Many people experience problems with memory as they get older, but sometimes the changes are greater than expected. The Dartmouth Memory and Aging Study aims to better understand these changes by using advanced brain imaging techniques to visualize memory processes as they occur in the brain.

The Dartmouth Memory and Aging Study is a five-year longitudinal study led by Dr. Andrew Saykin, and funded by several agencies including the Alzheimer's Association, Hitchcock Foundation, Ira DeCamp Foundation, National Institute on Aging, and National Science Foundation, and through an investigator-initiated grant funded by Pfizer, Inc. This study investigates cognitive and neurophysiological changes associated with amnestic Mild Cognitive Impairment (MCI) and early Alzheimer's disease (AD). We use a combination of neuropsychological assessment, genetic testing, and structural and functional brain imaging techniques to understand the neural mechanisms underlying memory impairment in these disease processes. We also assess the effects of established cognition-enhancing medications (e.g., Aricept®) on brain activity during memory processing. We plan to characterize longitudinal change patterns and identify baseline predictors of disease trajectory relevant to clinical outcome.

What is amnestic MCI? Amnestic MCI is a condition characterized by:   relatively isolated memory complaints   impairment on tests of standardized memory tests relative to demographically-matched peers   the absence of dementia, global deficits, or significant compromise of normal daily activities Individuals with MCI are at an increased risk for developing AD.

Participants are recruited through use of flyers, public lectures, newspaper advertisements, and referrals from our medical center's General Internal Medicine, Community Health, and Geropsychiatry Clinics. Comprehensive screening includes a standardized phone interview, in-person interview, and review of medical records. Inclusion criteria include being at least 65 years of age, right-handed, fluent in English, and having adequate hearing. Participants also are required to have an individual who knows them well who can answer questions about their cognition and general health. Exclusion criteria include significant medical, psychiatric, or neurological condition (other than MCI), history of head trauma with loss of consciousness lasting more than five minutes, current or past history of substance dependence, factors contraindicating MRI, and medications that could affect the study variables (e.g., cholinesterase inhibitors, anti-depressants).

Do you have more problems than other people your age REMEMBERING:   new information?   casual conversations?   where you put things?   appointments?   what you read in the newspaper or heard on TV?   what you intended to do?

Participants undergo a neuropsychological evaluation, including measures of memory, attention, executive function, language, spatial ability, general intellectual functioning and psychomotor speed, as well as dementia screens. Also included are self-report inventories, completed by participants and their informants. A geropsychiatrist conducts a semi-structured interview and examination to rule out depression or other psychiatric disorders. Results of this comprehensive evaluation are reviewed in a multidisciplinary consensus meeting to determine group classification. We also draw blood and bank DNA from consenting participants to examine the role of key genes (e.g., E4 form of the APOE gene) on cognitive performance and disease trajectory. Participants undergo structural brain MRI, which is read by a neuroradiologist blinded to clinical status, to rule out unexpected pathology. While in the scanner, participants also perform auditory functional MRI activation tasks probing working, semantic and episodic memory systems. Examples of some of our fMRI memory tasks include the following:

(1) 2-back working memory task: This is a blocked auditory n-back paradigm in which participants hear a list of consonants presented one every three seconds. In separate 0, 1 and 2-back conditions, they press a target button to indicate whether the letter they are hearing matches a pre-specified letter (0-back condition) or the letter 1 or 2 positions back in the list (1 or 2 back conditions). An alternative button is depressed for non-matches.
(2) Semantic memory task: In this event-related task, participants hear pairs of items, each pair occurring at a pseudo-random inter-stimulus interval of 5-8 seconds. There are word pairs and pseudo-word pairs. In each case the subject is asked to decide whether the second item in a pair matches the first item. For words, the first item in a pair is a category and the second item is or is not an example of that category (vehicle-truck is a match, vehicle-donut is not). For pseudo-words the items are either the same (e.g. yodb-yodb) or different (yodb-rea). Rest periods serve as a further low-level control condition.

In the past year, our research team has completed several exciting studies of brain structure and activity in individuals at risk for AD. These have been presented at international meetings and full reports are being prepared for publication. In one study, we examined the effects of donepezil hydrochloride (Aricept®), a cholinesterase inhibitor, on cognition and brain activity in patients with MCI. Nine older adults with MCI were compared to nine, healthy demographically matched controls. At baseline (Time 1), patients showed reduced activation of frontoparietal regions relative to controls during the 2-back working memory task. Two months after stabilization on Aricept (Time 2), patients showed increased frontal activity relative to controls. Patients' cognitive function was stable or improved throughout the study. Overall, the findings suggested that treatment with a cholinesterase inhibitor leads to increased frontal activity in patients with MCI. This research has implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of fMRI in early detection and treatment monitoring in AD and MCI (Saykin at al., in press).

The figure below shows areas with greater activity at Time 2 than Time 1. Controls' activation patterns (left) differed little between the baseline and follow-up sessions, whereas MCI patients (right) showed increased activation predominantly in left dorsolateral prefrontal cortex at Time 2, after stabilization on Aricept.

