves, item response theory, Neuropsychiatric inventory

DOI: 10.3233/ADR-200172

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 151-159, 2020

Authors: Wong, Louis X. | Bloom, Gail M. | Chee, Bryant

Article Type: Short Communication

Abstract: We intend for this article to provide a foundation toward the creation of a more patient-centric approach to the informed consent process. Our overall objectives are to promote ethical clinical research standards and procedures toward enhanced supportive systems for clinical trial participants. We provide a suggested format which multidisciplinary clinical trial researchers can adapt for their own clinical trial setting.

Keywords: Autonomy, decision-making, guidance, informed consent, participant, patient-centric approach, protection, trust-building

DOI: 10.3233/ADR-200187

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 161-164, 2020

Authors: Hattori, Naoya | Sherwin, Paul | Farrar, Gill

Article Type: Research Article

Abstract: Background: Brain amyloid is a neuropathological hallmark of Alzheimer’s disease (AD). By visualizing brain amyloid, positron emission tomography (PET) may influence the diagnostic assessment and management of patients with cognitive impairment. Objective: As part of a Japanese post-approval study to measure the safety of [18 F]flutemetamol PET, the association of amyloid PET results with changes in diagnosis and diagnostic confidence was assessed. Methods: Fifty-seven subjects were imaged for amyloid PET using [18 F]flutemetamol at a single Japanese memory clinic. The cognitive diagnosis and referring physician’s confidence in the diagnosis were recorded before and after availability of …PET results. Imaging started approximately 90 minutes after [18 F]flutemetamol administration with approximately 185 MBq injected. PET images were acquired for 30 minutes. Results: Amyloid PET imaging led to change in diagnosis in 15/44 clinical subjects (34%). Mean diagnostic confidence increased by approximately 20%, from 73% pre-scan to 93% post-scan, and this rise was fairly consistent across the main patient subgroups (mild cognitive impairment, AD, and non-AD) irrespective of the pre-scan diagnosis and scan result. Conclusion: The study examined the utility of amyloid PET imaging in a Japanese clinical cohort and highlighted the use of an etiological diagnosis in the presence of the amyloid scan. [18 F]Flutemetamol PET led to a change in diagnosis in over 30% of cases and to an increase in diagnostic confidence by approximately 20% consistent with other reports. Show more

Keywords: Alzheimer’s disease, amyloid imaging, dementia, diagnosis, [18F]flutemetamol, mild cognitive impairment, PET, safety

DOI: 10.3233/ADR-190150

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 165-174, 2020

Authors: Sinyor, Benjamin | Mineo, Jocelyn | Ochner, Christopher

Article Type: Review Article

Abstract: The World Health Organization refers to Alzheimer’s disease (AD) as a global health priority. As the average age of the world’s population is increasing, so too is the rate of AD. There are an estimated 47 million people globally who have been diagnosed with AD dementia, and researchers have yet to figure out the root cause. All misfolded aggregate proteins that are involved in neurodegenerative disorders (amyloid-β, Huntington’s tau, α -synuclein) induce oxidative stress. It is that oxidative stress that leads to inflammation and, in conjunction with amyloid protein and tau hyperphosphorylation, progresses to and exacerbates AD. The consumption of …antioxidants and nutrients, specifically vitamin E, caffeine, and turmeric, may slow the progression of AD and can be found in a wide variety of dietary foods. This review explores the role of inflammation on AD, the antioxidants that can potentially combat it, and future directions of how the treatment of the disease can be better understood. Show more

Keywords: Alzheimer’s disease, inflammation, antioxidants, vitamins, amyloid

DOI: 10.3233/ADR-200171

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 175-183, 2020

Authors: Sanders, Owen | Rajagopal, Lekshmy

Article Type: Review Article

Abstract: Background: Preclinical studies, clinical trials, and reviews suggest increasing 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer’s disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α ). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1α . PGC1α induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and …cGMP inhibit BACE1-inducing NFκ B and tau-phosphorylating GSK3β. Objective and Methods: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD. Results: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition. Conclusion: Phosphodiesterase inhibitors may prevent and treat AD. Show more

Keywords: Alzheimer’s disease, amyloid precursor protein secretases, clinical trial phase III, 3′, 5′-cyclic-AMP phosphodiesterases, 3′, 5′-cyclic-GMP phosphodiesterases, cyclic AMP response element-binding protein, cyclic nucleotides, glycogen synthase kinase 3, NF-E2-related factor 2, NF-kappa B, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Sirtuin 1

DOI: 10.3233/ADR-200191

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 185-215, 2020

Authors: Lennon, Jack C.

Article Type: Short Communication

Abstract: The COVID-19 pandemic has been met with studies on risk factors, characteristics, and clinical course. Among these characteristics are neurologic symptoms, which may provide improved insight into the mechanisms of this novel virus and the brain’s susceptibility to infectious diseases. This article aims to discuss 1) findings related to neurologic complications, 2) how they connect to and are bidirectionally impacted by bioimmunology, 3) how this combination of biological mechanisms impact and are impacted by psychosocial stressors, and 4) the importance of considering potential neurodegenerative consequences of COVID-19. Longitudinal studies on neuropathology and cognition are critical to avoiding premature conclusions related …to long-term neurologic effects. Show more

Keywords: Alzheimer’s disease, coronavirus disease 2019 (COVID-19), immunology, neurobiology, stress

DOI: 10.3233/ADR-200190

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 217-221, 2020

Authors: Schechter, Ginger | Azad, Gajendra Kumar | Rao, Rammohan | McKeany, Allison | Matulaitis, Matthew | Kalos, Denise M. | Kennedy, Brian K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic condition that progresses over time. While several therapeutic approaches have been developed, none have substantially altered disease progression. One explanation is that the disease is multi factorial. Objective: Using the Affirmativ Health Personal Therapeutic Program (PTPr), we sought to determine whether a comprehensive and personalized program could improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early stage AD. Methods: 35 individuals submitted blood samples and Montreal Cognitive Assessment (MoCA) scores, and answered intake questions. Individuals and caregivers participated in a four-day …immersion program, which included Personal Therapeutic Plans (PTP), consultations with clinical practitioners, and explanations of the PTPr and PTP. Participants had follow-up by telemonitoring, with repeat blood sample analysis, updates regarding lifestyle choices, current medications and supplements, and MoCA testing at least once between 3 and 12 months after the PTPr. Results: By comparing baseline to follow-up testing, we determined several risk factor scores, including blood glucose and insulin levels, and levels of vitamins B12, D3, and E, improved either in the entire participant pool or specifically in individuals with measures outside the normal range for specific factors. MoCA scores were stabilized in the entire participant pool and significantly improved in individuals scoring 24 or less at baseline. Conclusion: Our findings provide evidence that a comprehensive and personalized approach designed to mitigate AD risk factors can improve risk factor scores and stabilize cognitive function, warranting more extensive and placebo-controlled clinical studies. Show more

