Notice to Specify High-Priority Research Topics for PAR-19-070 and PAR-19-071

Notice Number: NOT-AG-18-048

Key Dates
Release Date: November 28, 2018

Related Announcements

PAR-19-070
PAR-19-071

Issued by
National Institute on Aging (NIA)

Purpose

This Notice of Information specifies two high-priority topics of interest for PAR-19-070 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)" and PAR-19-071 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)".

1. Novel Approaches to Characterizing and Diagnosing Alzheimer's Disease and Related Dementias

Background

This topic encourages research applications to develop and apply novel biomarkers to study the biology of Alzheimer’s disease and related dementias.

Tremendous strides have been made in recent years in studying the clinical neurobiology of Alzheimer’s Disease (AD) and related dementias (ADRD). Biomarkers play a key role in understanding AD and ADRD. They are crucial to translating basic neuroscience research into clinical settings, and biomarkers have become essential in trials of disease-modifying therapies for AD.

In the past, a definitive diagnosis of AD was only possible at postmortem. Now, however, positron emission tomography (PET) with b-amyloid or Tau specific radioligands, or immunoassays in cerebrospinal fluid (CSF) can demonstrate the presence of b-amyloid plaques or Tau tangles in vivo. We are now able to diagnose AD in living individuals, and even identify prodromal or preclinical illness. The recent NIA/AA ‘A-T-N’ research framework, characterizes dementia based on biomarkers: ‘A’, b-amyloid, ‘T’, Tau, and ‘N’, Neurodegeneration.

Magnetic resonance imaging (MRI) has made it possible to detect structural defects due to neurodegeneration, like localized thinning of cortical gray matter or loss of hippocampal volume. Vascular dementia (VD) can be identified by the presence of sub-cortical, lacunar infarcts, micro-infarcts or hemorrhages, and leukoaraiosis (white matter hyperintensities). Structural MRI and 18F-fluorodeoxyglucose (FDG) PET can recognize patterns of tissue loss and cerebral glucose hypometabolism, that distinguish AD from frontotemporal dementia (FTD).

The new NIA/AA ‘A-T-N’ research framework encourages development of new - as yet, unrecognized - dementia biomarkers. Unfortunately, there are no biomarkers specific for FTD or Lewy Body Dementia (LBD), comparable to PET and CSF measures of the plaques and tangles of AD, or the MRI changes in VD. We need antemortembiomarkers that can identify non-AD proteinopathies like a-synuclein Lewy Bodies (LBD, Parkinson’s Disease, and multi-system atrophy, MSA), FTLD Tau (FTD, and chronic traumatic encephalopathy, CTE), TDP-43 (FTD, amyotrophic lateral sclerosis, ALS, and spinocerebellar atrophy, SCA), or huntingtin (Huntington’s Disease).

This deficiency constrains our ability to study ADRDs: but just as important, failure to identify non-AD neuropathology, in vivo, limits our understanding of how neurodegenerative illnesses interact with one another to cause brain dysfunction. Autopsy studies consistently show that dementia (particularly in the oldest old) is rarely limited to AD plaques and tangles. As people age, more and more neuropathological abnormalities – VD, LBD, and TDP-43, along with AD – become evident.

It is important to recognize, however, that plaques and tangles, vascular changes, Lewy Bodies, and TDP-43 are also found at autopsy in people who never evidenced cognitively impairment during life. Neuropathogical signs of AD, VD, FTD, or LBD indicate neurodegeneration, but they do not diagnose dementia. There is no biomarker whose presence reliably distinguishes normal from abnormal brain function or cognition, and there is no established biomarker that robustly predicts or correlates with clinical decline. Biomarkers more closely tied to cognitive function, that might even serve as surrogate endpoints in dementia treatment trials, would be tremendously valuable.

Finally, currently available biomarkers are invasive to one degree or another. CSF sampling requires a lumbar puncture, which many people find objectionable; PET scans involve exposure to radioactivity; and MRI and PET scans are expensive. Current approaches are better suited to research at academic centers, not use in real life communities. Reliable biomarkers that could be applied in primary-care settings could have great impact.

Objective

The goal is to develop novel approaches to characterizing, diagnosing, and predicting outcomes in AD and ADRD. Examples of research that might be supported include, but are not limited to:

  1. Studies that improve antemortem characterization of dementia, particularly ADRDs
    1. Development of antemortem biomarkers to identify non-AD proteinopathies: a-synuclein (Lewy Bodies), FTD-Tau (4R and 3R), and TDP-43
    2. Biomarkers characterizing dementia subtypes:
      1. AD: Posterior cortical atrophy (PCA), hippocampal sparing, dysexecutive, etc
      2. LBD: Parkinson’s Dementia, REM sleep disorder, fluctuating levels of consciousness, etc
      3. FTD: Pick’s, BvFTD, PSP, CBD, FTD w/ MND, etc
      4. Tau vs TDP-43 FTD
  2. Studies providing new information about the pathophysiology of AD and/or ADRD
    1. Biomarkers of inflammation and microglia function altered in AD or ADRD
    2. Biomarkers of brain glucose metabolism altered in AD or ADRD
    3. Characterizing brain networks altered in AD or ADRD, using connectomics, task or resting state fMRI
  3. Identify common neurobiological mechanisms underlying concomitant symptoms and cognitive impairment in AD and ADRD
    1. Biomarkers of neuropsychiatric symptoms
    2. Movement disorders: FTD vs LBD vs AD
    3. Aphasias: logopenic primary progressive aphasia can be AD or FTD
    4. Surrogate marker for cognition, or a dementia/cognition “stress” test
  4. Address shortcomings of currently used biomarkers.

