Journal of Alzheimer's Disease - Volume 75, issue 2

Authors: Huang, Shu-Yi | Zhu, Jun-Xia | Shen, Xue-Ning | Xu, Wei | Ma, Ya-Hui | Li, Hong-Qi | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The National Institute on Aging and Alzheimer’s Association proposed an ATN classification system which divided Alzheimer’s disease biomarkers into three binary classes: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Objective: To estimate the prevalence of each profile and to describe the demographic characteristics of each group in Chinese cognitively intact older adults. Methods: In this cross-sectional study, 561 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study were classified into eight groups using cerebrospinal fluid amyloid-β 42/40 as A, phosphorylated tau as T, and total tau as N. …Multinomial models were used to determine the estimated prevalence of the eight groups. Results: The number and proportion of 561 participants in each ATN profile were 254 A-T-N- (45.3%), 28 A-T+N- (5.0%), 21 A-T-N+ (3.7%), 71 A-T+N+ (12.7%), 78 A + T-N- (13.9%), 14 A + T+N- (2.5%), 21 A + T-N+ (3.7%), and 74 A + T+N+ (13.2%). Individuals in N+ groups tend to be older than N- groups. A+ groups included more female individuals. The prevalence of A-T-N- profile declined with age, while that of A + T+N+ increased continuously. Conclusion: This is the first work to estimate the prevalence of each ATN profile and describe the demographic characteristics of ATN profiles based on a Chinese cohort. The clinical implications of our findings need to be scrutinized further in longitudinal studies of the ATN classification system. Show more

Keywords: Alzheimer’s disease, ATN classification system, biomarkers, prevalence

DOI: 10.3233/JAD-200059

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 483-492, 2020

Authors: Youn, Young Chul | Lee, Byoung Sub | Kim, Gwang Je | Ryu, Ji Sun | Lim, Kuntaek | Lee, Ryan | Suh, Jeewon | Park, Young Ho | Pyun, Jung-Min | Ryu, Nayoung | Kang, Min Ju | Kim, Hye Ryoun | Kang, Sungmin | An, Seong Soo A. | Kim, SangYun

Article Type: Research Article

Abstract: Background: Oligomeric amyloid-β (Aβ) is one of the major contributors to the pathomechanism of Alzheimer’s disease (AD); Aβ oligomerization in plasma can be measured using a Multimer Detection System-Oligomeric Aβ (MDS-OAβ) after incubation with spiked synthetic Aβ. Objective: We evaluated the clinical sensitivity and specificity of the MDS-OAβ values for prediction of AD. Methods: The MDS-OAβ values measured using inBlood™ OAβ test in heparin-treated plasma samples from 52 AD patients in comparison with 52 community-based subjects with normal cognition (NC). The inclusion criterion was proposed by the NINCDS-ADRDA and additionally required at least 6 months of …follow-up from the initial clinical diagnosis in the course of AD. Results: The MDS-OAβ values were 1.43±0.30 ng/ml in AD and 0.45±0.19 (p  < 0.001) in NC, respectively. Using a cut-off value of 0.78 ng/ml, the results revealed 100% sensitivity and 92.31% specificity. Conclusion: MDS-OAβ to measure plasma Aβ oligomerization is a valuable blood-based biomarker for clinical diagnosis of AD, with high sensitivity and specificity. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, blood, multimer detection system, oligomer

DOI: 10.3233/JAD-200061

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 493-499, 2020

Authors: Shiells, Helen | Schelter, Bjoern O. | Bentham, Peter | Baddeley, Thomas C. | Rubino, Christopher M. | Ganesan, Harish | Hammel, Jeffrey | Vuksanovic, Vesna | Staff, Roger T. | Murray, Alison D. | Bracoud, Luc | Wischik, Damon J. | Riedel, Gernot | Gauthier, Serge | Jia, Jianping | Moebius, Hans J. | Hardlund, Jiri | Kipps, Christopher M. | Kook, Karin | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. Methods: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response …analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. Results: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3–0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20–60 mg/day. A confirmatory placebo-controlled trial is now planned. Show more

Keywords: Behavioral variant frontotemporal dementia, clinical trials, hydromethylthionine, leucomethylthioninium, tau protein, TDP-43

DOI: 10.3233/JAD-191173

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 501-519, 2020

Authors: Yasar, Sevil | Moored, Kyle D. | Adam, Atif | Zabel, Fiona | Chuang, Yi-Fang | Varma, Vijay R. | Carlson, Michelle C.