Keywords: Alzheimer’s disease, metabolism, mild cognitive impairment, personalized treatment, subjective cognitive impairment

DOI: 10.3233/ADR-200185

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 223-230, 2020

Authors: Migliaccio, Raffaella | Bouzigues, Arabella

Article Type: Article Commentary

Abstract: In dementia research and in clinical practice, the COVID-19 pandemic represents an important challenge, not only for neurological staff and researchers, but above all for patients and their caregivers. It is important that the medical staff demonstrate flexibility, open-mindedness, and humanity when following patients and caregivers. It seems inevitable that caregivers will pay the highest price during this crisis.

Keywords: Caregiver, collateral damage, COVID-19, dementia, lockdown

DOI: 10.3233/ADR-200193

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 231-235, 2020

Authors: Wang, Ge | Li, Wei

Article Type: Research Article

Abstract: Background: Diabetes has been shown as a risk factor for cognitive impairments. However, it is still not clear about the time course of developing abnormal cognition in those with diabetes especially if the morbidity accelerates the cognitive deterioration process. Objective: To study how diabetes is related to the abnormal cognition development. Methods: A retrospective analysis was performed using data collected by the National Alzheimer’s Coordinating Center. Incidence, prevalence, and age at onset (AAO) of either mild cognitive impairment (MCI) or dementia were compared between participants with and without diabetes. Results: During a follow-up period …of more than 10 years, the diabetic group had a higher incidence and prevalence of MCI or dementia than the non-diabetic group. However, the AAO of either MCI or dementia was independent of the diagnosis of diabetes. Conclusion: Although diabetic patients have a higher incidence and prevalence of abnormal cognition than those without diabetes, diabetes does not accelerate the cognitive deterioration process. Show more

Keywords: Abnormal cognition, age at onset, dementia, diabetes, mild cognitive impairment

DOI: 10.3233/ADR-200181

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 237-242, 2020

Authors: Park, Kevin H.J. | Barrett, Tomás

Article Type: Research Article

Abstract: Background: The presence of cell cycle markers in postmortem Alzheimer’s disease (AD) brains suggest a potential role of cell cycle activation in AD. It was shown that cell cycle activation in postmitotic neurons in mice produces Aβ and tau pathologies from endogenous mouse proteins in the absence of AβPP or tau mutations. Objective: In this study, we examined the microglial and astrocytic responses in these mice since neuroinflammation is another key pathological feature in AD. Methods: Our neuronal cell cycle re-entry (NCCR) mouse model are bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. Using this tet-off …system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. TRE-SV40T Tg mice were used as SV40T transgene controls. The animals were examined at following time points: 2, 3, 4, 6, and 12 months of age. The microglia and astrocyte responses in our mice were determined by image analysis and stereology on brain sections immunofluorescently labeled using the following antibodies: Iba1, CD45, CD68, MHCII, and GFAP. Cellular senescent marker p16 was also used in this study. Results: Our NCCR mice demonstrate early and persistent activation of microglia and astrocytes. Additionally, proinflammatory and senescent microglia phenotype and brain leukocyte infiltration is present at 12 months of age. Conclusion: In the absence of FAD gene mutations, our NCCR mice simultaneously display many of the pathological changes associated with AD, such as ectopic neuronal cell cycle re-entry, Aβ and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model. Show more

Keywords: Alzheimer’s disease, amyloid-β, cell cycle, leukocyte infiltration, mouse model, neuroinflammation, senescence, sporadic AD, tau

DOI: 10.3233/ADR-200170

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 243-253, 2020

Authors: Marcum, Zachary A. | Rosenberg, Dori | Barnes, Deborah E. | Yaffe, Kristine | Larson, Eric B.

Article Type: Short Communication

Abstract: We administered a web-based survey to a convenience sample of 561 patients in a large health system to assess patient attitudes toward dementia prevention in the context of designing a multi-domain Alzheimer’s risk reduction intervention. The majority of respondents reported being very concerned about Alzheimer’s disease, wanted to know their personal risk factors, and were highly motivated to make healthy lifestyle changes to lower dementia risk. The areas they were most interested in targeting to reduce dementia risk included physical activity, cognitive stimulation, nutrition, and sleep. These results provided strong support for our conceptual framework to target higher-risk patients with …a personalized risk reduction strategy. Show more

Keywords: Alzheimer’s disease, dementia, patient participation, primary prevention

DOI: 10.3233/ADR-200210

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 255-260, 2020

Authors: Oberman, Klaske | Gouweleeuw, Leonie | Hoogerhout, Peter | Eisel, Ulrich L.M. | van Riet, Elly | Schoemaker, Regien G.

Article Type: Research Article

Abstract: Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer’s disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed. Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD. Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 …months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests. Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter. Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, vaccine

DOI: 10.3233/ADR-200213

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 261-280, 2020

Authors: Robinson, Andrew C. | Davidson, Yvonne S. | Roncaroli, Federico | Minshull, James | Tinkler, Phillip | Horan, Michael A. | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Short Communication

Abstract: While many studies have examined the associations between APOE genotype and mortality, findings have often been conflicting and it remains unclear whether APOE genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between APOE genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the APOE ɛ 4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, …APOE ɛ 2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that APOE genotype influences longevity, especially in cognitively impaired individuals who carry the APOE ɛ 4 allele. Show more

