Banner Sun Health Research Institute Research Articles

Parkinson's disease-associated shifts between DNA methylation and DNA hydroxymethylation in human brain in PD-related genes, including PARK19 (DNAJC6) and PTPRN2 (IA-2β).

The majority of Parkinson's disease (PD) cases are due to a complex interaction between aging, genetics, and environmental factors; epigenetic mechanisms are thought to act as important mediators of these risk factors. While multiple studies to date have explored the role of DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmC). Because 5hmC occurs at its highest levels in the brain and is thought to be particularly important in the central nervous system, particularly in the response to neurotoxicants, it is important to explore the potential role of 5hmC in PD. This study expands on our previously published epigenome-wide association study (EWAS) performed on DNA isolated from neuron-enriched nuclei from human postmortem parietal cortex from the Banner Sun Health Research Institute Brain Bank. The study aimed to identify paired changes in 5hmC and 5mC in PD in enriched neuronal nuclei isolated from PD post-mortem parietal cortex and age- and sex-matched controls. We performed oxidative bisulfite (oxBS) conversion and paired it with our previously published bisulfite (BS)-based EWAS on the same samples to identify cytosines with significant shifts between these two related epigenetic marks. Interaction differentially modified cytosines (iDMCs) were identified using our recently published mixed-effects model for co-analyzing βmC and βhmC data. We identified 1,030 iDMCs with paired changes in 5mC and 5hmC (FDR < 0.05) that map to 695 genes, including PARK19 (DNAJC6), a familial PD gene, and PTPRN2 (IA-2), which has been previously implicated in PD in both epigenetic and mechanistic studies. The majority of iDMC-containing genes have not previously been implicated in PD and were not identified in our previous BS-based EWAS. These data potentially link epigenetic regulation of the PARK19 and PTPRN2 loci in the pathogenesis of idiopathic PD. In addition, iDMC-containing genes have known functions in synaptic formation and function, cell cycle and senescence, neuroinflammation, and epigenetic regulation. These data suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes relevant to PD pathogenesis that are not captured by analyzing BS-based data alone or by analyzing each mark as a distinct dataset.

Biobanking best practices for research, Banner Sun Health Research Institute Brain and Body Donation Program standards and journey

AbstractThe Arizona Study of Aging and Neurodegenerative Disease (AZSAND)/Brain and Body Donation Program (BBDP) is a unique clinicopathological study of aging and neurodegenerative disease based in Sun City, AZ since 1987. The BBDP has made rapid autopsy a priority, with a constitutive 24‐7 rapid autopsy team and a 3.0‐hour median postmortem interval for the entire collection. Tissue quality is correspondingly high, with a median RNA Integrity Number (RIN) for frozen brain tissue of 8.9. The current holdings include fixed and frozen brain and body tissue, as well as biofluids from more than 850 Alzheimer’s Disease (AD) cases, 250 Parkinson’s Disease (PD) cases and more than 350 elderly control subjects. The program supports and leads national and international research focused on AD, AD related dementias and other debilitating neurodegenerative diseases. It provides basic scientists with de‐identified annual comprehensive standardized cognitive, motor, and non‐motor assessments data and neuropathologically characterized human samples that are suitable for the elucidation of the molecular mechanisms of disease and novel therapeutic targets. The BBDP is committed to distributing human samples and accompanying clinicopathological data to as many researchers as possible. All collected data are available to researchers through the program’s website https://www.brainandbodydonationregistration.org/ and personalized consultations.

