The research of Dr. van Dyck and the Alzheimer’s Disease Research Unit (ADRU) focuses on treatment, neuroimaging and genetic studies of Alzheimer's disease (AD) and healthy aging.
Direct link to:
| Alzheimer’s Disease Treatment Studies |
| Neuroimaging Studies |
| Genetic Studies |
Alzheimer’s Disease Treatment Studies
Dr. van Dyck and the ADRU are very active in national and international research in the treatment of AD. Since its inception in 1991 the Yale ADRU has been involved in approximately 60 multicenter clinical trials for AD, and the prodromal condition of Mild Cognitive Impairment (MCI). Since 1996 we have been a member site of the Alzheimer's Disease Cooperative Study (ADCS) funded by the National Institute of Aging (NIA). The ADCS is the principal consortium for AD therapeutic studies funded by NIH. Its mission is to carry out studies that would not otherwise be conducted by industry (for example, of non-proprietary agents like vitamin E and estrogen), however, it increasingly collaborates with pharmaceutical and small biotech companies in studies of novel proprietary agents. A good example of the work of the ADCS is contained in our paper in the New England Journal of Medicine (Petersen et al, 2005) entitled: “Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment” (PDF).
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Kaplan-Meier Estimates of the Rate of Progression from Mild Cognitive Impairment to Alzheimer’ Disease (AD). Panel A shows the survival estimates in all three groups during the three-year study. Panel B shows the pre-specified comparisons involving z-tests at 6 months (P=0.004 and 12 months (P=0.04). From Petersen et al, 2005 (PDF).
Collaborations with Industry
Much of the “cutting edge” basic research in AD treatment is based within the pharmaceutical industry, and the ADRU also works extensively with industry to test highly novel treatments. The ADRU was the nation’s top enrolling site in assessing memantine for late-stage AD, the only treatment currently approved for late-stage illness (PDF). Currently, the ADRU is helping to assess several anti-amyloid mechanisms that have the potential to actually arrest and reverse the course of the disease for the very first time: these include vaccines and antibodies, as well as inhibitors of amyloid aggregation and inhibitors of the amyloidogenic enzymes γ-secretase or ß-secretase (See Clinical Trials). The Yale PET Center has recently begun to perform amyloid imaging with [11C]PIB PET (See image below), and new studies will assess whether these novel treatment strategies truly reduce amyloid burden as hypothesized.
Our principal local research interest involves neuroimaging in AD and healthy aging. We have worked primarily with single photon emission computed tomography (SPECT) and positron emission tomography (PET), utilizing both neuroreceptor ligands and tracers of regional cerebral blood flow (rCBF).
Dopamine Transporter (DAT) Imaging
Dr. van Dyck and colleagues have conducted a series of investigations of the nigrostriatal dopamine system using the DAT radioligand [123I]ß-CIT and SPECT. Our contribution to this research has emphasized studies of healthy aging, but has also included the effects of sex and menstrual cycle (Best et al, 2005) (PDF), DAT genotype (van Dyck et al, 2005) (PDF), and a number of clinical disorders (e.g., adult Attention Deficit Hyperactivity Disorder—van Dyck et al, 2002a) (PDF). Our aging studies of the DAT have demonstrated that over the normal adult lifespan striatal DAT availability—as a marker of nigrostriatal terminals—declines by about 50% (van Dyck et al, 1995), at a rate that is approximately linear and with a pattern of striatal subregions and hemispheric asymmetry that differs from that of Parkinson’s disease (van Dyck et al, 2002b) (PDF).
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Age-Related Decline in Dopamine Transporters (DAT) with [123I]ß-CIT. Panel A: [123I]ß-CIT SPECT image co-registered with MRI, demonstrating uptake in caudate and putamen. Panel B: Images of striatal [123I]ß-CIT uptake in two subjects, aged 20 and 78 years, respectively. The older subject shows a 56% reduction in DA transporter binding (V3") relative to the younger one (From van Dyck et al, 1995). Panel C: Striatal dopamine transporter (DAT) availability (V3") versus age as measured by [123I]ß-CIT SPECT in 126 healthy subjects. Striatal V3" = –0.0604 * age + 10.225; r = –0.64; df = 124; P < 0.0001 (Pearson's test). Linear regression analysis revealed that V3" declined by 46% over the age range 18 to 88, or approximately 6.6% per decade (From van Dyck et al, 2002b (PDF))
Most recently (van Dyck et al, 2007 in press), we have begun to examine the functional significance of nigrostriatal dopaminergic degeneration in normal aging—which has heretofore been uncertain. In a study of 36 healthy elderly subjects, we have demonstrated that striatal DAT availability is correlated with reaction speed but not with several comparison tasks. This research has provided some of the first human evidence of a relationship between nigrostriatal dopaminergic function and a behavioral measure in normal aging. It specifically suggests that the motoric slowing of aging—with its consequences for daily functioning—is related to the degeneration of the brain's nigrostriatal dopamine system. Our results have laid the groundwork for development of drug treatments and other intervention strategies for the elderly.