Keywords: Alzheimer’s disease, APOE , cognition, longevity, mortality

DOI: 10.3233/ADR-200203

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 281-286, 2020

Authors: Sato, Kenichiro | Mano, Tatsuo | Suzuki, Kazushi | Toda, Tatsushi | Iwatsubo, Takeshi | Iwata, Atsushi | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Although aging is the strongest risk factor for the development of Alzheimer’s disease (AD), it remains uncertain if the blood DNA methylation clock, which reflects the effect of biological aging on DNA methylation (DNAme) status of blood cells, may be used as a surrogate biomarker for AD pathology in the central nervous system (CNS). Objective: We aimed to develop a practical model to predict for A/T/N-based AD biomarkers as the prediction targets using the aging acceleration of blood cells. Methods: We obtained data of North American ADNI study participants (n  = 317) whose blood DNA methylation …microarray (Illumina HumanMethylation EPIC Beadchips) and cerebrospinal fluid (CSF) AD biomarkers (Aβ , t-tau, and p-tau) were recorded simultaneously. Methylation clock was calculated to conduct machine learning, in order to predict binary statuses (+ or –) for A (corresponding to the lowered CSF Aβ ), T (the elevated CSF p-tau), or N (the elevated CSF t-tau). The predictive performance of the models was evaluated by area under curve (AUC) in the test subset within ADNI. Results: Among the 317 included samples, 194 (61.2%) were A+, 247 (77.9%) were T+, and 104 (32.8%) were N+. The degree of blood aging acceleration showed weak positive correlation with the CSF Aβ levels, even after adjustment with APOE genotype and other covariates. However, the contribution of aging acceleration to improve the predictive performance of models was not significant for any of A+, T+, or N+. Conclusion: Our exploratory attempts could not demonstrate the substantial utility of the peripheral blood cells’ methylation clock as a predictor for A/T/N-based CSF biomarkers of AD, and further additional work should be conducted to determine whether the blood DNAme signatures including methylation clock have substantial utility in detecting underlying amyloid, tau or neurodegeneration pathology of AD. Show more

Keywords: Alzheimer’s disease, A/T/N, blood biomarker, DNA methylation, epigenetic clock

DOI: 10.3233/ADR-200205

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 287-296, 2020

Authors: Figueiro, Mariana G. | Sahin, Levent | Kalsher, Michael | Plitnick, Barbara | Rea, Mark S.

Article Type: Research Article

Abstract: Background: Persons with Alzheimer’s disease and related dementias (ADRD) frequently experience sleep–wake (circadian) cycle disturbances that lead them to remain awake at night, causing stress and fatigue for families and caregivers. Light therapy shows promise as a nonpharmacological treatment for regulating sleep in this population. Objective: We investigated the long-term impact of a circadian-effective lighting intervention on sleep, mood, and behavior problems in persons with ADRD. Methods: This 25-week clinical trial administered an all-day lighting intervention to 47 patients with ADRD in 9 senior-care facilities, employing wrist-worn actigraphy measures and standardized measures of sleep quality, mood, …and behavior. Results: The intervention significantly improved Pittsburgh Sleep Quality Index scores, from an estimated mean±SEM of 11.89±0.53 at baseline to 5.36±0.63 at the end of the intervention. Additional improvements were noted for sleep efficiency data from actigraph measurements. The intervention significantly reduced Cornell Scale for Depression in Dementia scores (mean±SEM of 11.36±0.74 at baseline and 4.18±0.88 at the end of the intervention) and Cohen-Mansfield Agitation Inventory scores (mean±SEM of 47.10±1.98 at baseline and 35.33±2.23 at the end of the intervention). Conclusion: A regular circadian-effective daytime lighting intervention can improve sleep at night and reduce depression and agitation in patients with dementia living in controlled environments. More importantly, the positive effects of the tailored lighting intervention on these outcomes appear to be cumulative over time. Show more

Keywords: Alzheimer’s disease and related dementias, circadian system, lighting intervention, mood, rest–activity, sleep

DOI: 10.3233/ADR-200212

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 297-312, 2020

Authors: Ryan, Joanne | Woods, Robyn L. | Britt, Carlene J. | Murray, Anne M. | Shah, Raj C. | Reid, Christopher M. | Wolfe, Rory | Nelson, Mark R. | Orchard, Suzanne G. | Lockery, Jessica E. | Trevaks, Ruth E. | Storey, Elsdon | behalf of the ASPREE Investigator Group on

Article Type: Research Article

Abstract: Background: Processing speed, which can be assessed using the Symbol Digit Modalities Test (SDMT), is central to many brain functions. Processing speed declines with advanced age but substantial impairments are indicative of brain injury or disease. Objective: The purpose of this study was to provide SDMT normative data for older community-dwelling individuals in the U.S. and Australia. Methods: The ASPREE trial recruited 19,114 relatively healthy older men and women in Australia and the U.S. from the general community. All participants were without a diagnosis of dementia and with a Modified Mini-Mental State examination score of 78 …or more at enrolment. The SDMT was administered at baseline as part of a neuropsychological test battery. Results: The median age of participants was 74 years (range 65–99), and 56% were women. The median years of education was 12. Ethno-racial differences in SDMT performance were observed and normative data were thus presented separately for 16,289 white Australians, 1,082 white Americans, 891 African-Americans, and 316 Hispanic/Latinos. There were consistent positive associations found between SDMT and education level, and negative associations between SDMT and age. Mean scores for women were consistently higher than men with the exception of Hispanic/Latinos aged ≥70 years. Conclusion: This study provides comprehensive SDMT normative data for whites (Australian and U.S.), Hispanic/Latinos, and African-Americans, according to gender, age, and education level. These norms can be used clinically as reference standards to screen for cognitive impairments in older individuals. Show more

Keywords: Aging, cognition, impairment, normative data, Symbol Digit Modalities Test

DOI: 10.3233/ADR-200194

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 313-323, 2020

Authors: Olson, Nancy L. | Albensi, Benedict C.

