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http://www.medscape.com/viewarticle/874539?nlid=112050_2981&src=wnl_dne_170118_mscpedit&uac=155804AK&impID=1274198&faf=1



A new study suggests brain iron levels may predict disease progression in patients with Alzheimer's disease (AD) who carry the APOE e4 risk allele.

Iron in the brain is an "underappreciated driver of disease progression" in AD, study author Ashley I. Bush, MBBS, PhD, senior principal research fellow, Florey Institute of Neuroscience & Mental Health, University of Melbourne, Australia, told Medscape Medical News.

"Measuring brain iron could be used to predict disease progression, and lowering brain iron levels might present as a novel therapeutic target to slow the disease process."

Their findings were described in a letter published in the January issue of JAMA Neurology.

The researchers used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, which was launched in 2003 as a public–private partnership.

The primary goal of ADNI is to test whether serial MRI, positron emission tomography, other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment and early AD.

The current study looked at the level of ferritin in cerebrospinal fluid (CSF), which indicates the brain iron load. According to Dr Bush, it has been known since the 1950s that elevated iron is a pathologic feature of AD. Iron elevation, he said, may cause oxidative stress, which damages neurons.

"But we didn't previously have evidence that iron elevation actually impacts on the clinical presentation," he said.

Most Likely to Respond

One of the biggest challenges for neurologists is identifying patients with the earliest possible stages of AD. These patients, said Dr Bush, could be the most likely to respond to therapy.

For the study, researchers analysed CSF levels of amyloid ß 1-42 (Aß 1-42), tau, APOE, ferritin, factor H (an inflammatory marker), and hemoglobin (a blood leakage marker). They looked at cognitive performance over time on the Rey Auditory-Visual Learning Task (RAVLT) and the Alzheimer's Disease Assessment Scale-Cognitive subset (ADAS-Cog13).

The analysis found that for cognitively normal participants, the ferritin level was associated with cognitive deterioration in a three-way interaction with time and e4 allele (RAVLT: ß = –1.58, P = .004; ADAS-Cog13: ß = .11, P = .01).

Categorization of cognitively normal individuals according to e4 showed that ferritin level was strongly associated with cognitive decline in e4 carriers (RAVLT: ß = –1.4, P < .001; ADAS-Cog13: ß = .09, P = .02).

People who express the APOE e4 allele are at a high risk for cognitive decline, although not all will do so.

"The study found that in cognitively normal people who express the APOE e4 risk allele, high CSF ferritin almost perfectly predicted whether the individual will experience cognitive decline in the subsequent 7 years," said Dr Bush.

The effect of ferritin "was far greater than the most established biomarkers — tau and amyloid ß," he said.

Their results also showed that APOE e4 carriers who have low iron levels were protected from cognitive decline.

The study is important because it shows that the CSF ferritin level is "an excellent biomarker for predicting whether someone with APOE e4 might progress in the foreseeable future," said Dr Bush.

CSF ferritin or other iron biomarkers — for example, MRI techniques, such as quantitative susceptibility mapping — could be used in the clinic to predict the likely progression of cognitive decline in patients, said Dr Bush.

These biomarkers could also be used for clinical trial recruitment, he said.

Dr Bush and colleagues will be launching a phase 2b clinical trial to determine whether deferiprone, a brain-permeable drug that chelates iron, can slow disease progression among patients in the early stages of Alzheimer's disease.

Dr Bush is a shareholder in Prana Biotechnology Pty Ltd, Cogstate Pty Ltd, Eucalyptus Pty Ltd, Mesoblast Pty Ltd, Brighton Biotech LLC, Nextvet Ltd, Grunbiotics Pty Ltd, and Collaborative Medicinal Development LLC and a paid consultant for Collaborative Medicinal Development Pty Ltd. He and the other authors have filed a provisional patent encompassing findings from these data. Dr Bush has received funding relevant to this study from the Australian National Health and Medical Research Council, the Alzheimer's Association, Alzheimer's Research UK, the Michael J. Fox Foundation for Parkinson's Research, the Weston Brain Institute, and the Perpetual-Salteri Foundation.

JAMA Neurol. 2017;74):122-125. Abstract

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