Low circulating choline levels correlate with Alzheimer’s disease pathology severity and cognitive impairment

AbstractBackgroundModifiable environmental risk factors may help reduce Alzheimer’s disease (AD) incidence. Choline plays key roles in healthy body and brain function (Blusztajn, 1998) and supplementation above the adequate daily intake (ADI) reduces AD pathology (Velazquez et al., 2019). Choline deficiency increases AD risk and pathology (Dave et al., 2023; Yuan et al., 2022). Notably, recent reports estimate that ∼90% of Americans do not reach the ADI for dietary choline (Zeisel, 2017), making it imperative to better understand the link between choline and AD risk.MethodWe obtained serum samples from severe AD (AD‐Sev; Braak stage VI), moderate AD (AD‐Mod; Braak stage IV), and healthy control (CON; &lt; Braak stage III) subjects (n = 12/group; balanced for sex) from the Banner Sun Health Research Institute’s Brain and Body Donation Program. Cognitive test scores (Mini‐Mental State Examination (MMSE)), plaque burden, and Braak stage was characterized by Banner Sun Health. We assessed free choline, acetylcholine (ACh), and TNFα levels. Gas‐chromatography‐mass spectrometry was used to profile aqueous metabolites and short‐chain fatty acids.ResultThere were no significant group differences for post‐mortem interval (M = 3.79). We found disease associated differences, where AD‐Sev and AD‐Mod patients had lower levels of free choline and ACh, and higher levels of pro‐inflammatory cytokine TNFα, than CON. AD‐Mod showed a significant difference in all these measurements compared to AD‐Sev. Free choline and ACh were positively correlated to MMSE scores, whereas free choline and ACh levels were negatively correlated with total plaque and Braak Stage. Free choline and ACh were negatively correlated with TNFα. Metabolomics analysis revealed significant differences (p &lt; 0.05) in the metabolisms of beta‐alanine, linoleic acid, and of taurine and hypotaurine.ConclusionCollectively, as free choline and ACh levels decreased, AD pathology increased. Free choline was also associated with MMSE score. Increased TNFα was observed in cases with lower choline, illustrating increased inflammation. Together, this data expands on our recent (Dave et al., 2023) and others (Yuan et al., 2022) publications, highlighting links between low choline and AD risk.

Integrative Analysis of Proteome-wide Association Studies and Functional Enrichment Analysis to Identify Genes and Chemicals Associated with Alcohol Dependence.

Alcohol dependence accounts for a large proportion of the global burden of disease and disability. This study aims to investigate the candidate genes and chemicals associated with alcohol dependence. Using data from published alcohol dependence genome-wide association studies, we first conducted a proteome-wide association study of alcohol dependence by integrating alcohol dependence genome-wide association studies with 2 human brain reference proteomes of dorsolateral prefrontal cortex from the Religious Order Study and Rush Memory and Aging Project and the Banner Sun Health Research Institute. Then, based on the identified genes in proteome-wide association study, we conducted functional enrichment analysis and chemical-related functional enrichment analysis to detect the related Gene Ontology terms and chemicals. Proteome-wide association study identified several potential candidate genes for alcohol dependence, such as GOT2 ( P = 7.59 × 10 -6 ) and C3orf33 ( P = 5.00 × 10 -3 ). Furthermore, functional enrichment analysis identified multiple candidate Gene Ontology terms associated with alcohol dependence, such as glyoxylate metabolic process (adjusted P = 2.99 × 10 -6 ) and oxoglutarate metabolic process (adjusted P = 9.95 × 10 -6 ). Chemical-related functional enrichment analysis detected several alcohol dependence-related candidate chemicals, such as pitavastatin ( P = 2.00 × 10 -4 ), cannabinoids ( P = 4.00 × 10 -4 ), 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid ( P = 4.00 × 10 -4 ), and gabapentin ( P = 2.00 × 10 -3 ). Our study reports multiple candidate genes and chemicals associated with alcohol dependence, providing novel clues for understanding the biological mechanism of alcohol dependence.

