Journal of Alzheimer's Disease - Volume 78, issue 3

Authors: Bartels, Claudia | Kögel, Anna | Schweda, Mark | Wiltfang, Jens | Pentzek, Michael | Schicktanz, Silke | Schneider, Anja

Article Type: Research Article

Abstract: Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals …and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42 , tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p ≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p  = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed. Show more

Keywords: Alzheimer’s disease, biomarker, mild cognitive impairment, prediction, questionnaires, subjective cognitive decline, surveys

DOI: 10.3233/JAD-200794

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1137-1148, 2020

Authors: Hallab, Asma | Lange, Catharina | Apostolova, Ivayla | Özden, Cansu | Gonzalez-Escamilla, Gabriel | Klutmann, Susanne | Brenner, Winfried | Grothe, Michel J. | Buchert, Ralph | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Research in rodents identified specific neuron populations encoding information for spatial navigation with particularly high density in the medial part of the entorhinal cortex (ERC), which may be homologous with Brodmann area 34 (BA34) in the human brain. Objective: The aim of this study was to test whether impaired spatial navigation frequently occurring in mild cognitive impairment (MCI) is specifically associated with neurodegeneration in BA34. Methods: The study included baseline data of MCI patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative with high-resolution structural MRI, brain FDG PET, and complete visuospatial ability scores of the …Everyday Cognition test (VS-ECog) within 30 days of PET. A standard mask of BA34 predefined in MNI space was mapped to individual native space to determine grey matter volume and metabolic activity in BA34 on MRI and on (partial volume corrected) FDG PET, respectively. The association of the VS-ECog sum score with grey matter volume and metabolic activity in BA34, APOE4 carrier status, age, education, and global cognition (ADAS-cog-13 score) was tested by linear regression. BA28, which constitutes the lateral part of the ERC, was used as control region. Results: The eligibility criteria led to inclusion of 379 MCI subjects. The VS-ECog sum score was negatively correlated with grey matter volume in BA34 (β= –0.229, p  = 0.022) and age (β= –0.124, p  = 0.036), and was positively correlated with ADAS-cog-13 (β= 0.175, p  = 0.003). None of the other predictor variables contributed significantly. Conclusion: Impairment of spatial navigation in MCI is weakly associated with BA34 atrophy. Show more

Keywords: Entorhinal cortex, 18F-fluorodeoxyglucose, grid cells, magnetic resonance imaging, mild cognitive impairment, positron emission tomography, spatial navigation, volumetry

DOI: 10.3233/JAD-200520

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1149-1159, 2020

Authors: Zhang, Zhihua | Sheng, Hongxia | Liao, Li | Xu, Chen | Zhang, Ang | Yang, Yang | Zhao, Long | Duan, Lian | Chen, Hu | Zhang, Bin

Article Type: Research Article

Abstract: Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro . Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y …cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181 -tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, apoptosis, mesenchymal stem cell-conditioned medium, mitochondrial dysfunction, mitochondrial transfer

DOI: 10.3233/JAD-200686

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1161-1176, 2020

Authors: Innes, Kim E. | Sambamoorthi, Usha

Article Type: Research Article

Abstract: Background: Growing evidence suggests that chronic pain and certain chronic pain conditions may increase risk for cognitive decline and dementia. Objective: In this systematic review, we critically evaluate available evidence regarding the association of chronic pain and specific common chronic pain conditions to subsequent decline in cognitive function, new onset cognitive impairment (CI), and incident Alzheimer’s disease and related dementias (ADRD); outline major gaps in the literature; and provide a preliminary conceptual model illustrating potential pathways linking pain to cognitive change. Methods: To identify qualifying studies, we searched seven scientific databases and scanned bibliographies of identified …articles and relevant review papers. Sixteen studies met our inclusion criteria (2 matched case-control, 10 retrospective cohort, 2 prospective cohort), including 11 regarding the association of osteoarthritis (N  = 4), fibromyalgia (N  = 1), or headache/migraine (N  = 6) to incident ADRD (N  = 10) and/or its subtypes (N  = 6), and 5 investigating the relation of chronic pain symptoms to subsequent cognitive decline (N  = 2), CI (N  = 1), and/or ADRD (N  = 3). Results: Studies yielded consistent evidence for a positive association of osteoarthritis and migraines/headaches to incident ADRD; however, findings regarding dementia subtypes were mixed. Emerging evidence also suggests chronic pain symptoms may accelerate cognitive decline and increase risk for memory impairment and ADRD, although findings and measures varied considerably across studies. Conclusion: While existing studies support a link between chronic pain and ADRD risk, conclusions are limited by substantial study heterogeneity, limited investigation of certain pain conditions, and methodological and other concerns characterizing most investigations to date. Additional rigorous, long-term prospective studies are needed to elucidate the effects of chronic pain and specific chronic pain conditions on cognitive decline and conversion to ADRD, and to clarify the influence of potential confounding and mediating factors. Show more

Keywords: Alzheimer’s disease, chronic pain, cognitive decline, cognitive impairment, dementia, fibromyalgia, headache, osteoarthritis, rheumatic

DOI: 10.3233/JAD-200960

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1177-1195, 2020

Authors: Schmidt, Guilherme J. | Boechat, Yolanda Eliza Moreira | van Duinkerken, Eelco | Schmidt, Juliana J. | Moreira, Tayssa B. | Nicaretta, Denise H. | Schmidt, Sergio L.