Article Type: Research Article

Abstract: Background: There is emerging evidence about possible involvement of the renin-angiotensin system (RAS) in the pathogenesis of Alzheimer’s disease (AD) and decline of cognitive function. However, little is known about associations with brain biomarkers. Objective: Our study aimed to examine associations between blood ACE-1 and ANG II levels and brain MRI based volumes in non-demented participants, and whether these associations were mediated by blood pressure. Methods: This cross-sectional study was conducted in 34 older participants from the Baltimore Experience Corps Trial (BECT) Brain Health Sub-study (BHS). Blood ANGII and ACE-1 levels were measured by ELISA and …brain MRI volumes were generated using FreeSurfer 6.0. Multiple linear regression analysis, adjusting for intracranial volume and confounders, was used to determine associations between log transformed ANGII and ACE-1 levels and MRI volumes (mm3 ). Results: Participants were predominantly female (76%), African-American (94%), with mean age of 66.9 and education of 14.4 years. In the fully adjusted model we observed significant inverse associations between log ANGII levels and total grey matter (β=Angiotensin II associated with smaller hippocampus14,935.50, ±7,444.83, p  = 0.05), total hippocampus (β=–129.97, ±105.27, p  = 0.03), rostral middle frontal (β= –1580.40, ±584.74, p  = 0.02), and supramarginal parietal (β= –978.90, ±365.54, p  = 0.02) volumes. There were no associations between ANGII levels and total white matter or entorhinal cortex volumes, or ACE-1 levels and any brain volumes. Conclusion: We observed that increased blood ANGII levels were associated with lower total grey matter, hippocampal, rostral middle frontal, and supramarginal parietal volumes, which are associated with cognitive domains that decline in preclinical AD. Show more

Keywords: Angiotensin II, angiotensin converting enzyme-1, cohort study, MRI

DOI: 10.3233/JAD-200118

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 521-529, 2020

Authors: Kim, Bo-Hyun | Choi, Yong-Ho | Yang, Jin-Ju | Kim, SangYun | Nho, Kwangsik | Lee, Jong-Min | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by a heterogeneous distribution of pathological changes in the brain. Cortical thickness is one of the most sensitive imaging biomarkers for AD representing structural atrophy. The purpose of this study is to identify novel genes associated with cortical thickness. We measured the whole-brain mean cortical thickness from magnetic resonance imaging (MRI) scans in 919 subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort, including 163 AD patients, 488 mild cognitive impairment patients, and 268 cognitively normal participants. Based on the single-nucleotide polymorphism (SNP)-based genome-wide association study, we performed gene-based association analysis for …mean cortical thickness. Furthermore, we performed expression quantitative trait loci, protein-protein interaction network, and pathway analysis to identify biologically functional information. We identified four genes (B4GALNT1 , RAB44 , LOC101927583 , and SLC26A10 ), two pathways (cyclin-dependent protein kinase holoenzyme complex and nuclear cyclin-dependent protein kinase holoenzyme complex), and one protein-protein interaction (B4GALNT1 and GALNT8 pair). These genes are involved in protein degradation, GTPase activity, neuronal loss, and apoptosis. The identified pathways are involved in the cellular processes and neuronal differentiation, which contribute to neuronal loss that is responsible for AD. Furthermore, the most significant SNP (rs12320537) in B4GALNT1 is associated with expression levels of B4GALNT1 in several brain regions. Thus, the identified genes and pathways provide deeper mechanistic insight into the molecular basis of brain atrophy in AD. Show more

Keywords: Alzheimer’s disease, brain, cortical thickness, gene-based association analysis, genome-wide association study, imaging genetics