Head‐to‐Head Comparison of Four Plasma Phospho‐Tau Immunoassays in the Neuropathological Diagnosis of Alzheimer’s Disease

AbstractBackgroundPlasma ptau is a promising indicator of amyloid‐β (Aβ) mediated tau pathophysiology. We previously characterized the ability of Lilly’s MesoScale Discovery (MSD)‐based plasma ptau217 and ptau181 assays to discriminate between those with and without the neuropathological diagnosis of Alzheimer’s disease (AD) in Banner research participants with near‐end‐of‐life blood samples and extensive postmortem neuropathological assessments. We now extend this work in a head‐to‐head comparison of those assays to the University of Gothenburg’s Single molecule array (Simoa)‐based plasma ptau181 and 231 assays.MethodAssays were performed blindly in plasma samples acquired 1.0±0.7 years before death from up to 106 Banner research participants with and without cognitive impairment and different neuropathological diagnoses. ROC analyses were used to discriminate between those with and without the neuropathological diagnosis of AD and presence or absence of neuritic Aβ plaques. Spearman correlations were used to characterize their associations with mean cortical neuritic plaque counts and with mean cortical tau tangle counts in those with and without the diagnosis of AD or neuritic plaques.ResultLilly’s ptau217 assay was better than Lilly’s ptau181 and Gothenburg’s ptau231 and ptau181 assays in discriminating between the neuropathological diagnosis of Intermediate/High Likelihood versus Low Likelihood/No AD (respective AUCs=0.86, 0.67, 0.62 and 0.61), the diagnosis of High Likelihood versus Low Likelihood/No AD (AUCs=0.95, 0.83, 0.67 and 0.67), and presence or absence of neuritic Aβ plaques (AUCs=0.86, 0.70, 0.61 and 0.62). It also provided better indicators of mean cortical neuritic plaque (r’s=0.69, 0.35, 0.26 and 0.29) and tangle counts (r’s=0.73, 0.60, 0.19, ‐0.04) in those with the neuropathological diagnosis of AD or at least moderately frequent neuritic plaques (r’s=0.71, 0.59, 0.22, 0.01). The assays were not correlated with tangle counts in those without AD or neuritic plaques.ConclusionLilly’s MSD‐based plasma ptau217 assay performed better than the other three ptau assays in the neuropathological diagnosis of AD, discriminating between those with and without neuritic Aβ plaques, and providing an indicator of Aβ‐related tau tangle burden. Banner Sun Health Research Institute's growing brain donation program resources could help characterize and compare blood‐based biomarkers in the neuropathological diagnosis of AD, Parkinson’s disease and related diseases.

Integrated analysis of proteome-wide and transcriptome-wide association studies identified novel genes and chemicals for vertigo.

Vertigo is a leading symptom of various peripheral and central vestibular disorders. Although genome-wide association studies (GWASs) have identified multiple risk variants for vertigo, how these risk variants contribute to the risk of vertigo remains unknown. Discovery proteome-wide association study (PWAS) was first performed by integrating the protein quantitative trait loci from the dorsolateral prefrontal cortex (DLPFC) in the Banner Sun Health Research Institute dataset (n = 152) and GWAS summary of vertigo (n = 942 613), followed by replication PWAS using the protein quantitative trait loci from the DLPFC in Religious Orders Study or the Rush Memory and Aging Project dataset (n = 376). Transcriptome-wide association studies (TWASs) were then performed by integrating the same GWAS datasets of vertigo (n = 942 613) with mRNA expression reference from human fetal brain, and DLPFC. Chemical-related gene set enrichment analysis (GSEA) and Gene ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were finally conducted to further reveal the pathogenesis of vertigo. Permutation-based empirical P values were calculated in PWAS, TWAS, and GSEA. By integrating the GWAS of vertigo and two independent brain proteomes from human DLPFC, three genes were identified to genetically regulate protein abundance levels in vertigo, and were not previously implicated by GWAS, including MTERFD2 (P Banner = 0.045, P ROSMAP = 0.031), MGST1 (P Banner = 0.014, P ROSMAP = 0.018), and RAB3B (P Banner = 0.045, P ROSMAP = 0.035). Compared with TWAS results, we identified overlapping genes RAB3B (P TWAS = 0.017) and MTERFD2 (P TWAS = 0.003) that showed significant associations with vertigo at both proteome-wide and transcriptome-wide levels. Chemical-related GSEA identified multiple chemicals that might be associated with vertigo, such as nickel (P = 0.007), glycidamide (P = 0.005), and proanthocyanidins (P = 0.015). Our study provides novel clues for understanding the biological mechanism of vertigo, and highlights several possible risks and therapeutic chemicals for vertigo.