Article Type: Research Article

Abstract: Background: Scales for cognitive deterioration usually depend on education level. Objective: We aimed to study the clinical utility of a culture-free Go/No-Go task in a multi-ethnic cohort with low education level. Methods: Sixty-four participants with less than 4 years of formal education were included and divided on the basis of their Clinical-Dementia-Rate scores (CDR) into cognitively unimpaired (CDR = 0), mild cognitive impairment (MCI; CDR = 0.5), and early Alzheimer’s disease (AD, CDR = 1). All underwent a 90-s Continuous Visual Attention Test. This test consisted of a 90-s Go/No-go task with 72 (80%) targets and 18 (20%) non-targets. For each participant, …reaction times and intraindividual variability of reaction times of all correct target responses, as well as the number of omission and commission errors were evaluated. Coefficient of variability was calculated for each participant by dividing the standard deviation of the reaction times by the mean reaction time. A MANCOVA was performed to examine between-group differences using age and sex as covariates. Discriminate analysis was performed to find the most reliable test-variable to discriminate the three groups. Results: Commission error, intraindividual variability of reaction time, and coefficient of variability progressively worsened with increasing CDR level. Discriminant analysis demonstrated that coefficient of variability was the best discriminant factor, followed by intraindividual variability of reaction time and commission error. Conclusion: The Go/No-Go task was able to discriminate people with MCI or early AD from controls in the setting of illiteracy. Show more

Keywords: Attention, cognitive dysfunction, dementia, neuropsychology, reaction time

DOI: 10.3233/JAD-200881

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1197-1205, 2020

Authors: Clare, Linda | Martyr, Anthony | Henderson, Catherine | Gamble, Laura | Matthews, Fiona E. | Quinn, Catherine | Nelis, Sharon M. | Rusted, Jennifer | Thom, Jeanette | Knapp, Martin | Hart, Nicola | Victor, Christina

Article Type: Research Article

Abstract: Background: A significant proportion of people with dementia live alone, but little is known about their specific needs. Objective: To understand the profile of people living alone with mild-to-moderate dementia in the UK and identify any systematic differences associated with living situation. Methods: We analyzed cross-sectional data from 1,541 people with mild-to-moderate dementia and 1,277 caregivers participating in the IDEAL cohort at the first wave of assessment. Results: There were 1,256 (81.5%) people with dementia living with others and 285 (18.5%) living alone, of whom 51 (3% of whole sample) reported little or no …informal support. There were relatively few differences associated with living situation and odds ratios were generally small. People living alone were older on average, and more likely to be female, than those living with others. Those living alone were more likely to have higher cognitive ability and self-reported functional ability, and more social contact with those from other households. They were also lonelier, expressed less satisfaction with life, and used home care services and equipment more. There were no differences in symptoms, mood, quality of life, or well-being. Conclusion: The findings support the view that it is possible to ‘live well’ with mild-to-moderate dementia while living alone, given appropriate support, including home care and equipment. Nevertheless, it is important to consider how those living alone may be supported to have a more satisfactory experience, and how health and social care services can best respond to their needs. Show more

Keywords: Aids and adaptations, Alzheimer’s disease, service use, social capitals, assets and resources, vascular dementia

DOI: 10.3233/JAD-200638

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1207-1216, 2020

Authors: Zhang, Ying | Hao, Yajing | Li, Lang | Xia, Kai | Wu, Guorong | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Although the abnormal depositions of amyloid plaques and neurofibrillary tangles are the hallmark of Alzheimer’s disease (AD), converging evidence shows that the individual’s neurodegeneration trajectory is regulated by the brain’s capability to maintain normal cognition. Objective: The concept of cognitive reserve has been introduced into the field of neuroscience, acting as a moderating factor for explaining the paradoxical relationship between the burden of AD pathology and the clinical outcome. It is of high demand to quantify the degree of conceptual cognitive reserve on an individual basis. Methods: We propose a novel statistical model to quantify …an individual’s cognitive reserve against neuropathological burdens, where the predictors include demographic data (such as age and gender), socioeconomic factors (such as education and occupation), cerebrospinal fluid biomarkers, and AD-related polygenetic risk score. We conceptualize cognitive reserve as a joint product of AD pathology and socioeconomic factors where their interaction manifests a significant role in counteracting the progression of AD in our statistical model. Results: We apply our statistical models to re-investigate the moderated neurodegeneration trajectory by considering cognitive reserve, where we have discovered that 1) high education individuals have significantly higher reserve against the neuropathology than the low education group; however, 2) the cognitive decline in the high education group is significantly faster than low education individuals after the level of pathological burden increases beyond the tipping point. Conclusion: We propose a computational proxy of cognitive reserve that can be used in clinical routine to assess the progression of AD. Show more

