Non-Amnestic Alzheimer's Disease Biology

David Irwin, MD
Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2016244S
Award Type:
Standard
Award Region:
US Northeastern
David Irwin, MD

Genetic Risk and Clinical Expression of Tauopathy Across Alzheimer’s Disease and Frontotemporal Dementia

Summary

Alzheimer’s disease (AD) is defined by the presence of amyloid plaques and tau tangles in the brain associated with memory loss; however, a significant number of patients with AD have non-memory symptoms, such as language or visuospatial impairment. The underlying biology of these non-amnestic AD patients is understudied. Further understanding of the genetic influence and progression of tau pathology in non-amnestic AD will improve the diagnosis of patients who may benefit from emerging therapies that aim to halt or slow the progression of plaques and tangles in the brain and also identify new genetic targets for drug development in AD. 

Details

The goal of our project is to study the pattern of disease spread and genetic risk for non-amnestic clinical variants of Alzheimer's disease (AD). It is not uncommon for AD neuropathology to be associated with clinical symptoms that do not primarily involve memory loss, but instead resemble syndromes associated with frontotemporal lobar degeneration (sometimes known as frontotemporal dementia, or FTD). We hypothesize that the distribution and spread of tau pathology in these non-amnestic forms of AD diverges from traditional Braak tau stages, which begin in the medial temporal lobe, but instead originates in neocortical regions. To test this hypothesis, we are using a novel quantitative method to analyze digital images on histology slides to measure the burden of tau pathology in over 30 regions of the central nervous system. This analysis will be performed in a large autopsy cohort of patients with non-amnestic forms of AD.

We are comparing the severity of tau-mediated neurodegeneration between regions in serial autopsies with a panel of tau markers that are specific for early (ie, pre-tangle) and late (ie, ghost-tangle) morphologies of tangles to develop a staging model of disease progression in non-amnestic forms of AD. We are also examining longitudinal neuroimaging measures of grey matter thickness in living patients to develop an in vivo model of disease progression for converging evidence of our pathology staging model. We also hypothesize that non-amnestic forms of AD may have divergent genetic risk from amnestic AD, and may instead share genetic risk with other tauopathies. We are examining the frequency of previously-identified risk single nucleotide polymorphisms (SNPs) associated with amnestic AD, and those associated with tauopathies, in a large multi-center cohort of non-amnestic AD patients. We are also comparing SNP frequencies to reference groups of normal control, amnestic AD, and tauopathy patients to determine which risk factors are shared between groups. We are also relating SNP genotypes to the regional patterns of tau pathology from our histology experiments [deleted reference to “Aim 1” since the Aims are not specifically discussed/mentioned here] to determine genetic risk for neocortical spread of tau pathology in non-amnestic AD.

We created one of the largest multi-center cohorts of non-amnestic AD patients for these analyses, and our approach challenges the current dogma of Braak staging of tau pathology in this understudied AD population. We utilize novel objective techniques in quantitative digital image analysis of histopathology, with improved sensitivity for correlation with clinical and genetic variables that otherwise would not be possible using traditional subjective ordinal rating scales of neuropathologic burden. Our neuroimaging techniques include novel methods for image processing that support merging neuroimaging data across centers and imaging-pathology associations.

These efforts have important implications for clinical care as non-amnestic AD patients are often excluded from current clinical trials targeting AD pathology. Improving the clinical diagnosis of non-amnestic AD also will improve access for these patients to appropriate therapies; in addition, our staging model can have diagnostic and prognostic utility as outcome measures in clinical trials. Further, identification of genetic risk for non-amnestic AD will improve our understanding of the underlying biology of heterogeneity in AD and provide novel targets for drug development.

About the Researcher

Dr. David Irwin is an assistant professor of neurology at the University of Pennsylvania Perelman School of Medicine. Dr. Irwin is a former post-doctoral fellow at the Penn Center for Neurodegenerative Disease Research and Frontotemporal Degeneration Center. Dr. Irwin’s research is focused on clinical biomarker discovery through comparative clinicopathological studies in neurodegenerative disease using novel digital image analysis methods for use on human autopsy histology samples. The overarching goal of this approach is to improve the ante mortem diagnosis of underlying neuropathology for improved clinical trials targeting specific pathogenic proteins (eg, tau, TDP-43 [transactive response DNA binding protein 43], alpha-synuclein) that characterize these disorders.

Personal Story

My clinical interest and research focus on neurodegenerative disease began as a resident in neurology when I encountered patients with a social disorder consistent with a clinical diagnosis of frontotemporal dementia (FTD). As I learned more about this condition, I learned that there were three major classes of neuropathology that could cause this syndrome: frontotemporal lobar degeneration with tauopathy, frontotemporal lobar degeneration with TDP-43 proteinopathy, and Alzheimer's disease (AD) associated olaque and tangle pathology.

