Browsing by Subject "Alzheimer Disease"

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    ItemOpen Access
    A new algorithm for predicting time to disease endpoints in Alzheimer's disease patients.
    (J Alzheimers Dis, 2014) Razlighi, Qolamreza R; Stallard, Eric; Brandt, Jason; Blacker, Deborah; Albert, Marilyn; Scarmeas, Nikolaos; Kinosian, Bruce; Yashin, Anatoliy I; Stern, Yaakov
    BACKGROUND: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer's disease patients and caregivers, health policy, economics, and the design of intervention studies. OBJECTIVE: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer's disease patients. METHOD: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer's disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. RESULTS: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. CONCLUSION: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer's disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.
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    Accelerating stem cell trials for Alzheimer's disease.
    (The Lancet. Neurology, 2016-02) Hunsberger, Joshua G; Rao, Mahendra; Kurtzberg, Joanne; Bulte, Jeff WM; Atala, Anthony; LaFerla, Frank M; Greely, Henry T; Sawa, Akira; Gandy, Sam; Schneider, Lon S; Doraiswamy, P Murali
    At present, no effective cure or prophylaxis exists for Alzheimer's disease. Symptomatic treatments are modestly effective and offer only temporary benefit. Advances in induced pluripotent stem cell (iPSC) technology have the potential to enable development of so-called disease-in-a-dish personalised models to study disease mechanisms and reveal new therapeutic approaches, and large panels of iPSCs enable rapid screening of potential drug candidates. Different cell types can also be produced for therapeutic use. In 2015, the US Food and Drug Administration granted investigational new drug approval for the first phase 2A clinical trial of ischaemia-tolerant mesenchymal stem cells to treat Alzheimer's disease in the USA. Similar trials are either underway or being planned in Europe and Asia. Although safety and ethical concerns remain, we call for the acceleration of human stem cell-based translational research into the causes and potential treatments of Alzheimer's disease.
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    Complete Evaluation of Dementia: PET and MRI Correlation and Diagnosis for the Neuroradiologist.
    (AJNR. American journal of neuroradiology, 2021-06) Oldan, JD; Jewells, VL; Pieper, B; Wong, TZ
    This article will familiarize neuroradiologists with the pathophysiology, clinical findings, and standard MR imaging and PET imaging features of multiple forms of dementia as well as new emerging techniques. Cases were compiled from multiple institutions with the goal of improved diagnostic accuracy and improved patient care as well as information about biomarkers on the horizon. Dementia topics addressed include the following: Alzheimer disease, frontotemporal dementia, cerebral amyloid angiopathy, Lewy body dementia, Parkinson disease and Parkinson disease variants, amyotrophic lateral sclerosis, multisystem atrophy, Huntington disease vascular dementia, and Creutzfeldt-Jakob disease.
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    Do You Want to Hear the Bad News? The Value of Diagnostic Tests for Alzheimer's Disease.
    (Value Health, 2016-01) Mühlbacher, Axel; Johnson, F Reed; Yang, Jui-Chen; Happich, Michael; Belger, Mark
    OBJECTIVE: The diagnosis of Alzheimer's disease (AD) remains difficult. Lack of diagnostic certainty or possible distress related to a positive result from diagnostic testing could limit the application of new testing technologies. The objective of this paper is to quantify respondents' preferences for obtaining AD diagnostic tests and to estimate the perceived value of AD test information. METHODS: Discrete-choice experiment and contingent-valuation questions were administered to respondents in Germany and the United Kingdom. Choice data were analyzed by using random-parameters logit. A probit model characterized respondents who were not willing to take a test. RESULTS: Most respondents indicated a positive value for AD diagnostic test information. Respondents who indicated an interest in testing preferred brain imaging without the use of radioactive markers. German respondents had relatively lower money-equivalent values for test features compared with respondents in the United Kingdom. CONCLUSIONS: Respondents preferred less invasive diagnostic procedures and tests with higher accuracy and expressed a willingness to pay up to €700 to receive a less invasive test with the highest accuracy.
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    Estimation and validation of a multiattribute model of Alzheimer disease progression.
    (Med Decis Making, 2010-11) Stallard, Eric; Kinosian, Bruce; Zbrozek, Arthur S; Yashin, Anatoliy I; Glick, Henry A; Stern, Yaakov
    OBJECTIVES: To estimate and validate a multiattribute model of the clinical course of Alzheimer disease (AD) from mild AD to death in a high-quality prospective cohort study, and to estimate the impact of hypothetical modifications to AD progression rates on costs associated with Medicare and Medicaid services. DATA AND METHODS: The authors estimated sex-specific longitudinal Grade of Membership (GoM) models for AD patients (103 men, 149 women) in the initial cohort of the Predictors Study (1989-2001) based on 80 individual measures obtained every 6 mo for 10 y. These models were replicated for AD patients (106 men, 148 women) in the 2nd Predictors Study cohort (1997-2007). Model validation required that the disease-specific transition parameters be identical for both Predictors Study cohorts. Medicare costs were estimated from the National Long Term Care Survey. RESULTS: Sex-specific models were validated using the 2nd Predictors Study cohort with the GoM transition parameters constrained to the values estimated for the 1st Predictors Study cohort; 57 to 61 of the 80 individual measures contributed significantly to the GoM models. Simulated, cost-free interventions in the rate of progression of AD indicated that large potential cost offsets could occur for patients at the earliest stages of AD. CONCLUSIONS: AD progression is characterized by a small number of parameters governing changes in large numbers of correlated indicators of AD severity. The analysis confirmed that the progression of AD represents a complex multidimensional physiological process that is similar across different study cohorts. The estimates suggested that there could be large cost offsets to Medicare and Medicaid from the slowing of AD progression among patients with mild AD. The methodology appears generally applicable in AD modeling.
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    Evaluating Alzheimer Disease With Flortaucipir and Florbetapir PET: A Clinical Case Series.
    (Clinical nuclear medicine, 2021-07) James, Olga G; Linares, Alexandra R; Hellegers, Caroline; Doraiswamy, P Murali; Wong, Terence Z