Controls

Patients

Selected Study Presentations and Publications:

Rabin, L.A., Borgos, M.J., & Saykin, A.J. (2008). A survey of neuropsychologists' practices and perspectives regarding the assessment of judgment ability. Applied Neuropsychology, in press.

Saykin, A.J., Wishart, H.A., Rabin, L.A., Flashman, L.A., Mamourian, A.C., & Santulli, R.B. (in press). Cholinergic enhancement of frontal lobe activity in Mild Cognitive Impairment. Brain.

Saykin, A.J., Wishart, H.A., Rabin, L.A., Flashman, L.A., Mamourian, A.C., & Santulli, R.B. (submitted). Reduction of medial temporal gray matter density in older adults with amnestic MCI or cognitive complaints: A voxel-based morphometry study.

Nutter-Upham, K.E., Saykin, A.J., Rabin, L.A., Roth, R.M., Wishart, Pare, N., Flashman, L.A. (2008). Verbal fluency performance in amnestic MCI and older adults with cognitive complaints. Archives of Clinical Neuropsychology, 23, 229-241.

Wang, P., Flashman, L.A., Wishart, H.A., Rabin, L.A., Santulli, R., McHugh, T., MacDonald, J., Mamourian, A.C., & Saykin, A.J. (submitted). Corpus callosal atrophy in Alzheimer's disease and Mild Cognitive Impairment.

Nutter-Upham, K.E., Saykin, A.J., Rabin, L.A., Roth, R.M., Wishart, Pare, N., Flashman, L.A. (2008). Verbal fluency performance in amnestic MCI and older adults with cognitive complaints. Archives of Clinical Neuropsychology, 23, 229-241.

Rabin, L.A., Borgos, M.J., Saykin, A.J., Wishart, H.A., Crane, P.K., Nutter-Upham, K.E., & Flashman, L.A. (2007). Judgment in older adults: Development and psychometric evaluation of the Test of Practical Judgment (TOP-J). Journal of Clinical and Experimental Neuropsychology, 29, 752 - 767.

Rabin, L.A., Saykin, A.J., Wishart, H.A., Nutter-Upham, K.E., Flashman, L.A., Pare, N., & Santulli, R.B. (2007). The Memory and Aging Telephone Screen (MATS): Development and preliminary validation. Alzheimer¿s & Dementia, 3, 109 - 121.

Rabin, L.A., Roth, R.M., Isquith, P.K., Wishart, H.A., Nutter-Upham, K.E., Pare, N., Flashman, L.A., & Saykin, A.J. (2006). Self-and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints. Archives of Clinical Neuropsychology, 21, 721 - 732.

Rabin, L.A., Saykin, A.J., Wishart, H.A., Flashman, L.A., Santulli, R.B., & Mamourian, A. Compensatory brain activity associated with novelty detection and habituation in MCI and Cognitive Complaints. Poster presented at the 9th International Conference on Alzheimer's Disease and Related Disorders, Philadelphia, July, 2004.

Nutter-Upham, K.E., Flashman, L.A., Rabin, L.A., Wishart, H.A., Roth, R., Santulli, R.M., & Saykin, A.J. Awareness of cognitive impairment in MCI and Controls with Cognitive Complaints: Dimension variability and relationship to neuropsychological deficits and brain volume. Poster presented at the Thirty-Second Annual International Neuropsychological Society conference, Maryland, February, 2004.

Rabin, L.A., Saykin, A.J., Wishart, H.A., Copenhaver, B.R., Flashman, L.A., & Santulli, R.B. Telephone-based screening for MCI and Cognitive Complaints: Preliminary validation by comprehensive assessment. Poster presented at the Thirty-Second Annual International Neuropsychological Society conference, Maryland, February, 2004.

Saykin, A.J., Wishart, H.A., Santulli, R., Flashman, L.A., Rabin, L.A., McHugh, T.L., Ramirez, J.S., & Mamourian, A.C. (2003) Relation of decreased gray matter volume to verbal learning and subjective memory complaints in healthy older adults and patients with mild cognitive impairment. Journal of Neuropsychiatry and Clinical Neuroscience, 15, 263.

Wishart, H.A., Saykin, A.J., McDonald, B.C., Flashman, L.A., Santulli, R.B., McHugh, T.L., Schuschu, K.R., Rabin, L.A., & Mamourian, A.C. (2003) Gray matter volume predicts age-related alterations in brain fMRI activation pattern during working memory. Journal of Neuropsychiatry and Clinical Neuroscience, 15, 263.

For more information about the study or if you would like to participate, contact: Jessica Englert, Ph.D., Study Coordinator Dartmouth-Hitchcock Medical Center (603) 650-5811 To speak directly with the study investigators, contact Andrew Saykin, Psy.D. , Heather Wishart, Ph.D., or Laura Flashman, Ph.D., at Dartmouth-Hitchcock Medical Center, (603) 650-5824 or Robert Santulli, M.D., Dartmouth-Hitchcock Medical Center, (603) 650-5804.