17 Dec 2010

In an ideal future, physicians would diagnose people with incipient Alzheimer’s disease long before memory problems appear, and prescribe treatments that would slow or halt the progression of the disease. That future still appears a long way off, but at a November 16 press conference held at the 2010 Society for Neuroscience annual meeting in San Diego, California, four researchers presented work that could bring us closer to that vision. Two talks described the use of MRI imaging techniques to identify brain changes that may presage Alzheimer’s, potentially enabling earlier diagnosis of AD. Another group discussed efforts to develop a vaccine against Aβ while avoiding the inflammatory side effects that hobbled earlier attempts (see Part 2 of this series). The final talk focused on tau, showing that tau oligomers can disrupt memory processes and may be a promising therapeutic target as well.

Reiterating human AD research by other groups, session chair Sangram Sisodia of the University of Chicago, Illinois, pointed out that AD may begin more than 10 years before the onset of symptoms. Positron emission tomography (PET) with Pittsburgh Compound B, which decorates amyloid plaques, shows that amyloid deposition can start years before memory loss (e.g., see ARF related news story). And scientists have found other imaging markers that may help flag people at risk. PET imaging with the glucose analog FDG reveals that brain metabolism drops before the onset of dementia, while functional MRI makes apparent an early loss of connectivity (see ARF related news story and Drzezga et al., 2010). Another telltale warning sign is a shrinkage of the hippocampus, as seen by MRI (e.g., see ARF related news story). Some scientists believe synaptic damage may occur even earlier in some forms of dementia (see ARF related news story). All these data highlight the importance of intervening early, the speakers emphasized. Identifying people in this prodromal phase could be important in two ways. In the present day, it would boost the power of clinical trials by recruiting the people most likely to benefit from therapy. In the future, once reliable treatments for AD are available, it could enable treatment before the disease causes irreversible brain damage.

The hippocampus may not be the only part of the brain that gets smaller. Sarah Madsen, a graduate student in the lab of Paul Thompson at the University of California in Los Angeles, showed data indicating that shrinkage of the caudate nucleus, a C-shaped structure that curls around the lateral ventricles deep in each hemisphere of the brain, can predict disease progression as well (see Madsen et al., 2010). The caudate nucleus is part of the basal ganglia, and nestles next to the thalamus and amygdala. It participates in motor control, attention, and other cognitive processes. It is known to deteriorate in Parkinson’s disease, contributing to motor problems. Madsen was interested in it because the caudate nucleus develops amyloid plaques and neurofibrillary tangles in AD brains. The caudate is also believed to play a role in some forms of learning and memory.

Madsen used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to analyze structural brain MRIs of 100 people with AD, 200 people with mild cognitive impairment (MCI), and 100 healthy elderly. She found that the caudate nucleus was 4 percent smaller in people with MCI than in healthy elderly, and 7 percent smaller in people with AD. The right caudate consistently showed greater volume loss than the left, for reasons that are not clear, Madsen said. Volume loss in this structure also correlated with increased age, high body weight, and poor scores on the Mini-Mental Status Exam. In most of these conditions, the head of the caudate nucleus showed the greatest volume loss. Intriguingly, however, Madsen found that in people with mild cognitive impairment who went on to develop AD within the next year, the middle of the caudate nucleus displayed the greatest loss. Madsen suggested that combining MRI measurements of hippocampal and caudate nucleus volume might increase the predictive power of these scans and lead to more accurate early diagnoses. Another implication of the findings, Madsen said, is that maintaining a healthy body weight might help to protect against AD. Madsen is now looking at genetic data from ADNI participants to try to dissect the role that genes play in structural brain changes.

Another brain region of interest is the substantia innominata (SI), a small structure deep in the brain that contains cholinergic neurons and degenerates in AD. The SI sends projections to most regions of the cortex and the hippocampus, delivering the neurotransmitter acetylcholine and modulating attention, motivation, and cognition. Sarah George, working with Leyla Detoledo-Morrell at Rush University in Chicago, Illinois, had previously found that the SI is smaller in people with AD, but not in those with mild cognitive impairment (see George et al., 2009). George and colleagues wondered whether they might see a volume difference in the SI in people with MCI who went on to develop AD, as compared to those whose impairment did not progress. George followed 52 people with amnestic MCI (i.e., MCI with memory impairment) for six years. Within this time frame, 23 of them developed AD. SI volume was no different among people who converted to AD than those who did not, George found. However, several regions of the cortex that receive projections from the SI were significantly thinner in people who later developed the disease. Because this thinning is apparent before AD develops, it could serve as an early warning sign, George suggested. Cortical thinning also implies that AD pathology travels retrogradely down processes back to the SI, which atrophies later in the disease, George said.