    Abstract

    Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are β-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary β-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.
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    ItemRestricted
    Genome-wide scan of copy number variation in late-onset Alzheimer's disease.
    (J Alzheimers Dis, 2010) Heinzen, EL; Need, AC; Hayden, KM; Chiba Falek, O; Roses, AD; Strittmatter, WJ; Burke, JR; Hulette, CM; Welsh Bohmer, KA; Goldstein, DB
    Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.
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    High-resolution hybrid micro-CT imaging pipeline for mouse brain region segmentation and volumetric morphometry.
    (PloS one, 2024-01) Nadkarni, Rohan; Han, Zay Yar; Anderson, Robert J; Allphin, Alex J; Clark, Darin P; Badea, Alexandra; Badea, Cristian T

    Background

    Brain region segmentation and morphometry in humanized apolipoprotein E (APOE) mouse models with a human NOS2 background (HN) contribute to Alzheimer's disease (AD) research by demonstrating how various risk factors affect the brain. Photon-counting detector (PCD) micro-CT provides faster scan times than MRI, with superior contrast and spatial resolution to energy-integrating detector (EID) micro-CT. This paper presents a pipeline for mouse brain imaging, segmentation, and morphometry from PCD micro-CT.

    Methods

    We used brains of 26 mice from 3 genotypes (APOE22HN, APOE33HN, APOE44HN). The pipeline included PCD and EID micro-CT scanning, hybrid (PCD and EID) iterative reconstruction, and brain region segmentation using the Small Animal Multivariate Brain Analysis (SAMBA) tool. We applied SAMBA to transfer brain region labels from our new PCD CT atlas to individual PCD brains via diffeomorphic registration. Region-based and voxel-based analyses were used for comparisons by genotype and sex.

