Alzheimer's Disease-Related Dementias (ADRD) Conference 2013 -- Prioritized Research Recommendation Milestones

1. Develop and/or apply clinical algorithms for detecting primary dementias in outpatient general neurology. The algorithms should also be applicable to a primary care setting, and should yield appropriate referral guidance. Include a training component to support high quality clinical training for physicians and nonphysicians.

1. Develop and/or apply one or more biomarker algorithms to detect and differentiate among AD and other dementias (e.g. but not limited to FTD, VCID, LBD) in a general neurology setting. This algorithm should also be applicable to primary care settings.

1. Initiate at least one research study to develop biomarker algorithms for rapidly progressive dementias, and one study to develop biomarker algorithms for potentially treatable dementias, to enable recognition in general neurology and primary care settings and facilitate referral to specialists.

1. Initiate at least one research study using biomarkers or contributing to biomarkers discovery within a health disparities population that specifically examines dementia prevalence and incidence.

1. Establish at least one registry for enumerating and characterizing less common dementias, dementias in younger persons, rapidly progressive dementias, and potentially treatable dementias. The registry should implement efficient data acquisition and, when possible, leverage existing electronic medical records, for example, within large regional health care systems.

1. Develop and implement procedures to increase access by external sites to neuropathology services at specialized research centers.
2. Document increased number of research brain autopsies referred by external sites to specialized research centers.
3. Leverage this collaborative infrastructure to link neuropathologic findings to diagnostic and/or biomarker advances.

1. Timelines are approximate, and represent time to completion or full implementation of success criteria from the start of work. The actual pace of implementation of this milestone plan will reflect resources available.

1. 1. Identify and catalog ongoing diversity research cohorts, including associated biospecimens and clinical data, as well as potential diversity cohorts (e.g., cross sectional studies amenable to followup) that would strengthen research in the ADRDs, e.g. based on, but not limited to, race/ethnicity, socioeconomic status, or geography. Assess what steps are needed to assess and follow disparities in incident dementia in these cohorts/potential cohorts.
   2. Maximize diverse representation in dementia research by embedding sample collection (e.g. blood, CSF, & autopsy tissue) and clinical data in high impact research cohorts among those identified. To increase the range of co-morbidities represented, when possible, collection should emphasize samples based on the community or population, rather than memory clinics or other specialized medical settings. Facilitate wide sharing of the samples and clinical data for biomarkers discovery and other research.
   3. Enhance the power of diversity community-based research studies of middle age and older adults by developing, within the identified research cohorts, assessment tools for cognitive impairment and dementia and for neuropsychiatric status in diversity populations (guided by evidence from mixed methods studies to evaluate and improve population appropriate measures). These efforts should contribute to and be informed by leading edge development of best practices for assessing cognitive function, cognitive impairment, and dementia in diverse populations.

1. 1. 1-3 years
   2. 3-5 years
   3. 3-5 years

1. Use diverse community-based research cohorts and mixed methodology (e.g. including but not limited to clinical assessment, questionnaires, neuropsychiatric instruments, informant-based surveys, and adaptive psychometric tests) to develop best practices for assessing cognitive function, cognitive impairment, and dementia in diverse populations. These best practices will include validated tools for assessing AD and ADRD and tracking disease progression over time, and methodology for documenting salient symptoms and for understanding disease burden to individuals and family members/caregivers. Key priorities are that tools operate the same across time and populations, and that they facilitate harmonized comparison of assessment data among diverse populations, and, optimally, between existing and legacy assessment data. These best practices will reflect and account for how diverse populations understand and recognize dementias, and should address needs in primary care, specialized care, and for surveillance.
2. Facilitate harmonized comparisons among assessments of cognitive function, cognitive impairment, and dementia in diverse populations by developing and making available normative references for these developed using best practices for assessing cognitive function, cognitive impairment, and dementia in diverse populations.

1. Conduct mixed methods research to develop strategies (e.g., specific language and outreach mechanisms/venues) to recruit study participants in diverse populations, based on how each population understands and recognizes AD and ADRD.
2. Develop guidelines for increasing diverse participation in ADRD clinical research. Such guidelines should address logistical barriers, e.g., transportation, cultural issues, and should suggest how to identify and leverage local initiatives, institutions, agencies, and other organizations focused on health outcomes in disparities populations.

1. Complete at least one study embedded within large scale community-based health surveillance systems, including potentially primary care, designed to utilize and validate simple assessment tools applicable for a surveillance setting.
2. Initiate a national surveillance plan to monitor differences in AD and ADRD incidence, prevalence, and long term outcomes among racial/ethnic, socioeconomic, geographic and other population differences relevant to disparities. Develop and release a consensus report on risk factors, predictors, consequences, and levels of under-diagnosis of ADRD among disparities populations.