Elliott Mufson of Rush University Medical Center in Chicago, Illinois, a coauthor with George, said the new findings will help improve the accuracy of early AD diagnosis, and should be combined with previous imaging biomarkers such as changes in hippocampal size. With this combination, “You can begin to see a pattern of changes, an MRI signature of early AD,” he told ARF. “If you add that information to PIB scanning and CSF tau, you’re beginning to build a series of biomarkers that can give you a clinical diagnostic. You need to have multiple surrogate markers for the disease to do that.”—Madolyn Bowman Rogers

This is Part 1 of a two-part series. See also Part 2.

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References

News Citations

1. San Diego: The Future of AD—Can We Vaccinate? 17 Dec 2010
2. Philadelphia: All Eyes on PIB Imaging—Is It Coming Along? 27 Jul 2004
3. Toronto: Human Amyloid Imaging Conference Showcases a Maturing Field 4 May 2010
4. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain? 30 Oct 2009
5. Tau Toxicity—Tangle-free But Tied to Inflammation 5 Feb 2007

Paper Citations

1. Drzezga A, Becker JA, Sreenivasan A, Talukdar T, Van Dijk K, Sullivan C, Schultz AP, Sepulcre J, Buckner RL, Sperling RA. Relation between hypometabolism, impaired functional connectivity and ß-amyloid load in pre-dementia stages of Alzheimer’s disease. Human Amyloid Imaging 2010 Meeting Abstracts. 2010 April 9;
2. Madsen SK, Ho AJ, Hua X, Saharan PS, Toga AW, Jack CR, Weiner MW, Thompson PM, . 3D maps localize caudate nucleus atrophy in 400 Alzheimer's disease, mild cognitive impairment, and healthy elderly subjects. Neurobiol Aging. 2010 Aug;31(8):1312-25. PubMed.
3. George S, Mufson EJ, Leurgans S, Shah RC, Ferrari C, Detoledo-Morrell L. MRI-based volumetric measurement of the substantia innominata in amnestic MCI and mild AD. Neurobiol Aging. 2011 Oct;32(10):1756-64. PubMed.

External Citations

1. Alzheimer’s Disease Neuroimaging Initiative

Further Reading

News

1. San Diego: Pilin’ on the Pyro, Aβ Going Rogue 29 Nov 2010
2. San Diego: A New Tack on Insulin-Based Therapies? 5 Dec 2010
3. San Diego: Subcortical Blues—Locus Ceruleus in AD, Neurodegeneration 7 Dec 2010
4. San Diego: Across the Great Divide—Strategies for Spinal Cord Repair 9 Dec 2010
5. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain? 30 Oct 2009
6. San Diego: What—3 Percent? Money Woes Trump Science at SfN 19 Nov 2010
7. San Diego: Tau Oligomer Antibodies Relieve Motor Deficits in Mice 25 Nov 2010
8. San Diego: TDP-43 Targets Loom Large—But Where’s the Bull’s Eye? 25 Nov 2010
9. San Diego: ALS Research Goes to the Dogs 3 Dec 2010
10. San Diego: Aβ Oligomers Seen, With ApoE, at Synapses of Human Brain 6 Dec 2010
11. San Diego: ApoE, Aβ, and AD—Strengthening the Synaptic Connection 7 Dec 2010
12. San Diego: The Curious Case of ApoE, Cholesterol, and Cognition 8 Dec 2010
13. San Diego: Researchers Rejuvenate Neurons to Bridge Spinal Cord Gaps 8 Dec 2010
14. San Diego: Flexible N-Termini Key to Aβ42 Oligomer Toxicity? 9 Dec 2010
15. San Diego: Stimulating Autophagy Improves Symptoms in Mice 10 Dec 2010
16. San Diego: Tweakers and Tweezers—Grappling with Novel Aβ Therapies 14 Dec 2010
17. San Diego: Progranulin, Wnt, and Frizzled, Frazzle Neurons in FTD 16 Dec 2010
18. San Diego: Mutant SOD1 Bumps Mitochondrial Current Up—Or Down? 16 Dec 2010
19. San Diego: The Future of AD—Can We Vaccinate? 17 Dec 2010
20. Philadelphia: All Eyes on PIB Imaging—Is It Coming Along? 27 Jul 2004
21. Toronto: Human Amyloid Imaging Conference Showcases a Maturing Field 4 May 2010