Article Type: Review Article

Abstract: Randomized clinical trials (RCT) involve labor-intensive, highly regulated, and controlled processes intended to transform scientific concepts into clinical outcomes. To be effective and targeted, it is imperative they include those populations who would most benefit from those outcomes. Alzheimer’s disease (AD) is most detrimental to the aging population, and its clinical manifestation is influenced by socio-economic factors such as poverty, poor education, stress, and chronic co-morbidities. Indigenous populations in the United States and Canada are among the minority populations most influenced by poor socio-economic conditions and are prone to the ravages of AD, with Indigenous women carrying the added burden …of exposure to violence, caregiving stresses, and increased risk by virtue of their sex. Race- and sex-based disparities in RCT enrollment has occurred for decades, with Indigenous men and women very poorly represented. In this review, we examined literature from the last twenty years that reinforce these disparities and provide some concrete suggestions and guidelines to increase the enrollment numbers in AD RCT among this vulnerable and poorly represented population. Show more

Keywords: Aboriginal, Alzheimer’s disease, gender, Indian, indigenous, Inuit, Metis, native, randomized clinical trial, sex

DOI: 10.3233/ADR-200214

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 325-344, 2020

Authors: Jackson, Jordan M. | Bay, Allison A. | Barter, Jolie Denise | Ni, Liang | Caudle, William Michael | Serra, Monica C. | Wharton, Whitney | Hackney, Madeleine E.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a prevalent neurodegenerative disease. Treatments are necessary to target people at high risk for AD. Inflammation, particularly tumor necrosis factor alpha (TNFα ), appears to be an important marker associated with the development of AD pathophysiology. Consuming a high-fat diet induces tissue expression of TNFα . Objective: This study investigates the relationship between nutrition, circulating inflammation, and cognition in African American women (age: M  = 59.5 (±8.20) [42–73] years) at risk for developing AD. Methods: Participants were split into high-fat and low-fat groups based on total dietary fat consumption self-reported on the …Lower Mississippi Delta Nutrition Intervention Research Initiative Food Frequency Questionnaire (Delta NIRI FFQ). Results: A high-fat diet was associated with increased blood serum TNFα (p  = 0.02) compared to the low-fat diet. In addition, global cognition scores were 9.0% better in those who consumed a higher fat diet (p  = 0.04). No significant differences across groups were noted for executive function, dual-tasking, and visuospatial performance. Conclusion: These results indicate that there may be multiple biological pathways involved in AD development, suggesting the need for more holistic approaches to mitigate AD-development risk. Show more

Keywords: African American, Alzheimer’s disease, cognition, executive function, inflammation, nutrition, tumor necrosis alpha

DOI: 10.3233/ADR-200224

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 345-352, 2020

Authors: Moura, Eric L.R. | dos Santos, Hellin | Celes, Ana Paula M. | Bassani, Taysa B. | Souza, Leonardo C. | Vital, Maria A.B.F.

Article Type: Research Article

Abstract: Background: It has been studied that nutrition can influence Alzheimer’s disease (AD) onset and progression. Some studies on rodents using intraventricular streptozotocin (STZ) injection showed that this toxin changes cerebral glucose metabolism and insulin signaling pathways. Objective: The aim of the present study was to evaluate whether a nutritional formulation could reduce cognitive impairment in STZ-induced animals. Methods: The rats were randomly divided into two groups: sham and STZ. The STZ group received a single bilateral STZ-ICV injection (1 mg/kg). The sham group received a bilateral ICV injection of 0.9% saline solution. The animals were treated with …AZ1 formulation (Instanth® NEO, Prodiet Medical Nutrition) (1 g/kg, PO) or its vehicle (saline solution) for 30 days, once a day starting one day after the stereotaxic surgery (n  = 6–10). The rats were evaluated using the open field test to evaluate locomotor activity at day 27 after surgery. Cognitive performance was evaluated at day 28 using the object recognition test and the spatial version of the Y-maze test. At day 30, the rats were anesthetized with chloral hydrate (400 mg/kg, i.p) and euthanized in order to evaluate IBA1 in the hippocampus. The differences were analyzed using one-way ANOVA with Bonferroni’s or Kruskal Wallis with Dunn’s post-hoc test. Results/Conclusion: STZ-lesioned rats present memory impairment besides the increased microglial activation. The treatment with AZ1 formulation reversed the memory impairment observed in the object recognition test and Y-maze and also reduced IBA1 in CA1 and DG. Show more

Keywords: Alzheimer’s disease, IBA1, Instanth® NEO, object recognition test, streptozotocin, Y maze

DOI: 10.3233/ADR-200175

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 353-363, 2020

Authors: Young, John K.

Article Type: Research Article

Abstract: One unexplained feature of Alzheimer’s disease (AD) is that the lateral entorhinal cortex undergoes neurodegeneration before other brain areas. However, this brain region does not have elevated levels of amyloid peptides in comparison with undamaged regions. What is the cause of this special vulnerability of the entorhinal cortex? One special feature of the lateral entorhinal cortex is that it projects to newborn neurons that have undergone adult neurogenesis in the dentate gyrus of the hippocampus. Neurogenesis is abnormal in human AD brains, and modulation of neurogenesis in experimental animals influences the course of AD. This complex process of neurogenesis may …expose axon terminals originating from neurons of the entorhinal cortex to a unique combination of molecules that can enhance toxic effects of amyloid. Retrograde degeneration of neurons with axons terminating in the dentate gyrus provides a likely explanation for the spatial patterns of neuronal cell death seen in AD. Specialized astrocytes in the dentate gyrus participate in adult neurogenesis and produce fatty acid binding protein7 (FABP7). These FABP7+ cells undergo an aging-related mitochondrial pathology that likely impairs their functions. This age-related abnormality may contribute to the impairment in neurogenesis seen in aging and Alzheimer’s disease. Also, a compromised function of these astrocytes likely results in local elevations of palmitic acid, iron, copper, and glucose, which all enhance the toxicity of amyloid peptides. Treatments that modulate neurogenesis or diminish the production of these toxic substances may prove more successful than treatments that are solely aimed at reducing the amyloid burden alone. Show more

Keywords: Alzheimer’s disease, astrocytes, copper, entorhinal cortex, FABP7, Gomori-positive, neurogenesis

DOI: 10.3233/ADR-200218

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 365-371, 2020

Authors: Lehrer, Steven | Rheinstein, Peter H.

