Unit of Clinical & Translational Neuroscience
Although rapid strides have been made in our understanding of the basic biology of Alzheimer's disease (AD), there is concern that this knowledge has not been translated into earlier diagnosis and/or effective treatments for patients. The overall goals of the Clinical and Translational Neuroscience Unit in the Laboratory of Behavioral Neuroscience are to enhance understanding of disease mechanisms operating in AD as well as to identify novel biomarkers that might be predictive of disease before the onset of clinical symptoms. To achieve these goals, we use several approaches including:
- Applying mass spectrometry-based proteomics and metabolomics for the discovery of novel biomarkers predictive of disease before symptom onset.
- Relating genetic and environmental risk factors to changes in brain structure, function and pathology during aging.
While these studies rely primarily on clinical and neuroimaging datasets available within the Baltimore Longitudinal Study of Aging (BLSA), other datasets, such as those available through the Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) are also used in these analyses.
In our biomarker discovery studies, we use archived blood samples collected through the BLSA to identify changes over time in the concentrations of proteins and small metabolites that may be predictive of early cognitive decline and neuropathological changes associated with AD.
Details of Recent Studies
- Evidence for Brain Glucose Dysregulation in Alzheimer’s Disease
- Alpha2-macroglobulin (A2M) is a marker of neuronal injury in Alzheimer’s disease
- Midlife adiposity and the age-at-onset of Alzheimer’s disease
- Is there a common biology underlying both obesity and obesity-related behaviors?
- Insulin resistance (IR) and its relationship to AD pathology and brain function
- Proteome-based blood biomarkers of brain amyloid deposition during aging
- Plasma clusterin concentration is related to severity, pathology and progression in AD
From Mechanisms to Medicines: Realizing the DREAM of an Alzheimer’s Cure
Our ongoing ‘OMICS’ studies have identified numerous biochemical pathways that are abnormal in AD including glucose breakdown, fatty acid synthesis and phospholipid metabolism. We have identified several FDA-approved drugs prescribed for non-AD indications that may also target these abnormal pathways. We now propose to test whether prior exposure to these drugs results in protection against AD/dementia in large real-world prescription datasets. This project is called the DREAM (Drug Repurposing for Effective Alzheimer’s Medicines) Study and will test exposures to approximately 20 drugs that we have nominated as ‘candidate AD treatments.’ We will perform these analyses in multiple large prescription datasets from the US (Centers for Medicare Services), UK (Clinical Practice Research Datalink), Sweden/Finland (Nordic Prescription Registries) and Taiwan (National Health Insurance Database) which together represent more than 30 million older individuals. This is a unique study that will combine deep molecular phenotyping (i.e. ‘OMICS’ studies in brain/blood) with big-data analyses of patient-derived health record data to identify novel drug repurposing opportunities in AD. We expect that signals indicating a protective effect against AD with one or more drugs will be provide a sound rationale for subsequent confirmation in randomized clinical trials (RCTs).
- Mechanisms of Alzheimer's disease pathogenesis
- Genetic risk factors associated with Alzheimer's disease
- Proteomic and metabolomic approaches to identify biologically relevant biomarkers of Alzheimer's disease
Findings and Publications
Varma VR, Varma S, An Y, Hohman TJ, Seddighi S, Casanova R, Beri A, Dammer EB, Seyfried NT, Pletnikova O, Moghekar A, Wilson MR, Lah JJ, O'Brien RJ, Levey AI, Troncoso JC, Albert MS, Thambisetty M. Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry. 2017 Jan;22(1):13-23
Snowden SG, Ebshiana AA, Hye A, An Y, Pletnikova O, O'Brien R, Troncoso J, Legido-Quigley C, Thambisetty M. Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study. PLoS Med. 2017 Mar 21;14(3):e1002266
Chuang YF, An Y, Bilgel M, Wong DF, Troncoso JC, O'Brien RJ, Breitner JC, Ferruci L, Resnick SM, Thambisetty M. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation. Mol Psychiatry. 2016 Jul;21(7):910-5
Simpson BN, Kim M, Chuang YF, Beason-Held L, Kitner-Triolo M, Kraut M, Lirette ST, Windham BG, Griswold ME, Legido-Quigley C, Thambisetty M. Blood metabolite markers of cognitive performance and brain function in aging. J Cereb Blood Flow Metab. 2016 Jul;36(7):1212-23.