Microscopically, these diseases appear very different, so intuitively, any treatment that would ameliorate these conditions would have to be specific for each type of proteinopathy. Indeed, now, several years later, clinical trials are currently targeting amyloid-beta and tau proteins, while TDP-43-specific therapies are on the horizon.

I was fascinated by how such different underlying biologies could result in the identical clinical symptoms I encountered in clinic. Further, near this time, TDP-43 was discovered as the key protein accumulating in both the neocortex in forms of frontotemporal degeneration and also in the spinal cord in amyotrophic lateral sclerosis. I was also puzzled how two seemingly different diseases (cognitive and motor) could have very similar underlying biology.

These questions led me to train as a post-doctoral fellow at the Penn Center for Neurodegenerative Disease Research and Frontotemporal Degeneration Center. Here, I had the unique opportunity to both evaluate and treat patients with various forms of AD and FTD, and also study the underlying neuropathology in the laboratory.

I am now a member of the faculty at Penn and I am building my laboratory to study the distribution of these pathologies in the brain using new technologies that allow for parametric measurement of disease burden. These continuous measures allow for more in-depth study of these diseases with the goal of using this data to drive discovery of clinical biomarkers to improve diagnostic accuracy in the clinic. This approach is needed to improve clinical trials and help patients receive disease-specific therapies as they are discovered.

BrightFocus Foundation award has provided me with a wonderful opportunity to build my laboratory and work towards my goals of answering these questions that captivated me as a trainee. These questions still motivate me to continue this work to advance clinical care for these patients, who are in desperate need of effective therapies.

Publications

Olney NT, Ong E,Goh SM, Bajorek L, Dever R, Staffaroni AM, Cobigo Y, Bock M, Chiang K, Ljubenkov P, Kornak J, Heuer HW, Wang P, Rascovsky K, Wolf A, Appleby B, Bove J, Bordelon Y, Brannelly P, Brushaber D, Caso C, Coppola G, Dickerson BC, Dickinson S, Domoto-Reilly K, Faber K, Ferrall J, Fields J, Fishman A, Fong J, Foroud T, Forsberg LK, Gearhart DJ, Ghazanfari B, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford NR, Grant I, Grossman M, Haley D, Hsiung G, Huey ED, Irwin DJ, Jones DT, Kantarci K, Karydas AM, Kaufer D, Kerwin D, Knopman DS, Kramer JH, Kraft R, Kremers W, Kukull W, Lapid MI, Litvan I, Mackenzie IR, Maldonado M, Manoochehri M, McGinnis SM, McKinley EC, Mendez MF, Miller BL, Onyike C, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos EM, Rankin KP, Roberson ED, Rogalski E, Sengdy P, Shaw LM, Syrjanen J, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Weintraub S, Wong B, Wszolek Z, Boxer AL, Boeve BF, Rosen HJ; ARTFL and LEFFTDS consortia. Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration. Alzheimers Dement. 2019 Nov 26. pii: S1552-5260(19)35366-X. doi: 10.1016/j.jalz.2019.08.196. [Epub ahead of print] PubMed PMID: 31784375 PubMed Icon Google Scholar Icon

Boeve B, Bove J, Brannelly P, Brushaber D, Coppola G, Dever R, Dheel C, Dickerson B, Dickinson S, Faber K, Fields J, Fong J, Foroud T, Forsberg L, Gavrilova R, Gearhart D, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grossman M, Haley D, Heuer H, Hsiung GR, Huey E, Irwin D, Jones D, Jones L, Kantarci K, Karydas A, Knopman D, Kornak J, Kraft R, Kramer J, Kremers W, Kukull W, Lapid M, Lucente D, Mackenzie I, Manoochehri M, McGinnis S, Miller B, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos E, Rankin K, Rascovsky K, Sengdy P, Shaw L, Syrjanen J, Tatton N, Taylor J, Toga A, Trojanowski J, Weintraub S, Wong B, Wszolek Z, Boxer A, Rosen H; LEFFTDS Consortium. The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology. Alzheimers Dement. 2019 Oct 18. pii: S1552-5260(19)35113-1. doi: 10.1016/j.jalz.2019.06.4947. [Epub ahead of print] PubMed PMID: 31636026 PubMed Icon Google Scholar Icon

