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1/5 Neurocognitive and neuroimaging biomarkers: predicting progression towards dementia in patients with treatment-resistant late-life depression

Award Number: R01MH114970
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY DESCRIPTION: Dementia, especially Alzheimer’s dementia (AD), is a growing public health problem with a prevalence of 5M in the US alone (33M worldwide). Despite a decrease in incidence rates, with the aging of the population, the prevalence of dementia is expected to increase to 16M in the US (115M worldwide) with associated costs rising to $1T. Delaying long-term care by 1 month for older Americans would save $60B annually in direct care cost. Efforts to prevent or delay dementia have been largely unsuccessful. However, major depressive disorder in late life (“late-life depression”, LLD) has been identified as one of six treatable risk factors for dementia, especially AD and vascular dementia. The depression-dementia relationship may be magnified in elders who do not respond to antidepressant treatment and experience persistent symptoms. Thus, resolving whether those with treatment-resistant late-life depression (TRLLD) are at higher risk of cognitive decline and progression to dementia compared to those with treatment-responsive LLD is critically important. Leveraging a Patient-Centered Outcomes Research Institute (PCORI)-funded treatment study of N=1500 people with LLD, across 5 sites, we propose to comprehensively delineate neurocognitive and neuroimaging biomarkers associated with progression to dementia in people with persistent LLD (i.e., TRLLD) compared to those whose LLD remits with treatment. We anticipate enrolling 750 elders with LLD and characterizing their symptomatic trajectory over 24 months. We will assess each participant at three time points with neurocognitive and advanced neuroimaging. We hypothesize that changes in executive functions and the executive control network, as well as changes in episodic memory and the default mode/cortico-limbic network, will be greater in those with TRLLD than in those who respond to treatment and stay well. We also hypothesize that changes over two years in executive function and episodic memory will be specifically associated with changes in executive- control and cortico-limbic circuitry, respectively. Based on our recent findings that inflammatory and related molecularmarkers can differentiate those with neurocognitive impairment and LLD from those with LLD alone, we will build a predictive multivariate model combining baseline neurocognitive, neuroimaging, and plasmaprotein data to determine who is at greatest risk for cognitive decline and dementia. Finally, we will also explore whether latent class trajectories of depressive symptoms can go beyond the dichotomy of remission/non-remission to identify subsets of elders with LLD at highest risk of cognitive decline, neural circuit change, and progression to dementia. This work will set the stage for neural circuit- targeted preventive care to delay dementia in subsets of older patients with LLD. If successful, our work can accelerate therapeutic efforts and innovation targeting the depression- dementia pathway and reduce suffering for large numbers of elders and their families.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON			CAN	Mental Health Research Grants	000	5	7/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $410,356 )
2021	2021	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON			CAN	Mental Health Research Grants	000	5	7/13/2021	NON-COMPETING CONTINUATION	$410,356
														Subtotal = $410,356

Issue Date FY: 2020 ( Subtotal = $366,053 )
2020	2020	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	001	4	7/23/2020	NON-COMPETING CONTINUATION	$366,053
2020	2019	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	000	3	12/12/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $366,053

Issue Date FY: 2019 ( Subtotal = $487,557 )
2019	2019	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	001	3	8/28/2019	SUPPLEMENT FOR EXPANSION	$69,178
2019	2019	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	000	3	7/25/2019	NON-COMPETING CONTINUATION	$418,379
														Subtotal = $487,557

Issue Date FY: 2018 ( Subtotal = $383,495 )
2018	2018	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	000	2	8/3/2018	NON-COMPETING CONTINUATION	$383,495
														Subtotal = $383,495

Issue Date FY: 2017 ( Subtotal = $390,177 )
2017	2017	CENTRE FOR ADDICTION AND MENTAL HEALTH	1001 QUEEN ST W	TORONTO	ON	M6J 1H4		CAN	Mental Health Research Grants	000	1	9/18/2017	NEW	$390,177
														Subtotal = $390,177

Grand Total All Awards = $2,037,638

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1/5 Neurocognitive and neuroimaging biomarkers: predicting progression towards dementia in patients with treatment-resistant late-life depression

Award Number: R01MH114970

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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