DOI: 10.3233/JAD-191175

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 531-545, 2020

Authors: Henderson, Samuel T. | Morimoto, Bruce H. | Cummings, Jeffrey L. | Farlow, Martin R. | Walker, Judith

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β plaques, neurofibrillary tangles, and regional cerebral glucose hypometabolism. Providing an alternative metabolic substrate, such as ketone bodies, may be a viable therapeutic option. Objective: The objective was to determine the efficacy and safety of the AC-1204 formulation of caprylic triglyceride administered daily for 26 weeks in APOE4 non-carrier participants with mild-to-moderate AD. Methods: In a double-blind, placebo-controlled, randomized study (AC-12-010, NOURISH AD, NCT 01741194), 413 patients with mild-to-moderate probable AD were stratified by APOE genotype and randomized (1 : 1) to receive either placebo or AC-1204 for 26 …weeks. The primary outcome was the change from baseline to week 26 on the 11-item Alzheimer’s Disease Assessment Scale - Cognitive subscale (ADAS-Cog11) among APOE4 non-carriers. The key secondary outcome was the change from baseline to week 26 in the Alzheimer’s Disease Cooperative Study – Clinician’s Global Impression of Change scale. Results: Administration of AC-1204 was safe and well-tolerated. Mean changes from baseline in the primary outcome at 26 weeks in ADAS-Cog11 for placebo (n  = 138) was 0.0 and for AC-1204 (n  = 137) was 0.6 (LS differences of mean – 0.761, p  = 0.2458) and secondary outcome measures failed to detect any drug effects. Conclusion: The AC-1204 formulation of caprylic triglyceride failed to improve cognition or functional ability in subjects with mild-to-moderate AD. The lack of efficacy observed in this study may have several contributing factors including a lower ketone body formation from AC-1204 than expected and a lack of decline in the patients receiving placebo. Show more

Keywords: Apolipoprotein E4, clinical trial, glucose, ketone body, ketosis, metabolism

DOI: 10.3233/JAD-191302

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 547-557, 2020

Authors: Westfall, Susan | Dinh, Duy M. | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Background: Dysbiotic microbiota in the gastrointestinal tract promotes and aggravates neurodegenerative disorders. Alzheimer’s disease (AD) has been shown to correlate to dysbiotic bacteria and the immune, metabolic, and endocrine abnormalities associated with abnormal gut-brain-axis signaling. Recent reports also indicate that brain dysbacteriosis may play a role in AD pathogenesis. Objective: To evaluate the presence and differences of brain-region dependent microbiomes in control and AD subjects and the contribution of study bias. Methods: Two independent cohorts of postmortem AD brain samples were collected from separate locations, processed with different extraction protocols and investigated for the presence of …bacterial DNA indicative of a brain microbiome with V4 16S next generation sequencing. Results: In both cohorts, few differences between the control and AD groups were observed in terms of alpha and beta diversities, phyla and genera proportions. Independent of study in both AD and control subjects the most abundant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Variations in beta diversity between hippocampal and cerebellum samples were observed indicating an impact of brain region on the presence of microbial DNA. Importantly, differences in alpha and beta diversities between the two independent cohorts were found indicating a significant cohort- and processing-dependent effect on the microbiome. Finally, there were cohort-specific correlations between the gut microbiome and subject demographics indicate that postmortem interval may have a significant impact on brain microbiome determination. Conclusions: Regardless of the study bias, this study concludes that bacterial DNA can be isolated from the human brain suggesting that a brain microbiome may exist; however, more studies are required to understand the variation in AD. Show more

Keywords: Alzheimer’s disease, gut-brain-axis, microbiome, neurodegeneration, 16S sequencing