Targeted Metabolomic Analysis in Alzheimer's Disease Plasma and Brain Tissue in Non-Hispanic Whites.

Background:Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer’s disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis.Objective:In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers.Methods:This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer’s Research and Care Consortium – TARCC) and 71 postmortem cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500).Results:We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95 = 75–88%); for females specifically, AUC = 88% (CI95 = 80–95%). A reduced model using 20 features achieves AUC = 79% (CI95 = 71–85%); for females AUC = 84% (CI95 = 74–92%).Conclusion:Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis.

The study of sirtuins in Alzheimer's disease.

Previous studies have shown sirtuins 3 has neuroprotective effects in regulating oxidative stress and energy metabolism in Alzheimer's disease. However, it is unclear whether other sirtuins are associated with cognitive performance and pathological changes in AD. We used postmortem brains of AD (n= 16), mild cognitive impairment (n= 11) and age- and education-matched cognitively normal (CN, n= 11) subjects from the Banner Sun Health Research Institute Brain Bank. We measured the protein levels of Sirt1-7, synaptic proteins, nucleus signal molecules, AD pathology and cognitive performance. Besides Sirt3 as we previously reported, only Sirt6 level was reduced in the middle temporal gyrus of AD subjects compared to that of CN. This reduction was associated with the severity of tau pathology and poorer cognitive performance, which was consistent with impaired synaptic integrity. This study has shown that Sirt6 is downregulated in AD and is related to synaptic loss. Sirt6 may play a critical role in pathogenesis of AD.

Human Autopsy-Derived Scalp Fibroblast Biobanking for Age-Related Neurodegenerative Disease Research.

The Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program at Banner Sun Health Research Institute (BSHRI) is a longitudinal clinicopathological study with a current enrollment of more than 900 living subjects for aging and neurodegenerative disease research. Annual clinical assessments are done by cognitive and movement neurologists and neuropsychologists. Brain and body tissues are collected at a median postmortem interval of 3.0 h for neuropathological diagnosis and banking. Since 2018, the program has undertaken banking of scalp fibroblasts derived from neuropathologically characterized donors with Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. Here, we describe the procedure development and cell characteristics from 14 male and 15 female donors (mean ± SD of age: 83.6 ± 12.2). Fibroblasts from explant cultures were banked at passage 3. The results of mRNA analysis showed positive expression of fibroblast activation protein, vimentin, fibronectin, and THY1 cell surface antigen. We also demonstrated that the banked fibroblasts from a postmortem elderly donor were successfully reprogramed to human-induced pluripotent stem cells (hiPSCs). Taken together, we have demonstrated the successful establishment of a human autopsy-derived fibroblast banking program. The cryogenically preserved cells are available for request at the program website of the BSHRI.

Tissue biomarker for the detection of dementia with Levi bodies

Scientists from the Banner Sun Health research institute (Sun City, Arizona, USA) studied 228 histological preparations obtained by postmortem examination, including samples with diseases of Levi bodies: 46 with Parkinson's disease, 28 with dementia with Levi bodies, 9 with concomitant disease of Levi bodies, 33 with Alzheimer's disease with Levi bodies and two with progressive supranuclear palsy with Levi bodies. The drugs of the control group, defined as people without synucleopathy associated with Levy's disease of the body affecting the central nervous system, included 79 samples from healthy elderly people, 15 from people with Alzheimer's disease, 12 from people with progressive supranuclear palsy, 2 from individuals with corticobasal degeneration and 2 from individuals with multiple systemic atrophy. Tissue sections of the submandibular gland of exposed people were stained with an immunohistochemical method to detect serine phosphorylated α-synuclein 129. Researchers found a submandibular alpha-synuclein pathology in 42/47 (89%) of exposed patients with Parkinson's disease and in 20/28 (71% ) opened patients with dementia with Levy bodies, but not one of 110 representatives of the control group. The authors concluded that the findings could help with further clinical studies of a diagnostic biopsy of the submandibular gland in vivo to detect Parkinson's disease and dementia with Levi bodies. Accurate diagnosis using a peripheral biopsy will help select patients for clinical trials and can be used to check other biomarkers.Low diagnostic accuracy made it difficult to conduct effective clinical trials involving living people in the search for new drugs. With better diagnostic accuracy, clinical trials would have a higher chance of success and could be completed faster and have lower cost. In the next step, biopsy of the submandibular gland will be necessary for living people with dementia with Levi bodies to confirm the autopsy results.