Article Type: Research Article

Abstract: Background: The cause of Alzheimer’s disease (AD) is poorly understood. Neurotropic microbes, particularly herpesviruses, might set off chronic neuroinflammation. Amyloid-β (Aβ) has antimicrobial properties and could represent a brain defense against infection. Objective: We searched for protein sequence alignment between herpes simplex virus type I (HSV-1) HSV-2, and Aβ. Methods: Protein data bank (pdb) structures for Aβ, HSV-1, and HSV-2 were searched on the RCSB Protein Data Bank. The protein structures were superimposed and aligned on PYMOL v 2.3.4. Results: For HSV-1 and Aβ, amino acid residues ser549 – his569 of HSV-1 aligned closely …with residues asp7 - asn27 of Aβ. For HSV-2 and Aβ, amino acid residues of HSV-2 aligned less closely than those of HSV-1 with residues of Aβ. Conclusion: Conjugating and binding to the same alpha helix in the HSV-1 protease, Aβ could be marking HSV-1 for attack by the immune system, providing a rapid inherited immune response to a destructive neurotropic virus that would otherwise require the more time-consuming involvement of T-cells, B-cells, and the adaptive immune system. But older people do not respond to viral infections as well as younger individuals. When HSV-1 infection advances in an old person, more and more amyloid is produced, forming an adhesive web. As the brain tries to hold the pathologic process in check, neuroinflammation increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome. Show more

Keywords: Alignment, Alzheimer’s disease, amyloid-β, protein, virus

DOI: 10.3233/ADR-200231

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 373-377, 2020

Authors: Andreev, Alexander | Erdinc, Burak | Shivaraj, Kiran | Schmutz, Julia | Levochkina, Olga | Bhowmik, Dhrity | Farag, Fady | Money, Kelli M. | Primavera, Louis H. | Gotlieb, Vladimir | Sahni, Sonu

Article Type: Research Article

Abstract: Background: Dementia is a spectrum of neurological diseases characterized by memory impairment and cognitive decline with the pathogenesis and effective management remaining elusive. Several studies have identified a correlation between anemia and Alzheimer’s disease and related dementias (ADRD); however, anemia subtypes and association with ADRD have yet to be studied conclusively. Objective: To study an association between ADRD and anemia of chronic inflammation. Methods: We conducted a retrospective case-control study of the patients, diagnosed with ADRD at Brookdale Hospital. Pair-wise comparisons between means of controls and cases in terms of iron studies and laboratory results were …performed using a Mann–Whitney U test. Pair-wise comparisons between anemia subgroups (moderate and severe) were performed using a Two Sample proportion Z-Test, where for each couple of normally distributed population. Results: There was a total of 4,517 (1,274 ADRD group; 3,243 Control group) patients. There was significant difference in hemoglobin 10.15 versus 11.04 [p -value <0.001]. Iron studies showed a significant difference in ferritin 395±488.18 versus 263±1023.4 [p  < 0.001], total iron binding capacity 225±84.08 versus 266±82.30 [p  < 0.001] and serum iron level 64±39.34 versus 53±41.83 [p  < 0.001]. Folic acid and vitamin B12 levels were normal in both groups. Severe and moderate anemia in the ADRD group were respectively 6.2% [95% CI: 4.2–8.4] and 13% [95% CI: 9.8–16.2] higher. Overall, incidence of moderate-to-severe anemia was found to be 19% higher in ADRD group [95% CI: 15.8–22.1]. Conclusion: We demonstrated an association between ADRD and anemia of chronic inflammation independent of age, renal function, and HgbA1C levels. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementia, anemia, anemia of chronic inflammation, dementia

DOI: 10.3233/ADR-200178

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 379-391, 2020

Authors: Kudoh, Chiaki | Hori, Tomokatsu | Yasaki, Shunji | Ubagai, Ryu | Tabira, Takeshi

Article Type: Short Communication

Abstract: We conducted a multicenter, randomized, double-blind, placebo-controlled prospective trial examining a supplement containing ferulic acid and Angelica archangelica extract (Feru-guard ® ) for mild cognitive impairment (MCI). In the intention-to-treat population, Mini-Mental State Examination (MMSE) scores were significantly better at 24 weeks (p  = 0.041) in the active group. In the per protocol population, MMSE was significantly better in the active group at 24 weeks (p  = 0.008), and mixed effect models for repeated measures (MMRM) showed significant difference (p  = 0.016). ADAS-Jcog was significantly better at 24 (p  = 0.035) and 48 weeks (p  = 0.015) in the active group, and MMRM was significant …(p  = 0.031). Thus, Feru-guard ® may be useful for MCI. Show more

Keywords: Angelica archangelica, dementia, dietary supplement, double-blind randomized trial, ferulic acid, mild cognitive impairment

DOI: 10.3233/ADR-200211

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 393-398, 2020

Authors: Ben Zaken, Sara | Radomysky, Zorian | Koren, Gideon

Article Type: Research Article

Abstract: Background: High magnesium intake has been associated with a decreased risk of dementia. In contrast, other research has found that both low and high serum magnesium levels were associated with an increased risk of Alzheimer’s disease and mixed dementia. Hence, presently the role of magnesium levels in dementia is unclear. Objective: To investigate a possible association between serum magnesium concentrations and dementia in a large population-based sample. Methods: Maccabi Healthcare Service in Israel provides healthcare to over 2 million citizens. Maccabi maintains a registry with approximately 26,000 diagnosed dementia patients. We focused on patients of both …sexes with Alzheimer’s disease or mixed dementia aged 65 or older, excluding patients with clinical diagnoses that could affect serum magnesium level, or with other causes of cognitive decline. Our control group consisted of patients of the same age and sex without dementia. Results: No significant differences were found in mean, mode, and median magnesium levels between the dementia and control groups. However, there were marginally but significantly more cases with low magnesium levels among dementia patients than among controls: A total of 9.4% of tests done in patients with dementia and 7.81% done in non-dementia subjects were hypomagnesemic (p  <  0.00001). Conclusion: Despite similar means and medians of serum magnesium in dementia and controls, the proportion of lower than normal magnesium test results was slightly higher among dementia patients. It is possible that patients with dementia have more episodes of hypomagnesemia than controls, despite similar overall mean levels of magnesium. Show more

Keywords: Alzheimer’s disease, magnesium, mixed dementia, serum magnesium

DOI: 10.3233/ADR-200220

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 399-404, 2020

Authors: Trindade, Paula Gasparini Emery | Santos, Raquel Luiza | Johannessen, Aud | Neto, Jose Pedro Simões | Dourado, Marcia Cristina Nascimento