1. Develop and make widely available guidelines for brain health assessments in clinical trials of vascular interventions in diversity populations. These guidelines will include standardized outcome measures relevant to cognitive outcomes in diverse populations (e.g. clinical, imaging, neurological, cognitive, and vascular) that will facilitate meta-analyses of intervention studies of vascular health in diverse populations, and will draw from expertise in related fields, e.g. stroke, lipid metabolism, cardiovascular intervention, and immune function. The guidelines should provide tiers of vascular, cognitive, and other relevant assessments that are optimized for resources, such as caregiver time, and technology available at sites relevant for cognitive impairment and dementia research in diversity populations. Guidance should also include best practices for recruitment in diverse populations
2. Implement and validate, in vascular health intervention studies that include diverse populations, assessments of standardized outcome measures relevant to AD and ADRD.

1. Determine whether changes in risk factors for dementia, both traditional and novel, occur over the lifecourse in diversity populations in at least one study. Identify critical periods of life and critical lifestyle and other parameters with respect to dementia prevention.

1. Determine whether the prevalence of AD and ADRD risk factors (e.g., vascular, behavioral, environmental, or social risks), and their causal impact on outcomes, differs across disparities populations. Use this information to estimate the highest impact intervention targets (i.e., population burden associated with each risk factor) in disparities populations.

1. Establish guidelines for best research practices for understanding gene-environment Interactions as contributors to AD and ADRD disparities; these guidelines should address a full range of considerations, including statistical, theoretical, and practical
2. Complete at least one study in diverse populations that integrates genetic and environmental risk factors, and assesses their interactions. This study should be powered to evaluate whether genetic predictors of risk for dementia are similar or different across diverse populations, incorporating measures of environmental risk factors. Facilitate data availability for future research (e.g., via dbGaP).
3. Complete at least one study that assesses in disparities populations the co-occurrence and joint effects of social, environmental and biological (including genetic) risks for cognitive impairment and dementia. Assess such risk interactions for similarities and differences across diverse populations (considering dimensions of race/ethnicity, SES, and geography).

1. Timelines are approximate, and represent time to completion or full implementation of success criteria from the start of work. The actual pace of implementation of this milestone plan will reflect resources available.

1. Initiate at least 1 new clinical trial that leverages an existing clinical network infrastructure and one or more FDA-approved drugs for symptomatic improvement of one or more of the core clinical features of DLB and PDD.

1. At least one new study that leverages one or more existing neurodegeneration and/or dementia cohorts to develop and establish research tools to study DLB and PDD.
2. Create or leverage existing resource(s) to collect and share for research standardized clinical and neuropsychological data from individuals with potential early manifestations of DLB, including dream enactment behavior (also known as rapid eye movement sleep behavior disorder), hyposmia, autonomic dysfunction and non-amnestic mild cognitive impairment.

1. Inventory and report on existing autopsy samples with clinically well-characterized brains with antemortem diagnoses of DLB or PDD that meet high likelihood DLB neuropathological criteria. This report, the "PDD and DLB Sample and Clinical Data Report", will also comment on quality and availability of all these samples and clinical data.
2. Hold a planning workshop, informed by the "PDD and DLB Sample and Clinical Data Report", to determine and propose an optimized implementation plan for mapping brain changes in LBD using the samples, data, and other resources available to best effect .

1. Identify families with multiple affected members of PDD and/or DLB for genomic analyses.
2. Definitive assessment of genetic risk architecture in clinically wellcharacterized patients with PDD or DLB and/or autopsy confirmed high likelihood DLB.
3. Convene a workshop of interested parties to address methodological issues needed to explore gene-environment interactions for DLB and PDD.

1. At least one new study to validate available and proposed imaging tools for the diagnosis and classification of DLB and PDD against longitudinally followed cohorts or autopsy confirmed cases. Include in this study emerging technologies, e.g. fMRI and molecular imaging of α-synuclein.
2. Convene a workshop in which analytical approaches and standardization of neuroimaging methods can be addressed to facilitate multicenter studies.

1. Identify collections of tissue and biofluid samples from existing longitudinal case-control cohorts in which samples were collected in standardized protocols and in which the samples are linked to clinical data that includes DLB and PDD cases.
2. Initiate at least one large study to develop and validate novel biomarkers using well characterized DLB or PDD samples.

1. Establish basic research studies focused on developing a better understanding of the basic science of LBD, e.g., but not limited to, alpha synuclein biology and how it is related to LBD, and betaamyloid and alpha synuclein interactions.
2. Develop one or more new animal models that fit known molecular pathology of DLB and PDD. Optimally, new animal model/s will be informed by human based systematic mapping of DLB and PDD, and by results of biomarker studies.

1. Initiate one or more disease modifying clinical trials that prevent or alter disease processes using prospective therapies based on pharmaceutical approaches, gene therapy, regenerative medicine, surgical interventions, or other novel approaches.

1. Timelines are approximate, and represent time to completion or full implementation of success criteria from the start of work. The actual pace of implementation of this milestone plan will reflect resources available.