    Results

    Together, PCD and EID scanning take ~5 hours to produce images with a voxel size of 22 μm, which is faster than MRI protocols for mouse brain morphometry with voxel size above 40 μm. Hybrid iterative reconstruction generates PCD images with minimal artifacts and higher spatial resolution and contrast than EID images. Our PCD atlas is qualitatively and quantitatively similar to the prior MRI atlas and successfully transfers labels to PCD brains in SAMBA. Male and female mice had significant volume differences in 26 regions, including parts of the entorhinal cortex and cingulate cortex. APOE22HN brains were larger than APOE44HN brains in clusters from the hippocampus, a region where atrophy is associated with AD.

    Conclusions

    This work establishes a pipeline for mouse brain analysis using PCD CT, from staining to imaging and labeling brain images. Our results validate the effectiveness of the approach, setting a foundation for research on AD mouse models while reducing scanning durations.
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    ItemOpen Access
    Life-narrative and word-cued autobiographical memories in centenarians: comparisons with 80-year-old control, depressed, and dementia groups.
    (Memory, 2003-01) Fromholt, Pia; Mortensen, Dorthe B; Torpdahl, Per; Bender, Lise; Larsen, Per; Rubin, David C
    Centenarians provided autobiographical memories to either a request for a life narrative or a request to produce autobiographical memories to cue words. Both methods produced distributions with childhood-amnesia, reminiscence-bump, and recency components. The life-narrative method produced relatively more bump memories at the expense of recent memories. The life-narrative distributions were similar to those obtained from 80-year-old adults without clinical symptoms and from 80-year-old Alzheimer's dementia and depression patients, except that the centenarians had an additional 20-year period of relatively low recall between the bump and recency components. The centenarians produced more emotionally neutral memories than the other three groups and produced fewer and less detailed memories than the non-clinical 80-year-old sample.
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    Prefrontal contributions to relational encoding in amnestic mild cognitive impairment.
    (Neuroimage Clin, 2016) Foster, Chris; Addis, Donna; Ford, Jaclyn; Kaufer, Daniel; Browndyke, Jeffrey; Welsh-Bohmer, Kathleen; Giovanello, Kelly
    Relational memory declines are well documented as an early marker for amnestic mild cognitive impairment (aMCI). Episodic memory formation relies on relational processing supported by two mnemonic mechanisms, generation and binding. Neuroimaging studies using functional magnetic resonance imaging (fMRI) have primarily focused on binding deficits which are thought to be mediated by medial temporal lobe dysfunction. In this study, prefrontal contributions to relational encoding were also investigated using fMRI by parametrically manipulating generation demands during the encoding of word triads. Participants diagnosed with aMCI and healthy control subjects encoded word triads consisting of a category word with either, zero, one, or two semantically related exemplars. As the need to generate increased (i.e., two- to one- to zero-link triads), both groups recruited a core set of regions associated with the encoding of word triads including the parahippocampal gyrus, superior temporal gyrus, and superior parietal lobule. Participants diagnosed with aMCI also parametrically recruited several frontal regions including the inferior frontal gyrus and middle frontal gyrus as the need to generate increased, whereas the control participants did not show this modulation. While there is some functional overlap in regions recruited by generation demands between the groups, the recruitment of frontal regions in the aMCI participants coincides with worse memory performance, likely representing a form of neural inefficiency associated with Alzheimer's disease.
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    Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis.
    (Age Ageing, 2013-07) Akushevich, Igor; Kravchenko, Julia; Ukraintseva, Svetlana; Arbeev, Konstantin; Yashin, Anatoly I
    OBJECTIVES: time trends of age-adjusted incidence rates of 19 ageing-related diseases were evaluated for 1992-2005 period with the National Long Term Care Survey and the Surveillance, Epidemiology and End RESULTS Registry data both linked to Medicare data (NLTCS-Medicare and SEER-Medicare, respectively). METHODS: the rates were calculated using individual medical histories (34,077 individuals from NLTCS-Medicare and 199,418 from SEER-Medicare) reconstructed using information on diagnoses coded in Medicare data, dates of medical services/procedures and Medicare enrolment/disenrolment. RESULTS: increases of incidence rates were dramatic for renal disease [the average annual percent change (APC) is 8.56%, 95% CI = 7.62, 9.50%], goiter (APC = 6.67%, 95% CI = 5, 90, 7, 44%), melanoma (APC = 6.15%, 95% CI = 4.31, 8.02%) and Alzheimer's disease (APC = 3.96%, 95% CI = 2.67, 5.26%), and less prominent for diabetes and lung cancer. Decreases of incidence rates were remarkable for angina pectoris (APC = -6.17%, 95% CI = -6.96, -5.38%); chronic obstructive pulmonary disease (APC = -5.14%, 95% CI = -6.78,-3.47%), and ulcer (APC = -5.82%, 95% CI = -6.77,-4.86%) and less dramatic for carcinomas of colon and prostate, stroke, hip fracture and asthma. Incidence rates of female breast carcinoma, myocardial infarction, Parkinson's disease and rheumatoid arthritis were almost stable. For most diseases, an excellent agreement was observed for incidence rates between NLTCS-Medicare and SEER-Medicare. A sensitivity analysis proved the stability of the evaluated time trends. CONCLUSION: time trends of the incidence of diseases common in the US elderly population were evaluated. The results show dramatic increase in incidence rates of melanoma, goiter, chronic renal and Alzheimer's disease in 1992-2005. Besides specifying widely recognised time trends on age-associated diseases, new information was obtained for trends of asthma, ulcer and goiter among the older adults in the USA.
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    Use of high cost care among Veterans with comorbid mental illness and Alzheimer's Disease and related dementias.
    (PloS one, 2023-01) Shepherd-Banigan, Megan; Miller, Katherine EM; Hastings, S Nicole; Schleiden, Loren J; Thorpe, Joshua M

