Neurocognitive Outcomes of Depression in the Elderly
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Depression, Major Depression Disorder (MDD), Neurology |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 60 - Any |
| Updated: | 4/6/2019 |
| Start Date: | December 1995 |
| End Date: | December 2021 |
Clinical Studies of Mental Illness Not Involving Treatment Development, Efficacy, or Effectiveness Trials Phenotype-genotype Predictors of Cognitive Outcomes in Geriatric Depression
Late-life depression (LLD) and cognitive impairment (CI) are significant public health
problems among older adults, and their co-occurrence markedly increases disease burden and
dementia risk. This highlights the importance of identifying and treating CI in LDD; however,
current lack of reliable prognostic information from clinical, neuroimaging, and genetic data
impedes research on targeted prevention and treatment. Two critical ways to close current
knowledge gaps in predicting cognitive diagnostic outcomes of LLD involve: 1) increasing the
number of diagnostic cases available to existing studies, and 2) using those studies to
identify clinical, imaging, and genetic predictors that will improve future diagnosis. We
intend to do both in the current proposal. We plan to study the following SPECIFIC AIMS:
Aim 1: Identify baseline clinical-behavioral predictors of cognitive diagnostic outcomes in
LLD.
Working hypothesis: During acute LLD, CN will be associated with more frequent EOD and higher
negative life stress than PCI and AD; PCI will be associated with EOD and higher frailty than
CN and AD; AD will be associated with LOD, greater appetite loss, lower anxiety, and greater
memory impairment than CN and PCI.
Aim 2: Use multimodal neuroimaging at baseline to identify patterns associated with cognitive
diagnostic outcomes in individuals with LLD. Working Hypothesis: CN will be associated with
greater white matter integrity compared with PCI and AD; PCI will be associated with lower
white matter integrity and network abnormalities in anterior cingulate cortex compared with
CN; AD will be associated with lower hippocampal volume compared with CN and PCI.
Aim 3: (exploratory): Explore interrelationships among candidate genes, cognitive diagnostic
outcomes, and proposed phenotypic components relevant to LLD. Exploratory Hypotheses: 1) COMT
val158met polymorphism will be associated with CN; 2) 5-HTTPRL and APOE ε2 polymorphisms will
be associated with frailty; 3) genetic variation (SNPs) in TPH2 and AGTR1 will be associated
with risk factors of AD: LOD, episodic memory, hippocampal volume, and appetite loss.
problems among older adults, and their co-occurrence markedly increases disease burden and
dementia risk. This highlights the importance of identifying and treating CI in LDD; however,
current lack of reliable prognostic information from clinical, neuroimaging, and genetic data
impedes research on targeted prevention and treatment. Two critical ways to close current
knowledge gaps in predicting cognitive diagnostic outcomes of LLD involve: 1) increasing the
number of diagnostic cases available to existing studies, and 2) using those studies to
identify clinical, imaging, and genetic predictors that will improve future diagnosis. We
intend to do both in the current proposal. We plan to study the following SPECIFIC AIMS:
Aim 1: Identify baseline clinical-behavioral predictors of cognitive diagnostic outcomes in
LLD.
Working hypothesis: During acute LLD, CN will be associated with more frequent EOD and higher
negative life stress than PCI and AD; PCI will be associated with EOD and higher frailty than
CN and AD; AD will be associated with LOD, greater appetite loss, lower anxiety, and greater
memory impairment than CN and PCI.
Aim 2: Use multimodal neuroimaging at baseline to identify patterns associated with cognitive
diagnostic outcomes in individuals with LLD. Working Hypothesis: CN will be associated with
greater white matter integrity compared with PCI and AD; PCI will be associated with lower
white matter integrity and network abnormalities in anterior cingulate cortex compared with
CN; AD will be associated with lower hippocampal volume compared with CN and PCI.
Aim 3: (exploratory): Explore interrelationships among candidate genes, cognitive diagnostic
outcomes, and proposed phenotypic components relevant to LLD. Exploratory Hypotheses: 1) COMT
val158met polymorphism will be associated with CN; 2) 5-HTTPRL and APOE ε2 polymorphisms will
be associated with frailty; 3) genetic variation (SNPs) in TPH2 and AGTR1 will be associated
with risk factors of AD: LOD, episodic memory, hippocampal volume, and appetite loss.
Central hypothesis: the 5-year likelihood of each cognitive diagnostic outcome is associated
with distinct clinical, cognitive, and neural phenotypes during acute LLD, which in turn have
distinct genotypic correlates.
Specifically, CN individuals will have earlier first onset of depression (EOD) relative to
AD, more negative life stress during acute depression compared with AD and PCI, and greater
white matter integrity; CN will also be associated with the AA genotype of the COMT val158met
polymorphism, which may confer both neuroprotection and higher stress sensitivity. PCI will
have more EOD relative to AD, greater frailty, and lower white matter integrity than NC. AD
will be associated with later age of depression onset (LOD), greater appetite loss, lower
anxiety, smaller hippocampal volume, and greater memory impairment. To test these hypotheses,
we propose the following
with distinct clinical, cognitive, and neural phenotypes during acute LLD, which in turn have
distinct genotypic correlates.
Specifically, CN individuals will have earlier first onset of depression (EOD) relative to
AD, more negative life stress during acute depression compared with AD and PCI, and greater
white matter integrity; CN will also be associated with the AA genotype of the COMT val158met
polymorphism, which may confer both neuroprotection and higher stress sensitivity. PCI will
have more EOD relative to AD, greater frailty, and lower white matter integrity than NC. AD
will be associated with later age of depression onset (LOD), greater appetite loss, lower
anxiety, smaller hippocampal volume, and greater memory impairment. To test these hypotheses,
we propose the following
Inclusion Criteria:
For depressed group:
1. Age > 60 years
2. Major depression, single episode or recurrent
3. Ability to read and write English
4. MMSE >25
5. Willingness to participate in the follow-up study for at least two years.
For non-depressed group:
1. Age > 60 years
2. Ability to read and write English
3. MMSE >25
4. Willingness to participate in the follow-up study for at least two years.
Exclusion Criteria:
1. Lifetime alcohol or drug dependence
2. conditions associated with MRI abnormalities such hydrocephalus, benign and cancerous
brain tumors, epilepsy, Parkinson's disease, Huntington's chorea, dementia,
demyelinating diseases, etc.
3. endocrine disorder other than diabetes mellitus)
4. Any physical or intellectual disability that may affect completion of self rating
instruments
5. Established clinical diagnosis of dementia
6. Other primary psychiatric disorders, including panic disorder, social phobia, OCD,
non-affective psychosis (including schizo-affective disorder), schizophrenia, bipolar
disorder
7. Any metal or pacemaker in the body which precludes MRI.
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