Brain Imaging Technique Predicts Cognitive Decline

Brain Imaging Technique Predicts Cognitive Decline

Cognitive loss and brain degeneration currently affect millions of adults, and the number will increase, given the population of aging baby boomers. Today, nearly 20 percent of people age 65 or older suffer from mild cognitive impairment and 10 percent have dementia.

UCLA scientists previously developed a brain-imaging tool to help assess the neurological changes associated with these conditions. The UCLA team now reports in the February issue of the journal Archives of Neurology that the brain-scan technique effectively tracked and predicted cognitive decline over a two-year period.

The team has created a chemical marker called FDDNP that binds to both plaque and tangle deposits — the hallmarks of Alzheimer’s disease — which can then be viewed using a positron emission tomography (PET) brain scan, providing a “window into the brain.” Using this method, researchers are able to pinpoint where in the brain these abnormal protein deposits are accumulating.

“We are finding that this may be a useful neuro-imaging marker that can detect changes early, before symptoms appear, and it may be helpful in tracking changes in the brain over time,” said study author Dr. Gary Small, UCLA’s Parlow–Solomon Professor on Aging and a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA.

Small noted that FDDNP–PET scanning is the only available brain-imaging technique that can assess tau tangles. Autopsy findings have found that tangles correlate with Alzheimer’s disease progression much better than do plaques.

For the study, researchers performed brain scans and cognitive assessments on the subjects at baseline and then again two years later. The study involved 43 volunteer paricipants, with an average age of 64, who did not have dementia. At the start of the study, approximately half (22) of the participants had normal aging and the other half (21) had mild cognitive impairment, or MCI, a condition that increases a person’s risk of developing Alzheimer’s disease.

Researchers found that for both groups, increases in FDDNP binding in the frontal, posterior cingulate and global areas of the brain at the two-year follow-up correlated with progression of cognitive decline. These areas of the brain are involved in decision-making, complex reasoning, memory and emotions. Higher initial baseline FDDNP binding in both subject groups was associated with a decline in cognitive functioning in areas such as language and attention at the two-year follow-up.

“We found that increases in FDDNP binding in key brain areas correlated with increases in clinical symptoms over time,” said study author Dr. Jorge R. Barrio, who holds UCLA’s Plott Chair in Gerentology and is a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. “Initial binding levels were also predictive of future cognitive decline.”

Among the subjects with mild cognitive impairment, the level of initial binding in the frontal and parietal areas of the brain provided the greatest accuracy in identifying those who developed Alzheimer’s disease after two years. Of the 21 subjects with MCI, six were diagnosed with Alzheimer’s at follow-up, and these six subjects had higher initial frontal and parietal binding values than the other subjects in the MCI group.

In the normal aging subjects, three developed mild cognitive impairment after two years. Two of these three participants had had the highest baseline binding values in the temporal, parietal and frontal brain regions among this group.

Researchers said the next step in research will involve a longer duration of follow-up with larger samples of subjects. In addition, the team is using this brain-imaging technique in clinical trials to help track novel therapeutics for brain aging, such as curcumin, a chemical found in turmeric spice.

“Tracking the effectiveness of such treatments may help accelerate drug discovery efforts,” Small, the author of the new book “The Alzheimer’s Prevention Program,” said. “Because FDDNP appears to predict who will develop dementia, it may be particularly useful in tracking the effectiveness of interventions designed to delay the onset of dementia symptoms and eventually prevent the disease.”

Small recently received research approval from the U.S. Food and Drug Administration to use FDDNP–PET to study people with mild cognitive impairment to determine whether a high-potency form of curcumin — a spice with anti-amyloid, anti-tau and anti-inflammatory properties — can prevent Alzheimer’s disease and the accumulation of plaques and tangles in the brain.

UCLA owns three U.S. patents on the FDDNP chemical marker. The Office of Intellectual Property at UCLA is actively seeking a commercial partner to bring this promising technology to market.

Small and study authors Jorge R. Barrio and S. C. Huang are among the inventors. Disclosures are listed in the full study.

Additional authors included Prabha Siddarth, Linda M. Ercoli, Alison C. Burggren, Karen J. Miller, Dr. Helen Lavretsky and Dr. Susan Y. Bookheimer, all of the UCLA Department of Psychiatry and Biobehavioral Sciences, and Vladimir Kepe and S.C. Huang, who are part of the UCLA Department of Molecular and Medical Pharmacology.

The study was funded by the National Institutes of Health and the U.S. Department of Energy.

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Original Contributions | Feb 2012

Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau

Gary W. Small, MD; Prabha Siddarth, PhD; Vladimir Kepe, PhD; Linda M. Ercoli, PhD; Alison C. Burggren, PhD; Susan Y. Bookheimer, PhD; Karen J. Miller, PhD; Jeanne Kim, PsyD; Helen Lavretsky, MD; S.-C. Huang, PhD; Jorge R. Barrio, PhD

[+] Author Affiliations

Arch Neurol. 2012;69(2):215-222. doi:10.1001/archneurol.2011.559

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ABSTRACT

ABSTRACT | METHODS | RESULTS | COMMENT | AUTHOR INFORMATION | REFERENCES

Objective To determine whether 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.

Design Two-year, longitudinal follow-up study.

Setting A university research institute.

Participants Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.

Main Outcome Measures Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.

Results For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r = -0.32 to -0.37, P = .03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r = -0.31 to -0.56, P = .05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72-1.00) compared with 0.68 (95% CI, 0.45-0.91) for medial temporal binding.

Conclusions [18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.

A team of researchers from UCLA has been working on a new PET imaging approach to track and predict the progression of cognitive decline in patients from diseases such as Alzheimer’s disease. The researchers have reported in this month’s issue of the Archives of Neurology that the technique successfully tracked and predicted cognitive decline in individuals with and without mild cognitive impairment.

The approach uses a chemical biomarker [18f]FDDNP which binds to both plaque and tangle deposits, key indicators of Alzheimer’s disease, which can then be viewed and quantified using a PET scanner.

From the Archives of Neurology abstract:

Objective: To determine whether 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.

Design: Two-year, longitudinal follow-up study.

Setting: A university research institute.

Participants: Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.

Main Outcome Measures: Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.

Results: For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r = –0.32 to –0.37, P = .03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r = –0.31 to –0.56, P = .05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72-1.00) compared with 0.68 (95% CI, 0.45-0.91) for medial temporal binding.

Conclusions [18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.

The bio-marker has also been used to quantify plaque and tangle deposits in adults with Down Syndrome, and a number of patents have been issued on the bio-marker which seems to be yielding some impressive results already.

Source : http://newsroom.ucla.edu/portal/ucla/ucla-imaging-technique-predicts-220856.aspx

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