    Introduction/objective

    Alzheimer's Disease and Other Related Dementias (AD/ADRD) leads to frequent emergency department (ED) and inpatient use. Mental health symptoms among persons with AD/ADRD increases cognitive and functional disabilities and could contribute to these high rates of intensive health care use. The objective of this paper is to assess the relationship of mental illness on 12-month patterns in hospitalization and ED use among Veterans aged 65 and over with a new AD/ADRD diagnosis.

    Methods

    We used an existing dataset of administrative electronic health record data of Veterans with AD/ADRD from the US Veterans Health Administration linked with Medicare claims data from 2011-2015. We use multivariable logistic regression to examine the association between no pre-existing mental illness, pre-existing mental illness (e.g., major depressive disorder, generalized anxiety disorder, or post-traumatic stress disorder), and pre-existing severe mental illness-or SMI-(e.g., bipolar disorder, major depressive disorder with psychosis, or schizophrenia) and 12- month ED and hospitalization use and readmissions among Veterans who had an initial hospitalization visit. We estimated predicted probabilities, differential effect, and associated 95% confidence intervals.

    Results

    In our sample, 1.4% had SMI and 11% had non-SMI mental illness. The unadjusted percentage with inpatient and ED use was higher among Veterans with SMI (34% and 26%, respectively) and Veterans with non-SMI mental illness (20%, 16%) compared with Veterans without pre-existing mental illness (12%, 9%). Compared to individuals with no pre-existing mental illness, having a pre-existing mental illness (1.27 percentage points, 95% CI: 0.76, 1.78) and a pre-existing SMI (7.17 percentage points, 95% CI: 5.66, 8.69) were both associated with an increased likelihood of ED use. The same pattern was observed for any inpatient use (mental illness 2.18, 95% CI: 1.59, 2.77; SMI 9.91, 95% CI: 8.21, 11.61). Only pre-existing SMI was associated higher hospitalization readmission.