This topic is not intended to study biomarkers that are already validated or studied in AD or ADRD. The goals are limited to establishing proof of concept rather than full validation of a novel biomarker. It may be useful to employ an existing biomarker as a "gold standard", and novel applications of existing biomarkers (e.g., in different illnesses or at different stages) could be appropriate. Both clinical and preclinical studies may be supported by this high-priority topic.

Applications proposing clinical trials on this topic would not be considered a high priority.

2. Common Mechanisms and Interactions Among Neurodegenerative Diseases

Background

Etiologic and therapeutic research on dementia has focused on either individual disease syndromes (e.g., Alzheimer’s disease, AD; Lewy Body Dementia, LBD, Frontotemporal Dementia, FTD; or Vascular Dementia, VD) or distinct neurodegenerative processes (e.g., beta-amyloid, HPF-Tau, alpha-synuclein, TDP-43, small vessel disease). Aside from descriptive, postmortem neuropathology, different neurodegenerative diseases have generally been investigated in isolation from one another. There are few models for studying whether and how neurodegenerative disease processes relate to one another.

At autopsy, many patients with dementia, particularly older individuals, exhibit multiple neuropathologies: in addition to tau tangles and beta-amyloid plaques, vascular changes, Lewy bodies, and TDP-43 inclusions are often present. We know that the likelihood of antemortem dementia increases with co-occurring postmortem neuropathology. However, despite considerable evidence of interactions between different neuropathologies (see below), we do not understand how different neurodegenerative processes interact and relate to one another.

Co-occurring pathology complicates both pathophysiological investigation and treatment development. For instance, therapies to increase beta-amyloid clearance may be less effective if there is coincident VD or LBD. At the same time, commonalities between neurodegenerative diseases may provide clues to pathophysiological mechanisms. Can multiple neuropathologies interact synergistically to increase disease burden and worsen cognitive impairment? Could there be common pathways leading to synapse loss and cell death that might become targets for drug development? If either speculation is the case, what molecular, cellular, or organismic processes are involved?

Objective

We need to understand how different neurodegenerative processes interact clinically and physiologically. We need to be able to more precisely identify which neurodegenerative process or processes are active in individual patients. At the same time, we need to better understand how different neurodegenerative diseases resemble and differ from one another at the molecular, cellular, and organismic levels.

Two priorities are particularly germane to this high-priority topic:

  • Cellular and animal models for investigating concurrent neurodegenerative processes must be developed if we are to answer many of the questions raised in this high priority topic.
  • Development of CSF and PET biomarkers for in vivo brain beta-amyloid plaques and HPF-tau tangles have transformed AD research. In vivo measures for the presence of brain alpha-synuclein and TDP-43 will be important to elucidating how different neurodegenerative processes interact in vivo.

Examples of issues that are encouraged by this high-priority topic include (but are not limited to):

  • Many neurodegenerative diseases involve aggregation and accumulation of misfolded proteins. Rather than independent entities, could they be studied as clinical variants of common cellular and molecular biological defects? Shared pathways might include:
    • Clearance of misfolded proteins and proteostasis, ER stress and the unfolded protein response, proteosomes, lysosomes, autophagy;
    • Mitochondrial function: There is considerable evidence of mitochondrial involvement in Parkinson’s Disease (a synucleinopathy), Huntington’s Disease, and ALS;
    • RNA transcription and processing: Huntington’s and several Spinal-Cerebellar Atrophies are neurodegenerative disorders cause by trinucleotide repeat expansions. A hexanucleotide repeat expansion in the gene associated with C9ORF72 causes familial FTD and is the most frequent cause of familial ALS. TDP43 is an RNA binding protein;
    • Inflammation: microglial activation and the innate immune system play a major role in AD, with some evidence in other neurodegenerative diseases;
    • Identifying distinctions: pathophysiologic mechanisms unique to one neuropathologic entity, will be as informative as identifying commonalities.
  • There is evidence for prion like spread of alpha-synuclein and HPF-tau. HPF-tau can seed alpha-synuclein fibrilization and vice versa. There appear to be distinct HPF-tau and alpha-synuclein strains.
  • While AD, FTD, and LBD are characterized neuropathologically by deposits of insoluble protein aggregates (amyloids), the actual neurotoxic species all appear to be soluble oligomers.
  • The ApoE4 allele is a major genetic risk factor for both AD and LBD. How does a gene involved in lipid transport lead to increased beta-amyloid plaques, HPF-Tau tangles, and alpha-synuclein Lewy Bodies?
  • AD involves both beta-amyloid plaques and HPF-Tau tangles. Neocortical beta-amyloid plaques are the earliest manifestation, but HPF-Tau tangles are more closely associated with cognitive impairment. HPF-tau tangles in entorhinal cortex appear normally with age, and it appears that tau spread beyond entorhinal cortex requires the presence of beta-amyloid plaques. How do beta-amyloid plaques drive spread of HPF-tau tangles?
  • HPF-tau is an important component of AD and a subtype of FTD (albeit with different mixes of isoforms). What else, besides beta-amyloid, distinguishes AD from other tauopathies?

Applications proposing clinical trials on this topic would not be considered a high priority.

 

Submissions should indicate that they are in response to NOT-AG-18-048 in Field 4.b on the SF 424 form.

 

Inquiries

Please direct all inquiries to:

John Hsiao, M.D.

National Institute on Aging (NIA)

Telephone: 301-496-9350

Email: jhsiao@mail.nih.gov