Keywords: Alzheimer’s disease, cognitive reserve, computational proxy

DOI: 10.3233/JAD-201011

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1217-1228, 2020

Authors: Shams, Mana | Martola, Juha | Charidimou, Andreas | Granberg, Tobias | Ferreira, Daniel | Westman, Eric | Wintermark, Max | Iv, Michael | Larvie, Mykol | Kristoffersen Wiberg, Maria | Kaijser, Magnus | Forsgard, Niklas | Zetterberg, Henrik | Wahlund, Lars-Olof | Shams, Sara

Article Type: Research Article

Abstract: Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) …42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42 , T-tau, P-tau, and CSF/serum albumin ratios (p  < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOE ɛ 4 carriers. Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOE ɛ 4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive aging, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-200656

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1229-1236, 2020

Authors: Mehta, Pankaj D. | Patrick, Bruce A. | Miller, David L. | Coyle, Patricia K. | Wisniewski, Thomas

Article Type: Research Article

Abstract: Background: Amyloid-β42 (Aβ42 ) is associated with plaque formation in the brain of patients with Alzheimer’s disease (AD). Studies have suggested the potential utility of plasma Aβ42 levels in the diagnosis, and in longitudinal study of AD pathology. Conventional ELISAs are used to measure Aβ42 levels in plasma but are not sensitive enough to quantitate low levels. Although ultrasensitive assays like single molecule array or immunoprecipitation-mass spectrometry have been developed to quantitate plasma Aβ42 levels, the high cost of instruments and reagents limit their use. Objective: We hypothesized that a sensitive and cost-effective chemiluminescence …(CL) immunoassay could be developed to detect low Aβ42 levels in human plasma. Methods: We developed a sandwich ELISA using high affinity rabbit monoclonal antibody specific to Aβ42 . The sensitivity of the assay was increased using CL substrate to quantitate low levels of Aβ42 in plasma. We examined the levels in plasma from 13 AD, 25 Down syndrome (DS), and 50 elderly controls. Results: The measurement range of the assay was 0.25 to 500 pg/ml. The limit of detection was 1 pg/ml. All AD, DS, and 45 of 50 control plasma showed measurable Aβ42 levels. Conclusion: This assay detects low levels of Aβ42 in plasma and does not need any expensive equipment or reagents. It offers a preferred alternative to ultrasensitive assays. Since the antibodies, peptide, and substrate are commercially available, the assay is well suited for academic or diagnostic laboratories, and has a potential for the diagnosis of AD or in clinical trials. Show more

Keywords: Alzheimer’s disease, amyloid-β 1-42 (Aβ42) peptide, chemiluminescence, ELISA, plasma, rabbit monoclonal antibody (RabmAb) to Aβ42, sensitive and cost-effective method

DOI: 10.3233/JAD-200861

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1237-1244, 2020

Authors: Klinedinst, Brandon S. | Le, Scott T. | Larsen, Brittany | Pappas, Colleen | Hoth, Nathan J. | Pollpeter, Amy | Wang, Qian | Wang, Yueying | Yu, Shan | Wang, Li | Allenspach, Karin | Mochel, Jonathan P. | Bennett, David A. | Willette, Auriel A.

Article Type: Research Article

Abstract: Background: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer’s disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE 4 (ɛ 4). Objective: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. Methods: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total …diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). Results: Daily cheese intake strongly predicted better FIT scores over time (FH-: β = 0.207, p  < 0.001; ɛ 4–: β = 0.073, p  = 0.008; ɛ 4+: β = 0.162, p  = 0.001). Alcohol of any type daily also appeared beneficial (ɛ 4+: β = 0.101, p  = 0.022) and red wine was sometimes additionally protective (FH+: β = 0.100, p  = 0.014; ɛ 4–: β = 0.59, p  = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: β = 0.066, p  = 0.008; ɛ 4+: β = 0.097, p  = 0.044). Among at risk groups, added salt correlated with decreased performance (FH+: β = –0.114, p  = 0.004; ɛ 4+: β = –0.121, p  = 0.009). Conclusion: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes. Show more

Keywords: Aging, APOE4, cognitive decline, functional food, lamb, Mediterranean diet, nutrition policy, preventive medicine, red wine, salt

DOI: 10.3233/JAD-201058

Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1245-1257, 2020