    Discussion

    Pre-existing mental illness increases use of high cost, intensive health care and this association is higher of more severe mental health conditions. We also show that pre-existing mental illness exerts a unique influence, above and beyond other comorbidities, such as diabetes, on ED and inpatient visits. More needs to be done to increase recognition of the unique risks of this combination of health conditions and encourage strategies to address them. Developing, testing, and implementing comprehensive strategies that address the intersection of ADRD and mental illness is promising approach that requires more focused attention.
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    ItemOpen Access
    Vitamin D levels and cognition in elderly adults in China.
    (Journal of the American Geriatrics Society, 2014-11) Chei, Choy-Lye; Raman, Prassanna; Yin, Zhao-Xue; Shi, Xiao-Ming; Zeng, Yi; Matchar, David B

    Objectives

    To evaluate the association between vitamin D level and cognitive impairment in individuals aged 60 and older.

    Design

    Cross-sectional cohort study.

    Setting

    Chinese Longitudinal Healthy Longevity Survey, a community-based cohort study in areas in China where the density of centenarians is exceptionally high.

    Participants

    Individuals with mean age of 84.9 ± 12.7 (N = 2,004).

    Measurements

    Participants' cognitive state was evaluated using the Mini-Mental State Examination (MMSE). Vitamin D was measured in plasma using an enzyme-linked immunoassay.

    Results

    The cross-sectional association between quartiles of plasma vitamin D level and cognitive impairment (MMSE score <18) was modeled using logistic regressions. Plasma vitamin D levels were lower in individuals with cognitive impairment (31.9 ± 15.3 nmol/L) than in those without (45.6 ± 19.6 nmol/L). There was a reverse association between plasma vitamin D and cognitive impairment. After adjusting for age, sex, chronic conditions, smoking and drinking habits, outdoor activities, depression, and activity of daily living limitations, the association remained significant. The multivariable-adjusted odds ratio for lowest versus highest vitamin D levels was 2.15 (95% confidence interval (CI) = 1.05-4.41) for cognitive impairment, and the multivariable odds ratio associated with a 1-standard deviation decrement in plasma vitamin D was 1.32 (95% CI = 1.00-1.74) for cognitive impairment.

    Conclusion

    Low plasma vitamin D levels were associated with greater odds of cognitive impairment. Further prospective studies in Asian populations are needed to examine the causal direction of this association.
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    Vulnerability to Hypertension Is a Major Determinant of Racial Disparities in Alzheimer's Disease Risk.
    (American journal of hypertension, 2022-08) Akushevich, Igor; Kolpakov, Stanislav; Yashkin, Arseniy P; Kravchenko, Julia

    Background

    Higher incidence levels of Alzheimer's disease (AD) in Black Americans are well documented. However, quantitative explanations of this disparity in terms of risk-factor diseases acting through well-defined pathways are lacking.

    Methods

    We applied a Blinder-Oaxaca-based algorithm modified for censored data to a 5% random sample of Medicare beneficiaries age 65+ to explain Black/White disparities in AD risk in terms of differences in exposure and vulnerability to morbidity profiles based on 10 major AD-risk-related diseases.

    Results

    The primary contribution to racial disparities in AD risk comes from morbidity profiles that included hypertension with about 1/5th of their contribution due to differences in prevalence (exposure effect) and 4/5ths to differences in the effects of the morbidity profile on AD risk (vulnerability effect). In total, disease-related effects explained a higher proportion of AD incidence in Black Americans than in their White counterparts.

    Conclusions

    Disease-related causes may represent some of the most straightforward targets for targeted interventions aimed at the reduction of racial disparities in health among US older adults. Hypertension is a manageable and potentially preventable condition responsible for the majority of the Black/White differences in AD risk, making mitigation of the role of this disease in engendering higher AD incidence in Black Americans a prominent concern.