Article Type: Research Article

Abstract: Background: Awareness of functional status may underlie specific profiles and differences related to stage severity in individuals with Alzheimer’s disease (AD). Objective: This study aimed to assess self-reported experiences of awareness of functional activity in people with mild and moderate AD. Methods: This is a mixed methods approach. The qualitative part was conducted through semi-structured interviews concerning the experiences and awareness of deficits in 38 older adults with mild or moderate AD. The quantitative approach included a comparison between groups with regard to concerns of awareness and clinic and demographic data. Results: Impairment on …awareness of disease and awareness of functional deficits was observed even in the mild stages of AD. There was also a noticeable progression of impairments of both kinds of awareness from mild to moderate stage of disease. The majority of participants with mild and moderate AD were partially aware of their functional deficits. Both groups of participants reported some negative impact; however, they were not able to entirely describe their functional status. Also, deficits to recognize the need for help with hygiene and general tasks were observed. Significant differences were found in awareness of need for help with general tasks and awareness of need for help with hygiene tasks. Conclusion: People with mild and moderate AD may describe their aware of the disease better than specific functional deficits, and most of them can provide some reports concerning to the impact of the disease. Show more

Keywords: Activities of daily living, awareness, cognition, dementia, disease

DOI: 10.3233/ADR-200227

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 405-415, 2020

Authors: Pradeep, Sushma | Jain, Anisha S. | Dharmashekara, Chandan | Prasad, Shashanka K. | Kollur, Shiva Prasad | Syed, Asad | Shivamallu, Chandan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) was first described in 1907 and got its name after Alois Alzheimer, a German psychiatrist and neuropathologist. This disease starts slow, increasing gradually to worsen in the due course of time. AD is mainly characterized by the associated dementia, which is a decline of cognitive effects such as memory, praxis, and orientation. The dementia is further highlighted by the presence of psychological and behavioral symptoms. Additionally, AD is also associated with the multiple interconnected pathways linked neuropathological changes such as the formation of neurofibrillary tangles and amyloid-β plaques inside the brain. AD therapeutics have been of prime …concern over the decades, resulting in the elucidation of promising therapeutic targets. The requirement of AD stage dependent optimized conditions has necessitated a combinatorial approach toward treatment. The priority in AD research has remained to develop disease-modifying and development-reducing drugs for treatment regimens followed during the early and later stages, respectively. Show more

Keywords: Dementia, neuropathologist, plaques, psychiatrist, tangles

DOI: 10.3233/ADR-200228

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 417-429, 2020

Authors: Franco-Macías, Emilio | Rodrigo-Herrero, Silvia | Luque-Tirado, Andrea | Méndez-Barrio, Carlota | Medina-Rodriguez, Manuel | Graciani-Cantisán, Eugenia | Sánchez-Arjona, María Bernal | Maillet, Didier

Article Type: Research Article

Abstract: Background: Memory tests focused on binding may be more sensitive to diagnose Alzheimer’s disease (AD) at an early phase. TMA-93 examines relational binding by images. Objective: Evaluate the reliability (internal consistency and inter-rater and test-retest reliability) and feasibility of the TMA-93 in a clinic setting with low-educated individuals and limited face-to-face time per patient. Methods: The study was undertaken in a neurology outpatient clinic of a hospital in Southern Spain. The internal consistency of the TMA-93 was estimated in 35 patients with amnestic mild cognitive impairment (aMCI) and 40 healthy controls (HCs). The inter-rater reliability (by …two raters) and feasibility (by recording the percentage of participants who completed the test, and by timing the administration time) were evaluated in HCs (n  = 16), aMCI patients (n  = 18), and mild dementia patients (n  = 15). The test-retest reliability for the TMA-93 total score was studied in 51 HCs tested by the same examiner 2–4 months apart. The internal consistency was estimated by Cronbach’s alpha. The inter-rater and test-retest reliability was quantified by the intraclass correlation coefficient (ICC). The administration time was compared by diagnosis. Results: The internal consistency was “optimal” (Cronbach’s alpha = 0.936). The test-retest reliability was “good” [ICC = 0.802 (CI 95%  = 0.653–0.887)]. The inter-rater reliability was “optimal” [ICC = 0.999, (CI 95%  = 0.999–1)]. All participants completed the test. The administration time ranged from less than 3 min in HCs to 6 min in aMCI patients, and 7 min in mild dementia patients. Conclusion: Good feasibility and reliability support using the TMA-93 for examining visual relational binding, particularly in the context of low-educational attainment and limited time per patient. Show more

Keywords: Binding, feasibility, inter-rater reliability, internal consistency, mild cognitive impairment, test-retest reliability, TMA-93

DOI: 10.3233/ADR-200215

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 431-440, 2020

Authors: Nakanishi, Miharu | Niimura, Junko | Ziylan, Canan | Bakker, Ton TJEM | Granvik, Eva | Nägga, Katarina | Shindo, Yumi | Nishida, Atsushi

Article Type: Research Article

Abstract: Background: There are no studies on how the same psychosocial dementia care program is adapted to both in-home and residential care settings. Objective: To evaluate the time investment required by professionals to implement a psychosocial dementia care program to manage neuropsychiatric symptoms. Methods: A prospective observational study design was used. The program consisted of 1) a one-day training course, 2) three interdisciplinary discussion meetings in five months, and 3) a web-based tool for the continued assessment of neuropsychiatric symptoms. Care professionals implemented the intervention in in-home (19 in-home care management agencies and 14 multiple in-home service …providers) and residential care settings (19 group homes and eight nursing homes) in Japan from October 2019 to February 2020. The level of neuropsychiatric symptoms for the participants was evaluated using the Neuropsychiatric Inventory (NPI: 0–144). The time investment was reported by participating professionals. A total of 125 persons with dementia were included at baseline. Results: Neuropsychiatric symptoms were significantly decreased at the final follow-up in all types of providers (Cohen’s drm  = 0.44–0.61). The mean (SD) time required for the five-month implementation was 417.9 (219.8) minutes. There was a mean (SD) decrease of 8.6 (14.0) points in the total NPI score among the 103 persons with completed interventions. The time investment was significantly lower in in-home care management agencies than in group homes, and lower in follow-ups than at baseline assessment. Conclusion: The program implementation may incur a substantial time investment regardless of setting. An additional benefit scheme to reward the time investment would be helpful to encourage implementation until the follow-ups. Show more

Keywords: Behavioral symptoms, dementia, group homes, home care agencies, nursing homes, psychosocial support systems

DOI: 10.3233/ADR-200235

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 441-453, 2020

Authors: El Haj, Mohamad | Larøi, Frank | Gallouj, Karim

Article Type: Short Communication

Abstract: While social distancing may be deemed necessary in order to avoid COVID-19 infections, the lockdown may impact mental health of patients with Alzheimer’s disease (AD). We present a case study involving hallucinations in a patient with AD who lives in a nursing home during the COVID-19 crisis. We compared this patient’s hallucination scores before and during the lockdown. We observed increased hallucinations during, compared to before, the lockdown. These increased hallucinations can be attributed to a number of elements such as the decreased in daily activities, social distancing, lack of physical contact with family members, and loneliness during the lockdown.