A-018 Informant and Participant-Report of Functioning Predicts Performance on Objective Cognitive Screening

Abstract Objective Montreal Cognitive Assessment (MoCA) and Alzheimer’s Disease 8 questionnaire (AD8) are widely used measures for clinical screening of dementia related disorders. Previous research on MoCA and AD8 has been solely focused on participant-report AD8 measures without consideration of informant reports. We hypothesize informant reported AD8 and participant MoCA scores will be inversely related, participant-reported AD8 will be weakly associated with MoCA performance, and informant reported AD8 will more reliably predictor cognitive performance. Methods Participants (N = 212) were seen from 2018 to 2020 through a free community screening service (Brain Health Check-In) at Banner Sun Health Research Institute in Arizona. First and second hypotheses were analyzed with Spearman’s Rho (r), third hypothesis utilized a linear regression. Results Both participant and informant reported AD8 directly correlated with overall cognitive performance classification (r = 0.639 [informant] confidence interval [CI] = .0552–0.712, p &amp;lt; .000; r = 0.610 [participant] CI = 0.518–0.688, p &amp;lt; .000). Informant reported AD8 ratings were significantly inversely correlated with MoCA performance (r = −0.497, p &amp;lt; .000). Participant reported AD8 ratings also inversely correlated with overall MoCA scores with a weaker association (r = −0.296, p &amp;lt; .000). Neither participant nor informant reported AD8 were able to reliably predict categorical cognitive performance classification, but informant reported AD8 (r = −.686, p &amp;lt; .000) did emerge as a reliable predictor of MoCA performance. Conclusion(s) This study extends and reaffirms prior research about AD8 and suggests both informant- and participant-reports are valuable; however, informant often provides more clinically useful information related to cognitive functioning.

QUANTITATION OF THE BACTERIAL PRODUCT LIPOPOLYSACCHARIDE (LPS) IN POSTMORTEM SERUM AND BRAIN TISSUE FROM AD, MCI, AND CONTROL PATIENTS

Aspects of Alzheimer's disease (AD) pathology suggest a microbial response. Studies indicate that Aβ may act as an anti-microbial peptide. 16S rRNA gene sequencing by our lab and others indicates that many kinds of bacteria are present in brain tissue from AD patients, and to some extent, in normal controls. As 16S analysis is sensitive to contamination and is non-quantitative, we sought a second to assess presence of bacteria in the brain. Lipopolysaccharide (LPS) has been previously localized within amyloid plaques. We quantified LPS from post-mortem serum and brain tissue to 1) confirm that LPS is present and 2) determine if LPS in the brain may originate from the bloodstream or instead indicate the presence of resident bacteria. Tissues were acquired from the Brain and Body Donation Program at the Banner Sun Health Research Institute. Post-mortem serum was tested for LPS by ELISA. Frozen tissue from the superior frontal gyrus of the same subjects was homogenized and sonicated in PBS to create lysates for ELISAs. There were four subject groups (n=12 per group): AD, MCI (mild cognitive impairment), HPC (high pathology controls), and normal non-demented controls. LPS was detected in the serum of most subjects at pg/ml levels. Average levels in AD subjects were significantly higher than in normal controls. In brain tissue, subjects from all groups showed easily detectable levels of LPS, primarily in the ng/ml range. Levels in serum did not correlate well with levels observed in the brain tissue from the same subjects. Our data shows the presence of substantial amounts of LPS in both serum and brain tissue from our MCI and AD subjects, and even in many normal controls. The disconnection of serum LPS levels from brain tissue levels may indicate that the bloodstream is not the primary source of LPS in the brain, although it is possible LPS from blood accumulates in the brain over time. However, given our previous 16s rRNA gene sequencing analysis of brain tissue from these same subjects, which showed DNA from a large variety of bacteria, the LPS most likely derives from resident bacteria in the brain.

