Neurocognitive Outcomes of Depression in the Elderly (NCODE)

• Change in Depression status (measured by Montgomery Asberg Depression Rating Scale) [ Time Frame: Minimum of once per year, up to 21 years ] [ Designated as safety issue: No ]
• Change in Cognitive impairment (as measuring using cognitive tests including those found in the CERAD battery) [ Time Frame: Once per year, up to 21 years ] [ Designated as safety issue: No ]
• Development of dementia (Determined by Clinical Consensus Conference) [ Time Frame: once per year, up to 14 years ] [ Designated as safety issue: No ]

• Depression status (measured by Montgomery Asberg Depression Rating Scale) [ Time Frame: Up to five years ] [ Designated as safety issue: No ]
• Cognitive impairment (as measuring using cognitive tests including those found in the CERAD battery) [ Time Frame: Up to five years ] [ Designated as safety issue: No ]
• Development of dementia (Determined by Clinical Consensus Conference) [ Time Frame: Up to five years ] [ Designated as safety issue: No ]

• Change in Cognition (as measured by tests including those in the CERAD battery) Change in Brain MRI markers (e.g., volume of white matter and gray matter lesions) [ Time Frame: once per year, up to 21 years ] [ Designated as safety issue: No ]
• Change in Impairment in Instrumental or Basic Activities of Daily Living [ Time Frame: at least once per year, up to 21 years ] [ Designated as safety issue: No ]
• Packing density of prefrontal cortex neurons with pyramidal morphology in post-mortem neuroanatomical studies [ Time Frame: once post-mortem ] [ Designated as safety issue: No ]

• Change in Cognition (as measured by tests including those in the CERAD battery) Change in Brain MRI markers (e.g., volume of white matter and gray matter lesions) [ Time Frame: Up to five years ] [ Designated as safety issue: No ]
• Impairment in Instrumental or Basic Activities of Daily Living [ Time Frame: Up to five years ] [ Designated as safety issue: No ]

This study seeks to examine clinical, genetic, and neuroanatomical variables related to mood and cognitive outcomes of depression in late life. We plan to study the following SPECIFIC AIMS:

Aim 1. To compare cognitive outcomes among older adults with and without depression, and to examine depression and cognitive outcomes in patients with cognitive impairment or neuroimaging changes.

Aim 2. To examine the role of genes in long-term depression outcomes in the elderly.

Aim 3. To determine neuroanatomical and neuropathological correlates of late-life depression outcomes.

We will test the following hypotheses:

Hypothesis 1. Compared with non-depressed elderly controls, depressed elderly patients will have an increased incidence of development of mild cognitive impairment and dementia.

Hypothesis 2. Depressed subjects with mild cognitive impairment will have a worse depression course compared with depressed subjects who do not have mild cognitive impairment.

Hypothesis 3. Depressed subjects with worsening deep white matter disease and smaller hippocampal volumes on longitudinal (baseline to two year) magnetic resonance imaging brain scans will have a worse depression course and more cognitive decline compared with depressed subjects without these brain changes.

Hypothesis 4. Depressed subjects with the 5HTTLPR short allele will have a worse depression course compared with depressed subjects without these risk genes.

Hypothesis 5. Depressed subjects with the apolipoprotein E (APOE) epsilon-4 allele and vascular risk gene polymorphisms such as ACE receptor will have an increased risk of cognitive decline compared with depressed subjects without these risk genes.

Hypothesis 6. Compared with brains of non-depressed controls, brains of depressed subjects will demonstrate increased density of blood vessels in the prefrontal cortex, including orbital frontal cortex and dorsolateral prefrontal cortex.

Hypothesis 7. Compared with brains of non-depressed controls, brains of depressed subjects will demonstrate decreased packing density of prefrontal cortex neurons with pyramidal morphology.

Hypothesis 8. Compared with non-demented depressed subjects, depressed individuals who become demented will have more neuritic plaques, neurofibrillary tangles and cerebrovascular pathology.

We will examine secondary aims related to 1) mortality and 2) social factors, with the following hypotheses:

1. Depressed subjects with a larger increase in volume of hyperintensities will have a higher mortality rate.
2. Subjects with poor social support and functional status will have worse depression and cognitive outcomes.

Primary care clinic Outpatient psychiatry clinic Inpatient psychiatry clinic Self-referral

• Major Depression
• Dementia

• Depressed
  Older individuals with major depression
• Non-depressed
  Older individuals without psychiatric disorder

• Steffens DC, Potter GG, McQuoid DR, MacFall JR, Payne ME, Burke JR, Plassman BL, Welsh-Bohmer KA. Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. Am J Geriatr Psychiatry. 2007 Oct;15(10):839-49. Epub 2007 Jul 10.
• Steffens DC, Taylor WD, McQuoid DR, Krishnan KR. Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression. Int J Geriatr Psychiatry. 2007 Aug 14; [Epub ahead of print]
• Potter GG, Blackwell AD, McQuoid DR, Payne ME, Steffens DC, Sahakian BJ, Welsh-Bohmer KA, Krishnan KR. Prefrontal white matter lesions and prefrontal task impersistence in depressed and nondepressed elders. Neuropsychopharmacology. 2007 Oct;32(10):2135-42. Epub 2007 Feb 14.

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.