Keywords: Alzheimer’s disease, COVID-19, hallucinations, social distancing

DOI: 10.3233/ADR-200241

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 455-458, 2020

Authors: Wu, Zimu | Phyo, Aung Zaw Zaw | Al-harbi, Tagrid | Woods, Robyn L. | Ryan, Joanne

Article Type: Review Article

Abstract: Background: Cognitive aging is a dynamic process in late life with significant heterogeneity across individuals. Objective: To review the evidence for latent classes of cognitive trajectories and to identify the associated predictors and outcomes. Methods: A systematic search was performed in MEDLINE and EMBASE for articles that identified two or more cognitive trajectories in adults. The study was conducted following the PRISMA statement. Results: Thirty-seven studies were included, ranging from 219 to 9,704 participants, with a mean age of 60 to 93.4 years. Most studies (n  = 30) identified distinct cognitive trajectories using latent class …growth analysis. The trajectory profile commonly consisted of three to four classes with progressively decreasing baseline and increasing rate of decline—a ‘stable-high’ class characterized as maintenance of cognitive function at high level, a ‘minor-decline’ class or ‘stable-medium’ class that declines gradually over time, and a ‘rapid-decline’ class with the steepest downward slope. Generally, membership of better classes was predicted by younger age, being female, more years of education, better health, healthier lifestyle, higher social engagement and lack of genetic risk variants. Some factors (e.g., education) were found to be associated with cognitive function over time only within individual classes. Conclusion: Cognitive aging in late life is a dynamic process with significant inter-individual variability. However, it remains unclear whether similar patterns of cognitive aging are observed across all cognitive domains. Further research into unique factors which promote the maintenance of high-cognitive function is needed to help inform public policy. Show more

Keywords: Cognitive function, longitudinal, older adults, prospective, risk factors, trajectory

DOI: 10.3233/ADR-200232

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 459-478, 2020

Authors: Robbins, James | Busquets, Oriol | Tong, Ming | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Brain insulin resistance and deficiency are well-recognized abnormalities in Alzheimer’s disease (AD) and likely mediators of impaired energy metabolism. Since apolipoprotein E (APOE ) is a major risk factor for late-onset AD, it was of interest to examine its potential contribution to altered insulin-linked signaling networks in the brain. Objective: The main goal was to evaluate the independent and interactive contributions of AD severity and APOE ɛ 4 dose on brain expression of insulin-related polypeptides and inflammatory mediators of metabolic dysfunction. Methods: Postmortem fresh frozen frontal lobe tissue from banked cases with known APOE …genotypes and different AD Braak stages were used to measure insulin network polypeptide immunoreactivity with a commercial multiplex enzyme-linked immunosorbent assay (ELISA). Results: Significant AD Braak stage and APOE genotype-related abnormalities in insulin, C-peptide, gastric inhibitory polypeptide (GIP), glucaton-like peptide-1 (GLP-1), leptin, ghrelin, glucagon, resistin, and plasminogen activator inhibitor-1 (PAI-1) were detected. The main factors inhibiting polypeptide expression and promoting neuro-inflammatory responses included AD Braak stage and APOE ɛ 4/ɛ 4 rather than ɛ 3/ɛ 4. Conclusion: This study demonstrates an expanded role for impaired expression of insulin-related network polypeptides as well as neuroinflammatory mediators of brain insulin resistance in AD pathogenesis and progression. In addition, the findings show that APOE has independent and additive effects on these aberrations in brain polypeptide expression, but the impact is decidedly greater for APOE ɛ 4/ɛ 4 than ɛ 3/ɛ 4. Show more

Keywords: Alzheimer’s disease, APOE, Braak stage, human brain, incretins, insulin resistance, leptin, multiplex ELISA, neurodegeneration, neuroinflammation

DOI: 10.3233/ADR-200238

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 479-493, 2020

Authors: Klawitter, Lukus | Mahoney, Sean J. | Dahl, Lindsey | Hackney, Kyle J. | Herrmann, Stephen D. | Edwards, Bradley | McGrath, Ryan

Article Type: Short Communication

Abstract: Handgrip dynamometers are used to assess handgrip strength (HGS), and low HGS is linked to poor cognitive function. Although HGS is a reliable measure of muscle function, it is only measuring maximal grip force. Other aspects of muscle function such as force control, fatigability, and steadiness are unaccounted for in current HGS protocols. This pilot study sought to determine the role of maximal HGS, submaximal HGS force control, HGS fatigability, and HGS neuromuscular steadiness on cognitive function in older adults. Our findings indicate that these additional HGS measurements could factor into detecting poorer cognitive functioning, while also evolving HGS protocols.

Keywords: Aging, geriatrics, geriatric assessment, mental status and dementia tests, muscle strength, muscle weakness, nervous system diseases

DOI: 10.3233/ADR-200225

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 495-499, 2020

Authors: Kanagasingam, Shalini | Chukkapalli, Sasanka S. | Welbury, Richard | Singhrao, Sim K.