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Simple Reaction Time (SRT) versus striatal dopamine transporter (DAT) availability (V3") as measured by [123I]ß-CIT and SPECT in healthy elderly subjects (N=36). SRT represents the median speed (in ms) with which subjects responded to a visual stimulus (presented on a computer monitor) by pressing a single microswitch key with the index finger of the dominant hand. The simple zero-order correlation between SRT and V3" was significant (r=–.40, df=36, P=.016), as was the partial correlation after controlling for age (rSRT,V3"|AGE=–.40, df=33, P=.017). From van Dyck et al, 2007 (PDF).
Other Studies of Neuroreceptor Imaging
In addition, we have conducted studies of the central serotonin transporter (SERT) using [123I]ß-CIT and SPECT (Neurobiol Aging, 2000;21:497-501), the 5HT2A receptor using [18F]deuteroaltanserin and PET (J Nucl Med, 2000;41:234-241. Nucl Med Biol, 2000;27:715-722), and studies of the a4ß2 nicotinic receptor using the SPECT ligand [123I]5-I-A-85380.
Studies of Regional Cerebral Blood Flow (rCBF) in AD
SPECT studies or regional cerebral blood flow (rCBF) have shown among their greatest promise as diagnostic and research tools in AD. Our previous rCBF SPECT studies have compared the diagnostic utility of different rCBF tracers in AD (J Nucl Med 1996;37:1749-1755) and have examined the effects of an experimental cholinergic therapy (linopirdine) on rCBF deficits in AD (Junior Investigator Award, American Association for Geriatric Psychiatry; Psychopharmacology 1997;132:217-226). Linopirdine treatment was found to "reverse" 24% of the baseline parietal perfusion deficit in the AD patients. These data support the conclusion that rCBF abnormalities in AD are, in part, truly “functional" and can be selectively altered with pharmacological interventions. The parietal activation seen with linopirdine, in conjunction with other convergent evidence, suggests that, in the development of cholinergic drug therapies for AD, greater utilization should be made of tasks subserved by the parietal lobes. We have also completed a study of the effect of the Apolipoprotein E e4 (ApoE e4) allele on the pattern of SPECT rCBF in AD (Arch Neurology 1998;55:1460-1466). This work has demonstrated significantly greater parietal rCBF asymmetry in the ApoE e4– patients than the ApoE e4+ patients. If replicated, this study suggests that ApoE e4– AD may be associated with other (as yet undiscovered) genetic or environmental risk factors which confer greater neuropathological asymmetry.
Finally, in addition to our participation in NIH consortia for AD treatments, we are also a key site for the NIH Alzheimer’s Disease Neuroimaging Initiative (ADNI) consortium, which is performing MRI and PET scans in patients with mild AD and MCI, and healthy elderly subjects.
The Apolipoprotein E e4 (ApoE e4) Phenotype of AD
Phenotype of AD During the past several years, our research group in collaboration with Dr. Joel Gelernter has completed a number of studies to examine phenotypic correlates of the ApoE e4 allele—the major genetic risk factor for AD—in individuals who suffer from probable AD. A highlight of this research has been the finding that AD patients who carry the ApoE e4 allele are at greater risk than non-carriers for developing debilitating psychotic symptoms, particularly as the severity of their dementia progresses (Zdanys et al, Neuropsychopharmacology, 2007) (PDF).
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Frequency of psychosis by ApoE e4 carrier status and dementia severity. Mini Mental State Examination (MMSE) score was used to classify AD patients as mild (MMSE≥20, n=103), moderate (MMSE=12-19, n=121), or severe (MMSE<12, n=42). Separate multiple logistic regression analyses were performed for each severity category, with presence of psychosis as dependent variable and the following independent variables (in addition to e4 carrier status): age, sex, educational attainment, and MMSE. *Only at the severe stage was the presence of e4 significantly associated with psychosis (odds ratio [OR]=16.61, 95% CI=2.11–130.51, P=.008). From Zdanys et al, 2007 (PDF).
However, ApoE e4 does not appear to influence the rate of cognitive or functional deterioration in patients with AD (e.g., Kleiman et al, Dement Geriatr Cogn Disord, 2006)(PDF). Efforts to establish neural substrates for a behavioral ApoE e4 phenotype in AD have thus far yielded unclear results. The structural MRI literature is fairly unified in observing greater medial temporal lobe atrophy in association with the e4 allele in AD (e.g., Basso et al, Neurobiol Aging, 2006) (PDF). However, functional imaging studies with PET and SPECT have not established a consistent pattern of regional cerebral activity associated with e4 (e.g., van Dyck et al, Arch Neurology, 1998) (PDF).
We are currently furthering this effort with the new PET ligand, [11C]PIB, to assess amyloid plaques in healthy subjects who are at risk for AD. In a study funded by the Alzheimer’s Association, we are examining whether amyloid burden, as measured using [11C]PIB, is increased in healthy individuals (age 50-65) with a family history of AD who also carry ApoE e4.
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PET Images of the uptake of [11C]PIB in a subject with Alzheimer’s disease (AD) and a healthy elderly control, demonstrating increased ß-amyloid binding in the brain of the AD subject (from Klunk WE, Mathis CA, et al. University of Pittsburgh).
Disclosure statement: Dr. Christopher H. van Dyck and Yale University receive research grant support from several pharmaceutical companies for the development of treatments for Alzheimer’s disease, Mild Cognitive Impairment, and Adult Attention Deficit Hyperactivity Disorder. Dr. van Dyck also serves as a consultant and paid speaker for some of these companies.