Frailty assessment in older adults using upper-extremity function: index development

BackgroundNumerous multidimensional assessment tools have been developed to measure frailty; however, the clinical feasibility of these tools is limited. We previously developed and validated an upper-extremity function (UEF) assessment method that incorporates wearable motion sensors. The purpose of the current study was to: 1) cross-sectionally validate the UEF method in a larger sample in comparison with the Fried index; 2) develop a UEF frailty index to predict frailty categories including non-frail, pre-frail, and frail based on UEF parameters and demographic information, using the Fried index as the gold standard; and 3) develop a UEF continuous score (points scores for each UEF parameter and a total frailty score) based on UEF parameters and demographic information, using the Fried index as the gold standard.MethodsWe performed a cross-sectional validation and index development study within the Banner Medical Center, Tucson, and Banner Sun Health Research Institute, Sun City, Arizona. Community-dwelling and outpatient older adults (≥60 years; n = 352; 132 non-frail, 175 pre-frail, and 45 frail based on Fried criteria) were recruited. For the UEF test, each participant performed a 20-s elbow flexion, within which they repetitively and rapidly flexed and extended their dominant elbow. Using elbow motion outcomes two UEF indexes were developed (categorical and score). The Fried index was measured as the gold standard.ResultsFor the categorical index, speed of elbow flexion, elbow range of motion, elbow moment, number of flexion, speed variability and reduction within 20 s, as well as body mass index (BMI) were included as the pre-frailty/frailty predictor parameters. Results from 10-fold cross-validation showed receiver operator characteristic area under the curve of 0.77 ± 0.07 and 0.80 ± 0.12 for predicting Fried pre-frailty and frailty, respectively. UEF score (0.1 to 1.0) was developed using similar UEF parameters.ConclusionsWe present an objective, sensor-based frailty assessment tool based on physical frailty features including slowness, weakness, exhaustion (muscle fatigue), and flexibility of upper-extremity movements. Within the current study, the method was validated cross-sectionally using the Fried index as the gold standard and the UEF categorical index and UEF frailty score were developed for research purposes and potentially for future clinical use.

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer's Disease: Analysis of 13 Cases.

BackgroundMitochondrial dysfunction may play a central role in the pathologic process of Alzheimer’s disease (AD), but there is still a scarcity of data that directly links the pathology of AD with the alteration of mitochondrial DNA. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue.Patients and MethodsPostmortem frozen human brain cerebral cortex samples were obtained from the Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, AZ. Mitochondria were isolated and direct sequence by using MiSeq®, and analyzed by relative software.ResultsThree types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched control. These observed rearrangements include a deletion, F-type rearrangement, and R-type rearrangement. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9%versus 6.7%; p = 0.0052). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%; p = 0.0005).ConclusionsOur data showed that failure of mitochondrial DNA in AD brain might be important etiology of AD pathology.

Neurofibrillary Tangle Predominant Dementia: Clinical and Pathological Description in a Case Series