Spotorno N, Hall S, Irwin DJ, Rumetshofer T, Acosta-Cabronero J, Deik AF, Spindler MA, Lee EB, Trojanowski JQ, van Westen D, Nilsson M, Grossman M, Nestor PJ, McMillan CT, Hansson O. Diffusion Tensor MRI to Distinguish Progressive Supranuclear Palsy from α-Synucleinopathies. Radiology. 2019 Oct 15:190406. doi: 10.1148/radiol.2019190406. [Epub ahead of print] PubMed PMID: 31617796. PubMed Icon Google Scholar Icon

Phillips JS, Da Re F, Irwin DJ, McMillan CT, Vaishnavi SN, Xie SX, Lee EB, Cook PA, Gee JC, Shaw LM, Trojanowski JQ, Wolk DA, Grossman M. Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer's disease. Brain. 2019 Jun 1;142(6):1701-1722. doi: 10.1093/brain/awz091. PubMed PMID: 31135048; PubMed Central PMCID: PMC6585881 PubMed Icon Google Scholar Icon

Staffaroni AM, Bajorek L, Casaletto KB, Cobigo Y, Goh SM, Wolf A, Heuer HW, Elahi FM, Ljubenkov PA, Dever R, Kornak J, Appleby B, Bove J, Bordelon Y, Brannelly P, Brushaber D, Caso C, Coppola G, Dheel C, Dickerson BC, Dickinson S, Dominguez S, Domoto-Reilly K, Faber K, Ferrall J, Fields JA, Fishman A, Fong J, Foroud T, Forsberg LK, Gavrilova R, Gearhart D, Ghazanfari B, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grant I, Grossman M, Haley D, Hsiung GY, Huey ED, Irwin DJ, Jones DT, Jones L, Kantarci K, Karydas A, Kaufer DI, Kerwin DR, Knopman DS, Kraft R, Kremers WK, Kukull WA, Litvan I, Lucente D, Lungu C, Mackenzie IR, Maldonado M, Manoochehri M, McGinnis SM, McKinley E, Mendez MF, Miller BL, Multani N, Onyike C, Padmanabhan J, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos EM, Rankin KP, Rascovsky K, Roberson ED, Rogalski E, Sengdy P, Shaw LM, Syrjanen J, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Weintraub S, Wang P, Wong B, Wszolek Z, Boxer AL, Boeve BF, Kramer JH, Rosen HJ; ARTFL/LEFFTDS consortium. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint. Alzheimers Dement. 2019 May 11. pii: S1552-5260(19)30044-5. doi: 10.1016/j.jalz.2019.01.012. [Epub ahead of print] PubMed PMID: 31088775. PubMed Icon Google Scholar Icon

Meeter LHH, Steketee RME, Salkovic D, Vos ME, Grossman M, McMillan CT, Irwin DJ, Boxer AL, Rojas JC, Olney NT, Karydas A, Miller BL, Pijnenburg YAL, Barkhof F, Sánchez-Valle R, Lladó A, Borrego-Ecija S, Diehl-Schmid J, Grimmer T, Goldhardt O, Santillo AF, Hansson O, Vestberg S, Borroni B, Padovani A, Galimberti D, Scarpini E, Rohrer JD, Woollacott IOC, Synofzik M, Wilke C, de Mendonca A, Vandenberghe R, Benussi L, Ghidoni R, Binetti G, Niessen WJ, Papma JM, Seelaar H, Jiskoot LC, de Jong FJ, Donker Kaat L, Del Campo M, Teunissen CE, Bron EE, Van den Berg E, Van Swieten JC. Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia. J Neurol Neurosurg Psychiatry. 2019 May 23. pii: jnnp-2018-319784. doi: 10.1136/jnnp-2018-319784. [Epub ahead of print] PubMed PMID: 31123142. PubMed Icon Google Scholar Icon

Phillips, J. S., Da Re, F., Irwin, D. J., McMillan, C. T., Vaishnavi, S. N., Xie, S. X., ... & Trojanowski, J. Q. (2019). Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer’s disease. Brain. (in press) PMID: DOI: https://doi.org/10.1093/brain/awz091

Gibbons GS, Kim SJ, Robinson JL, Changolkar L, Irwin DJ, Shaw LM, Lee VM, Trojanowski JQ. Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau). Acta Neuropathol Commun. 2019 Mar 4;7(1):34. doi: 10.1186/s40478-019-0687-5. PubMed PMID: 30832741 PubMed Icon Google Scholar Icon

Giannini LAA, Irwin DJ, McMillan CT, Ash S, Rascovsky K, Wolk DA, Van Deerlin VM, Lee EB, Trojanowski JQ, Grossman M. Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia. Neurology. 2017 May 17. pii: 10.1212/WNL.0000000000004034. doi: 10.1212/WNL.0000000000004034. [Epub ahead of print] PubMed PMID: 28515265. PubMed Icon Google Scholar Icon

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