Article Type: Review Article

Abstract: Porphyromonas gingivalis (P. gingivalis ) is one of the several important bacterial pathogens associated with the sporadic Alzheimer’s disease (AD). Different serotypes are either capsulated or are non-capsulated. It has been demonstrated that P. gingivalis (non-capsulated) can reproduce the neurodegenerative AD-like changes in vitro , and a capsular P. gingivalis (strain W83) could reproduce the cardinal hallmark lesions of AD in a wild-type mouse model. All P. gingivalis forms express proteolytically active proteases that enable cleavage of the amyloid-β protin precursor (AβPP) and tau resulting in the formation of amyloid-β and neurofibrillary tangles. Tau is an …established substrate for gingipains, which can cleave tau into various peptides. Some of the P. gingivalis fragmented tau protein peptides contain “VQIINK” and “VQIVYK” hexapeptide motifs which map to the flanking regions of the microtubule binding domains and are also found in paired helical filaments that form NFTs. P. gingivalis can induce peripheral inflammation in periodontitis and can also initiate signaling pathways that activate kinases, which in turn, phosphorylate neuronal tau. Periodontal disease related inflammation has metabolic implications for an individual’s peripheral and brain health as patients suffering from generalized periodontitis often have related co-morbidities and are “at risk” of developing AD. The aim here is to discuss the role of P. gingivalis behind such associations with the backdrop of huge efforts to test P. gingivalis virulence factors clinically (GAIN Trial: Phase 2/3 Study of COR388 in Subjects with AD) with inhibitors, which may lead to an intervention by reducing the pathogenic bacterial load. Show more

Keywords: Alzheimer’s disease, gingipains, periodontal disease, Porphyromonas gingivalis

DOI: 10.3233/ADR-200250

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 501-511, 2020

Authors: Garba, Asabe E. | Grossberg, George T. | Enard, Kimberly R. | Jano, Fabian J. | Roberts, Emma N. | Marx, Charlotte A. | Buchanan, Paula M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the 6th leading cause of death in the United States and has no cure or progression prevention. The Cognitive Reserve (CR) theory poses that constant brain activity earlier in life later helps to deter pathological changes in the brain, delaying the onset of disease symptoms. Objective: To determine the reliability and validity of the Cognitive Reserve Index questionnaire (CRIq) in AD patients. Methods: Primary data collection was done using the CRIq to quantify CR in 90 participants. Correlations and multivariable linear regressions were used to assess reliability and validity. …Results: Reliability was tested in 34 participants. A Pearson correlation coefficient of 0.89 (p  < 0.001) indicated a strong positive correlation. Validity was tested in 33 participants. A Pearson correlation coefficient of 0.30 (p  = 0.10) indicated an insignificant weak positive correlation. Conclusion: The CRIq was found reliable. Gaining a better understanding of how CR tools can be used in various cognitive populations will help with the establishment of a research tool that is universally accepted as a true CR measure. Show more

Keywords: Alzheimer’s disease, cognitive reserve, reliability and validity, surveys and questionnaires, wechsler scales

DOI: 10.3233/ADR-200244

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 513-524, 2020

Authors: Madsen, Steven J. | DiGiacomo, Phillip S. | Zeng, Yitian | Goubran, Maged | Chen, Yuanxin | Rutt, Brian K. | Born, Donald | Vogel, Hannes | Sinclair, Robert | Zeineh, Michael M.

Article Type: Research Article

Abstract: Background: Recent evidence suggests that the accumulation of iron, specifically ferrous Fe2+ , may play a role in the development and progression of neurodegeneration in Alzheimer’s disease (AD) through the production of oxidative stress. Objective: To localize and characterize iron deposition and oxidation state in AD, we analyzed human hippocampal autopsy samples from four subjects with advanced AD that have been previously characterized with correlative MRI-histology. Methods: We perform scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and electron energy loss spectroscopy (EELS) in the higher resolution transmission electron microscope on the surface and cross-sections of …specific iron-rich regions of interest. Results: Specific previously analyzed regions were visualized using SEM and confirmed to be iron-rich deposits using EDS. Subsequent analysis using focused ion beam cross-sectioning and SEM characterized the iron deposition throughout the 3-D volumes, confirming the presence of iron throughout the deposits, and in two out of four specimens demonstrating colocalization with zinc. Analysis of traditional histology slides showed the analyzed deposits overlapped both with amyloid and tau deposition. Following higher resolution analysis of a single iron deposit using scanning transmission electron microscope (STEM), we demonstrated the potential of monochromated STEM-EELS to discern the relative oxidation state of iron within a deposit. Conclusion: These findings suggest that iron is present in the AD hippocampus and can be visualized and characterized using combined MRI and EM techniques. An altered relative oxidation state may suggest a direct link between iron and oxidative stress in AD. These methods thus could potentially measure an altered relative oxidation state that could suggest a direct link between iron and oxidative stress in AD. Furthermore, we have demonstrated the ability to analyze metal deposition alongside commonly used histological markers of AD pathology, paving the way for future insights into the molecular interactions between Aβ, tau, iron, and other putative metals, such as zinc. Show more

Keywords: Alzheimer’s disease, correlative microscopy, histopathology, iron, neuroinflammation, oxidative stress, specimen MRI

DOI: 10.3233/ADR-200234

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 525-536, 2020

Authors: Rangon, Claire-Marie | Krantic, Slavica | Moyse, Emmanuel | Fougère, Bertrand

Article Type: Review Article

Abstract: Coronavirus Disease 2019 (COVID-19) pandemic-triggered mortality is significantly higher in older than in younger populations worldwide. Alzheimer’s disease (AD) is related to aging and was recently reported to be among the major risk factors for COVID-19 mortality in older people. The symptomatology of COVID-19 indicates that lethal outcomes of infection rely on neurogenic mechanisms. The present review compiles the available knowledge pointing to the convergence of COVID-19 complications with the mechanisms of autonomic dysfunctions in AD and aging. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is prone to neuroinvasion from the lung along the vagus nerve up to the brainstem …autonomic nervous centers involved in the coupling of cardiovascular and respiratory rhythms. The brainstem autonomic network allows SARS-CoV-2 to trigger a neurogenic switch to hypertension and hypoventilation, which may act in synergy with aging- and AD-induced dysautonomias, along with an inflammatory “storm”. The lethal outcomes of COVID-19, like in AD and unhealthy aging, likely rely on a critical hypoactivity of the efferent vagus nerve cholinergic pathway, which is involved in lowering cardiovascular pressure and systemic inflammation tone. We further discuss the emerging evidence supporting the use of 1) the non-invasive stimulation of vagus nerve as an additional therapeutic approach for severe COVID-19, and 2) the demonstrated vagal tone index, i.e., heart rate variability, via smartphone-based applications as a non-serological low-cost diagnostic of COVID-19. These two well-known medical approaches are already available and now deserve large-scale testing on human cohorts in the context of both AD and COVID-19. Show more

Keywords: Brainstem, dysautonomia, heart rate variability, neuro-immune axis, pulmonary ventilation, vagus nerve, vagus nerve stimulation

DOI: 10.3233/ADR-200273

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 537-551, 2020