Journal of Alzheimer's Disease - Volume 72, issue 1

Authors: Castora, Frank J. | Conyers, Barbara L. | Gershon, Blake S. | Kerns, Kimberly A. | Campbell, Jr , Robert | Simsek-Duran, Fatma

Article Type: Research Article

Abstract: Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been reported in AD brains and platelets. We previously identified a point mutation at np 9861 in AD brain mitochondrial DNA (mtDNA) that alters amino acid 219 of subunit III of CO from phenylalanine to leucine. We rapidly screened and quantitated levels of T9861C in samples using mismatched PCR-RFLP and nucleotide extension assays. Six of 40 AD brains possessed the T9861C mutation (designated AD+ ) compared to zero of 40 …age-matched control brains. The 15% frequency of T9861C in AD brain is 115-fold higher than the frequency (0.13%) reported in 9,986 human mtDNA samples queried in world-wide databases. T9861C is heteroplasmic, with mutant load varying from 11% to >95%. Detected initially in parietal cortex, T9861C is not localized to that region but is also found in temporal cortex and caudate but not in hippocampus. The mutant load is unequally distributed throughout these brain regions with the highest load occurring in the parietal or temporal cortex. CO activity normalized to citrate synthase (CS) is reduced an average of 48.5% in AD+ brains. CO/CS ratios amongst controls and the two AD populations (AD and AD+) were significantly different (p  = 0.001). Post hoc differences were also significant between controls and AD+ (p  = 0.001) and controls and AD (p  = 0.019). There was no significant difference between AD and AD+ (p  = 0.317). Show more

Keywords: Alzheimer’s disease, cytochrome oxidase subunit III, DNA, DNA mutational analysis, mitochondrial

DOI: 10.3233/JAD-190176

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 257-269, 2019

Authors: Jingami, Naoto | Uemura, Kengo | Asada-Utsugi, Megumi | Kuzuya, Akira | Yamada, Shigeki | Ishikawa, Masatsune | Kawahara, Takashi | Iwasaki, Takuya | Atsuchi, Masamichi | Takahashi, Ryosuke | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. Methods: We analyzed CSF concentrations of tau, amyloid-β (Aβ) 42 and 40, and leucine rich α -2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap …test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p  = 0.003, VCSF/FD = 2.76, p  = 0.02). Conversely, Aβ42 (LD/FD = 0.80, p  < 0.001, VCSF/FD = 0.38, p  = 0.03) and LRG (LD/FD = 0.74, p  < 0.001, VCSF/FD = 0.09, p  = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p  = 0.02) and LRG (p  = 0.04), respectively. Conclusions: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid biomarker, idiopathic normal pressure hydrocephalus, leucine rich α-2-glycoprotein, tap test, tau

DOI: 10.3233/JAD-190775

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 271-277, 2019

Authors: Robinson, Rebecca L. | Rentz, Dorene M. | Bruemmer, Valerie | Scott Andrews, Jeffrey | Zagar, Anthony | Kim, Yongin | Schwartz, Ronald L. | Ye, Wenyu | Fillit, Howard M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the costliest diseases in the United States. Objective: To describe aspects of real-world patient and caregiver burden in patients with clinician-diagnosed early AD, including mild cognitive impairment (MCI) and mild dementia (MILD) due to AD. Methods: Cross-sectional assessment of GERAS-US, a 36-month cohort study of patients seeking care for early AD. Eligible patients were categorized based on study-defined categories of MCI and MILD and by amyloid positivity [+] or negativity [–] within each severity cohort. Demographic characteristics, health-related outcomes, medical history, and caregiver burden by amyloid status are described. …Results: Of 1,198 patients with clinician-diagnosed early AD, 52% were amyloid[+]. For patients in both cohorts, amyloid[–] was more likely to occur in those with: delayed time to an AD-related diagnosis, higher rates of depression, poorer Bath Assessment of Subjective Quality of Life in Dementia scores, and Hispanic/Latino ethnicity (all p  < 0.05). MILD[–] patients (versus MILD[+]) were more medically complex with greater rates of depression (55.7% versus 40.4%), sleep disorders (34.3% versus 26.5%), and obstructive pulmonary disease (11.8% versus 6.6%); and higher caregiver burden (Zarit Burden Interview) (all p  < 0.05). MILD[+] patients had lower function according to the Functional Activities Questionnaire (p  < 0.001), yet self-assessment of cognitive complaints across multiple measures did not differ by amyloid status in either severity cohort. Conclusions: Considerable patient and caregiver burden was observed in patients seeking care for memory concerns. Different patterns emerged when both disease severity and amyloid status were evaluated underscoring the need for further diagnostic assessment and care for patients. Study Registry: H8A-US-B004; ClinicalTrials.gov: NCT02951598. Show more