1. Identify specific tau-related pathophysiological events, and corresponding targets, that contribute to neurodegeneration in humans with tauopathy.
2. Develop model systems that verify and enable testing of interventions for new therapeutic targets in tauopathy.
3. Determine the relationship between tau misfolding and assembly to spread of tau aggregation and neurodegeneration.

1. Generate in vivo and cell-based models of TDP-43/FUS, GRN haploinsufficiency, and C9ORF72 expansion models that recapitulate key biochemical, neuropathological and functional aspects of FTD and can contribute to therapeutic development.
2. Develop and validate in vivo functional assays and neuropathological endpoints for mammalian models that are aligned with FTD anatomy.

1. Identify key mechanism(s) of C9ORF72 FTD/ALS and GRN-related pathogenesis that can be targeted for intervention.

1. Identify key mechanism(s) of TDP-43 and FUS-related pathogenesis that can be targeted for intervention.

1. Initiate at least one new large study to discover new genes and risk alleles for FTD. Where appropriate and synergistic, these efforts should include amyotrophic lateral sclerosis (ALS) kindreds in gene discovery studies.

1. Initiate at least one new large study focused on development, testing, and pathological confirmation of novel PET ligands and/or CSF/blood biomarkers for the molecular diagnosis of FTLD-tau, -TDP and .FUS.
2. Development and testing of sensitive, systems-level surrogate biomarkers (e.g. MRI/fMRI/PET/EEG/clinical) to detect and monitor prodromal FTD and progression during early stage disease; the goal is to inform early in disease clinical proof- of-concept studies, complement clinical outcome measures in Phase III clinical trials, and ultimately the foundation for endpoints on which drug registration can be based.

1. Develop a patient registry for FTD clinical studies and a centralized database for de-identified clinical, genetic and biomarker data that can be shared with the broader research community to refine disease models, clinical endpoints and trial design.

1. Completion of at least 1 natural history study of preclinical inherited FTD (especially MAPT, GRN and C9ORF72-related FTD) by following individuals from health to disease. Data enable identification of novel genetic and environmental disease modifiers that influence clinical presentation and biomarkers for diagnosis and disease progression.
2. Completion of at least 1 natural history studies of patients with sporadic FTLD, starting from early symptomatic FTD and prioritizing clinical syndromes for which the clinico-pathological correlation is high (e.g., progressive supranuclear palsy and tau, semantic variant primary progressive aphasia and TDP-43 Type C, FTD with MND and TDP-43 Type B). Data will enable identification of novel genetic and environmental disease modifiers that influence clinical presentation and biomarkers for diagnosis and disease progression.

1. Timelines are approximate, and represent time to completion or full implementation of success criteria from the start of work. The actual pace of implementation of this milestone plan will reflect resources available.

1. Establish new animal models that: (i) reproduce small vessel disease and other key pathogenic processes thought to result in cognitive impairment; or (ii) are easily applicable to both VCID and AD research for advances in mixed dementias; or (ii) address vascular contributions to dementia via both white matter and grey matter;
2. Develop tools for cell- (endothelial, smooth muscle, pericyte, etc.) and region- (gray vs. white matter, cortex vs. striatum, etc.) specific characterization of the effects of altered cerebrovascular and neurovascular unit (glia, immune cells, etc.) function.

1. Initiate new basic research that provides rigorous and novel insight into how factors involved in AD pathogenesis (Aß, tau, apoE, other AD-associated gene products, etc.) affect cerebrovascular function or vascular-related brain injury.

1. Initiate at least one new basic research project that provides rigorous and novel insight into how cerebrovascular disease (small vessel) or cerebrovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, etc.) impact the development or progression of AD-related neurdegeneration.

1. Identify neuroimaging or biochemical biomarker(s) that independently correlate with the presence and severity of advanced small vessel disease (SVD) in at least two human SVD cohorts.
2. Identify a neuroimaging marker for the vascular pathology of arteriolosclerosis.

Validation:

1. Establish a direct link from in vivo imaging to ex vivo imaging to histopathology for biomarker(s) identified in the Development phase.
2. Establish a link between the presence or progression of the biomarker(s) identified in the development phase and cognitive/neurologic impairment or decline in at least two SVD cohorts.

1. Perform comprehensive studies of the independent associations between biomarkers of cerebrovascular disease and biomarkers of Aß- and tau-related pathology/neurodegeneration in a human cohort.
2. Initiate at least one intervention study to identify the effects of modifying vascular risk factors on biomarkers of Aß- and tau-related pathology/neurodegeneration.

1. Use leading edge biomarkers of small vessel disease and of cognitive/neurologic function in human trials of interventions aimed at decreasing the burden of VCID by modifying vascular risk factors or processes.
2. Initiate a human clinical trial of an intervention derived from SVD-related biological pathways identified in animal or human studies, using leading edge biomarkers.

1. Timelines are approximate, and represent time to completion or full implementation of success criteria from the start of work. The actual pace of implementation of this milestone plan will reflect resources available.