Casanova R, Varma S, Simpson B, Kim M, An Y, Saldana S, Riveros C, Moscato P, Griswold M, Sonntag D, Wahrheit J, Klavins K, Jonsson PV, Eiriksdottir G, Aspelund T, Launer LJ, Gudnason V, Legido Quigley C, Thambisetty M. Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals. Alzheimers Dement. 2016 Jul;12(7):815-22.
Recent Publications at PubMed
Awards & Recognition
In a significant recognition of our work, the American Academy of Neurology (AAN) awards the 2016 Norman Geschwind Prize in Behavioral Neurology to Dr. Madhav Thambisetty. The Geschwind prize is given in recognition of outstanding research contributions to the field of behavioral neurology and is named in honor of Dr. Norman Geschwind, the father of modern Behavioral Neurology.
Public outreach and lectures of general interest
Why are study partners important in Alzheimer’s disease clinical trials?
Video produced by the NIA Office of Communication and Public Liaison. Courtesy: Stephanie Dailey and Margaret Vaughn (OCPL; NIA; NIH)
Adiposity and insulin resistance in Alzheimer’s disease: when state meets trait
Neurology Grand Rounds, Johns Hopkins Bayview Medical Center, May 2014
Medicine for the Public Lecture
Since 1977, NIH researchers have educated the public about biomedical research through yearly "Medicine for the Public" programs. This unique forum, hosted by the NIH Clinical Center, engaged NIH scientists to present state-of-the art research in lay language to the public. Attendees had the singular opportunity not only to learn about basic research from those who did it, but also to understand how that research could diagnose, treat, and prevent disease - and ultimately, preserve health. In this way, Medicine for the Public has contributed to the NIH Clear Communication Initiative, which seeks to improve the nation's health literacy.
- Video press release by the NIA on our work in Molecular Psychiatry (Midlife Adiposity predicts earlier onset of Alzheimer’s dementia, neuropathology and presymptomatic cerebral amyloid accumulation).
- Links to some press coverage of our results reporting associations between midlife BMI and AD onset in Molecular Psychiatry:
Excess Weight at Age 50 Linked to Early Alzheimers Onset
Midlife Weight Alzheimers
BMI Predicts How Soon Alzheimers Will Develop
- Interview on the BBC World Service on our finding that clusterin is a blood biomarker of Alzheimer’s disease
- Interview on Voice of America on our work identifying blood biomarkers for brain amyloid deposition
- Medscape story on our finding that plasma apoE concentration is related to extent of brain amyloid deposition
- Medscape story on our finding that the CR1 risk variant gene is associated with lower brain amyloid deposition in non-demented older individuals
- ScienceDaily story on our findings reporting a lack of association between peripheral insulin resistance and Alzheimer’s neuropathology
- Discover magazine story highlighting our CR1 results as one of the top 100 scientific discoveries of 2013 (PDF, 629K)
- News Story & Video Report on our findings published in Molecular Psychiatry on the obesity gene FTO and its effects on adiposity, brain function, impulsivity and diet during aging
Blood, brain metabolites could be earlier biomarkers of Alzheimer’s disease
NIA Featured Research highlight on our recent publication in PLoS MEDICINE Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.
- Nature Reviews Neurology on our finding that alpha2 macroglobulin (A2M) may be a sex-specific marker of neuronal injury in AD (PDF, 557K)
- BRAIN PUZZLE Nature Medicine on our finding that the CR1 risk variant gene is associated with lower brain amyloid deposition in non-demented older individuals (PDF, 529K)
- CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer's Disease (link to paper). See also: commentary in Biological Psychiatry (PDF, 860K).