Keywords: Alzheimer’s disease, amyloid, burden of illness, florbetapir F18, mild Alzheimer’s dementia, mild cognitive impairment

DOI: 10.3233/JAD-190430

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 279-292, 2019

Authors: Meysami, Somayeh | Raji, Cyrus A. | Merrill, David A. | Porter, Verna R. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy. Objective: To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment. Methods: IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n  = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included …head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n  = 17, MoCA in n  = 27, n  = 14 in both) were performed. Results: Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history. Conclusion: Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer’s disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment. Show more

Keywords: Magnetic resonance imaging, traumatic brain injury, volumetric quantification

DOI: 10.3233/JAD-190708

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 293-300, 2019

Authors: Amlie-Wolf, Alexandre | Tang, Mitchell | Way, Jessica | Dombroski, Beth | Jiang, Ming | Vrettos, Nicholas | Chou, Yi-Fan | Zhao, Yi | Kuzma, Amanda | Mlynarski, Elisabeth E. | Leung, Yuk Yee | Brown, Christopher D. | Wang, Li-San | Schellenberg, Gerard D.

Article Type: Research Article

Abstract: Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer’s disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed …to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1 ). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk. Show more

Keywords: Alzheimer’s disease, bioinformatics, genetics, genomics, long noncoding RNA

DOI: 10.3233/JAD-190568

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 301-318, 2019

Authors: Paley, Elena L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD)-associated sequence (ADAS) of cultured fecal bacteria was discovered in human gut targeted screening. This study provides important information to expand our current understanding of the structure/activity relationship of ADAS and putative inhibitors/activators that are potentially involved in ADAS appearance/disappearance. The NCBI database analysis revealed that ADAS presents at a large proportion in American Indian Oklahoman (C&A) with a high prevalence of obesity/diabetes and in colorectal cancer (CRC) patients from the US and China. An Oklahoman non-native group (NNI) showed no ADAS. Comparison of two large US populations reveals that ADAS is more frequent in individuals aged ≥66 …and in females. Prevalence and levels of fecal metabolites are altered in the C&A and CRC groups versus controls. Biogenic amines (histamine, tryptamine, tyramine, phenylethylamine, cadaverine, putrescine, agmatine, spermidine) that present in food and are produced by gut microbiota are significantly higher in C&A (e.g., histamine/histidine 95-fold) versus NNI (histamine/histidine 16-fold). The majority of these bio-amines are cytotoxic at concentrations found in food. Inositol phosphate signaling implicated in AD is altered in C&A and CRC. Tryptamine stimulated accumulation of inositol phosphate. The seizure-eliciting tryptamine induced cytoplasmic vacuolization and vesiculation with cell fragmentation. Present additions of ADAS-carriers at different ages including infants led to an ADAS-comprising human sample size of 2,830 from 27 studies from four continents (North America, Australia, Asia, Europe). Levels of food-derived monoamine oxidase inhibitors and anti-bacterial compounds, the potential modulators of ADAS-bacteria growth and biogenic amine production, were altered in C&A versus NNI. ADAS is attributable to potentially modifiable risk factors of AD associated diseases. Show more

Keywords: Alzheimer’s human gut metagenome, angiogenesis, biogenic amines, food, gut metabolomics, protein biosynthesis

DOI: 10.3233/JAD-190873

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 319-355, 2019

Article Type: Correction

DOI: 10.3233/JAD-199009

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 357-357, 2019

Article Type: Correction

DOI: 10.3233/JAD-199010

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 359-359, 2019