DOI: 10.3233/JAD-191328

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 559-570, 2020

Authors: Li, Lin | Wu, Dan-Hong | Li, Hong-Qi | Tan, Lin | Xu, Wei | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The role of cerebral microbleeds (CMBs) in cognitive impairment remains controversial. Objective: To investigate the possible links between the presence, progression, number, and location of CMBs and cognition. Methods: We assessed 792 subjects from the Alzheimer’s Disease Neuroimaging Initiative who underwent both brain 3 Tesla MRI scans and cognitive testing. The association between CMBs and cognitive change was explored using linear mixed-effects models (LME). Results: Presence and number of CMBs were associated with memory (β= –0.03, p  = 0.015; β= –0.01, p  = 0.003), executive function (β= –0.04, p  = 0.010; β= –0.01, p  = 0.014), and global cognitive function (β= –0.06, …p  = 0.025; β= –0.03, p  < 0.001). Progression of CMBs showed significant negative associations with executive function (β= –0.05, p  = 0.025) and global cognitive function (β= –0.12, p  = 0.015). The relations with cognitive performance (memory, executive function and global cognitive function) were mainly driven by lobar CMBs (β= –0.03, p  = 0.041; β= –0.04, p  = 0.010; β= –0.07, p  = 0.029, respectively), especially those located in temporal lobe (β= –0.08, p  = 0.027; β= –0.13, p  = 0.001; β= –0.26, p  < 0.001, respectively). Furthermore, white matter hyperintensities may mediate the association between CMBs and cognition. Conclusion: The presence, progression, number, and location of CMBs, especially those located in temporal lobe, are associated with cognitive decline. These findings suggest CMBs play a role in cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebral microbleeds, cognitive function

DOI: 10.3233/JAD-191257

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 571-579, 2020

Authors: Piovezan, Ronaldo D. | Oliveira, Déborah | Arias, Nicole | Acosta, Daisy | Prince, Martin J. | Ferri, Cleusa P.

Article Type: Research Article

Abstract: Background: Dementia is the main cause of disability in older people living in low- and middle-income countries (LMIC). Monitoring mortality rates and mortality risk factors in people with dementia (PwD) may contribute to improving care provision. Objective: We aimed to estimate mortality rates and mortality predictors in PwD from eight LMICs. Methods: This 3–5-year prospective cohort study involved a sample of 1,488 older people with dementia from eight LMIC. Total, age- and gender-specific mortality rates per 1,000 person-years at risk, as well as the total, age- and gender-adjusted mortality rates were estimated for each country’s sub-sample. …Cox’s regressions were used to establish the predictors of mortality. Results: At follow-up, vital status of 1,304 individuals (87.6%) was established, of which 593 (45.5%) were deceased. Mortality rate was higher in China (65.9%) and lower in Mexico (26.9%). Mortality risk was higher in males (HR = 1.57; 95% CI: 1.32,1.87) and increased with age (HR = 1.04; 95% CI: 1.03,1.06). Neuropsychiatric symptoms (HR = 1.03; 95% CI: 1.01,1.05), cognitive decline (HR 1.04; 95% CI: 1.03,1.05), undernutrition (HR = 1.55; 95% CI: 1.19, 2.02), physical impairments (HR = 1.15; 95% CI: 1.03,1.29), and disease severity (HR = 1.43; 95% CI: 1.22,1.63) predicted higher mortality risk. Conclusion: Several factors predicted higher mortality risk in PwD in LMICs. Males, those with higher age, higher severity of neuropsychiatric symptoms, higher number of physical impairments, higher disease severity, lower cognitive performance, and undernutrition had higher mortality risk. Addressing these indicators of long-term adverse outcomes may potentially contribute to improved advanced care planning, reducing the burden of disease in low-resourced settings. Show more

Keywords: Dementia, low- and middle-income countries, mortality risk, population-based studies

DOI: 10.3233/JAD-200078

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 581-593, 2020

Authors: Domínguez-Vivero, Clara | Wu, Liwen | Lee, Seonjoo | Manoochehri, Masood | Cines, Sarah | Brickman, Adam M. | Rizvi, Batool | Chesebro, Anthony | Gazes, Yunglin | Fallon, Emer | Lynch, Timothy | Heidebrink, Judith L. | Paulson, Henry | Goldman, Jill S. | Huey, Edward | Cosentino, Stephanie

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread. Objective: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers. Methods: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT …mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences). Results: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis. Conclusion: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset. Show more

Keywords: Atrophy, brain atrophy, early detection, frontotemporal lobar degeneration, MAPT mutation

DOI: 10.3233/JAD-190820

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 595-606, 2020