Objective: The aim of this study is to contribute to an understanding of the clinical presentation and pathological features of neurofibrillary tangle predominant dementia (NFTPD) that will assist with the eventual development of methods for its ante-mortem identification. Method: We contrast eight NFTPD cases identified in the Banner Sun Health Research Institute Brain and Body Donation Program (SHRI-BBDP) database to 114 Alzheimer’s disease (AD) subjects, in terms of their demographics, clinical features, and pathological features. Results: When NFTPD subjects were compared to AD subjects, they were found to have a later onset of symptoms, an older age at death, less impairment prior to death, and less frequent appearance of the Apolipoprotein E ε4 variant. None of the eight NFTPD subjects met the clinical criteria for probable AD. They possessed a diverse range of diagnoses including possible AD, mixed vascular dementia (VAD), dementia NOS, and dementia with Lewy bodies (DLB). AD-related pathology, for both amyloid plaques and neurofibrillary tangles, was less severe in NFTPD subjects than in AD subjects. All eight NFTPD subjects were classified as neurofibrillary tangle Braak stage IV and therefore had fewer tangles in the neocortex when compared to AD subjects with mean Braak stage V (range II–VI). Conclusion: NFTPD subjects have dementia despite a lower pathological burden when compared to AD subjects. In this small sample, the ante-mortem presentation is such that NFTPD subjects are not diagnosed with probable AD. The cognitive and non-cognitive clinical features (delusions, depression, parkinsonism, and hallucinations) of NFTPD and AD are very similar and do not serve as indicators for a diagnosis, but older age (>80), lack of an ApoE ε4 allele and less severe cognitive impairment should further inform the differential diagnosis of NFTPD from AD.

Description and cohort characterization of the Longevity Study: learning from our elders.

The purpose of this article is to describe the Longevity Study: Learning From Our Elders, a research program on healthy aging that began in 2007 at the Center for Healthy Aging at Banner Sun Health Research Institute. As of June 2015, 1139 participants (age range of 50-110years) completed baseline assessments with the majority living in the Sun Cities retirement communities northwest of Phoenix, Arizona but expanding throughout the state. The registry includes over 830 currently active participants with 450 aged 80years and older, 188 aged 90 and older, and 27 centenarians. Data from in-person interviews at the Center for Healthy Aging in Sun City or in the participants' residences which includes sociodemographic, medical, cognitive, physical and psychosocial variables have been collected since the study's inception. This paper outlines some of the key demographic and clinical characteristics of the Longevity Study, its progress, and future directions. It also reflects on how exceptional aging individuals function psychosocially, cognitively and physically, particularly among individuals aged 85 and older.

Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease.

There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue. To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships. We measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium. A comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity. The PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = -0.48; P < .01) and tangles (Pearson r = -0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex. Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

Characterization of fibromyalgia symptoms in patients 55-95 years old: a longitudinal study showing symptom persistence with suboptimal treatment.

Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption. To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms. A longitudinal, observational study of 51 subjects with FM (range 55-95years) and 81 control subjects (58-95years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment. Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80% or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin. In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated. Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Differences in Cerebrospinal Fluid Biomarkers between Clinically Diagnosed Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease.

ObjectiveIn the present study, cerebrospinal fluid (CSF) profiles were assessed to determine how idiopathic normal pressure hydrocephalus (NPH) and Alzheimer’s disease (AD) differs.MethodsSubjects were drawn from patients who underwent lumbar punctures as part of their diagnostic evaluations in the Banner Sun Health Research Institute Memory Disorders clinic. The clinical sample included 11 iNPH subjects (mean age 81.36±2.58) and 11 AD subjects (mean age 61.46±8.24). Concentrations of amyloid-β (Aβ42), total-tau (t-tau), phospho-tau181 (p-tau) Aβ42, and an Aβ42-Tau Index (ATI) were measured by commercial assay (Athena Diagnostics). and compared to each other. The Mann-Whitney test was used to assess group differences on the raw values for Aβ42, t-tau, p-tau, ATI, age, education, and MMSE.ResultsIn a univariate analysis, p-tau was found to be significantly (P = 0.009) lower in patients diagnosed with iNPH than those with AD. Amyloid-β (Aβ42), total-tau (t-tau) did not differ between groups. In multi-variate analysis, the differences in p-tau between groups did not differ.ConclusionAlthough age could represent a significant confound, p-tau is significantly lower in iNPH compared to AD. P-tau would be expected to increase with age but in this sample is lower suggesting the difference might be explained by the underlying condition.