Dr. Harrington joined HMRI and established the Molecular Neurology Program in 1998. He studies how the cerebrospinal fluid composition explains the intermittent disorder of migraine and the progressive neurodegeneration of Alzheimer’s disease. He also studies molecules that are transported to/from the brain in blood (including changes after mild traumatic brain injury), and those excreted in urine. Mike enjoys collaborating with other clinical and scientific colleagues that apply complementary measures of brain function so as to gain as much information from the same study participants. This approach is important to understand what is causing brain disorder, develop tests that identify disease, and direct treatment to the underlying mechanism.
Dr. Harrington is also a research professor of psychology in the School of Psychology at Fuller Theological Seminary as well as a research professor of neurology at the University of Southern California.
Dr. Harrington received his medical degree in 1976 from Glasgow University, Scotland, and was awarded membership into the Royal College of Physicians and Surgeons in 1979. He was elected as a fellow in 1993.
At Glasgow Royal Infirmary, Dr. Harrington completed a medical internship in 1977 and trained in internal medicine through 1979. Mike’s growing interest in neurological diseases led him to the Institute of Neurological Sciences at Glasgow, where he trained in neurology and initiated two-dimensional electrophoresis studies of spinal fluid proteins, which were altered in diseases of the nervous system.
In 1983, Dr. Harrington continued this research as a visiting fellow with Dr. Carl R Merril at the Laboratory of General and Comparative Biochemistry at the National Institute of Mental Health. He also served as a visiting associate with Dr. Elliot Gershon at the Laboratory of Neurogenetics, NIMH during this time.
Moving to the California Institute of Technology in 1988, Dr. Harrington served as a member of the Beckman Institute with Dr. Leroy Hood, where he improved technologies for a variety of protein studies. Mike is known for the discovery and development of the diagnostic test for the family of prion diseases (Mad Cow Disease). This test is based on his discovery of a protein in spinal fluid, 14-3-3 gamma, that is diagnostic of the spongiform encephalopathy diseases of humans (Creutzfeldt-Jakob Disease) and other mammals (scrapie in sheep and bovine spongiform encephalopathy in cattle).
Dr. Harrington’s contributions to science:
During his neurology training, Dr. Harrington investigated blood biochemistry in patients with basal ganglia calcification and reported renal toxicity from normal doses of acyclovir. He saw patients with transient altered conscious levels that had bizarre presentations referred to as “funny (peculiar) turns”; to investigate, he prospectively tested glucose metabolism and, surprisingly, found insulinomas in 2 of 25 consecutive patients. This diagnosis led these two patients to curative surgery for their “funny turns” by removal of their benign tumors. The impact of these initial projects was to hook Dr. Harrington on a research career.
Harrington MG, Macpherson P, McIntosh WB, Allam BF, Bone I. The significance of the incidental finding of basal ganglia calcification on computed tomography. J Neurol Neurosurg Psychiatry. 1981 Dec;44(12):1168-PubMed PMID: 7334414; PubMed Central PMCID: PMC491242.
Harrington MG, Durward WF, Simpson JA. Renal impairment and acyclovir. 1981 Dec 5;2(8258):1281. PubMed PMID: 6118687.
Harrington MG, McGeorge AP, Ballantyne JP, Beastall G. A prospective survey for insulinomas in a neurology department. 1983 May 14;1(8333):1094-5. PubMed PMID: 6133118.
Harrington started biochemical protein surveys (two-dimensional electrophoresis) of cerebrospinal fluid to find molecular measures of brain dysfunction with the support of his mentor at the Institute of Neurological Sciences in Glasgow, Professor J.A. Simpson. He was offered a position at NIH in Bethesda to continue this work, which surveyed >2,000 protein “spots” that could be quantified and assessed qualitatively. Dr. Harrington found changes with gender, age, and every disorder studied. The most clinically useful result of this research was that he discovered acidic, 30,000 molecular weight proteins in 1986 that were diagnostic for Creutzfeldt-Jakob disease. Dr. Harrington sequenced the CJD biomarker in 1996, the 14-3-3 gamma protein, which became the first clinically useful biomarker discovered by the proteomics approach. This test is still a useful clinical tool to diagnosis prion disease.
Harrington MG, Merril CR, Asher DM, Gajdusek DC. Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. N Engl J Med. 1986 Jul 31;315(5):279-83. PubMed PMID: 3523251.
Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996 Sep 26;335(13):924-30. PubMed PMID: 8782499.
Lee KH, Harrington MG. 14-3-3 and BSE. Vet Rec. 1997 Feb 22;140(8):206-7. PubMed PMID: 9061874.
The development in analytical tools, especially mass spectrometry and the human genome, opened up the possibility of more detailed definition of brain disease, for which Dr. Harrington joined HMRI to recruit research study participants prospectively from the local community. He discovered a new mechanism for migraine based on altered regulation of brain sodium. He is now exploring methods to correct the sodium disturbance in a rodent migraine model with his colleagues Dr.’s Arakaki, Fonteh, and Gross at HMRI.
Harrington MG, Fonteh AN, Cowan RP, Perrine K, Pogoda JM, Biringer RG, Hühmer AF. Cerebrospinal fluid sodium increases in migraine. 2006 Jul-Aug;46(7):1128-35. PubMed PMID: 16866716.
Harrington MG, Fonteh AN, Arakaki X, Cowan RP, Ecke LE, Foster H, Hühmer AF, Biringer RG. Capillary endothelial Na(+), K(+), ATPase transporter homeostasis and a new theory for migraine pathophysiology. 2010 Mar;50(3):459-78. doi: 10.1111/j.1526-4610.2009.01551.x. Epub 2009 Oct 21. Review. PubMed PMID: 19845787.
Harrington MG, Chekmenev EY, Schepkin V, Fonteh AN, Arakaki X. Sodium MRI in a rat migraine model and a NEURON simulation study support a role for sodium in migraine. 2011 Sep;31(12):1254-65. doi: 10.1177/0333102411408360. Epub 2011 Aug 4. PubMed PMID: 21816771; PubMed Central PMCID: PMC3474349.
Between 2000 and 2006, Dr. Harrington, Dr. Fonteh, and colleagues had sequenced over 6,000 different proteins in CSF, and found that one-quarter of them were integral membrane proteins. What membranes? Using differential ultracentrifugation, he found many heterogeneous membranous structures between 30 and 300 nanometers in diameter. These nanoparticles include synaptic vesicles, large dense core vesicles, and many other blobs, that we defined by transmission electron microscopy, immuno-EM, Western blotting, and mass spectrometry. We also found some nanoblobs had functionally active enzymes, including cyclooxygenases a and b. This was the first report to demonstrate and define nanoparticles in CSF. This work has opened up studies to investigate the physiological roles of these previously unknown particles as well as how they inform on disease.
Harrington MG, Fonteh AN, Oborina E, Liao P, Cowan RP, McComb G, Chavez JN, Rush J, Biringer RG, Hühmer AF. The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid. Cerebrospinal Fluid Res. 2009 Sep 7;6:10. doi: 10.1186/1743-8454-6-10. PubMed PMID: 19735572; PubMed Central PMCID: PMC2746175.
Aging and Alzheimer’s Disease Study. Our strategy is to define the clinical status of study participants in detail, including the NIH’s Common Disease Elements and the Alzheimer’s disease (AD) Uniform Data Set, and use compositional studies of human samples to identify molecular changes that correlate with clinical dysfunction. We recruited 149 people with classifications of AD, mild cognitive impairment (MCI), or no cognitive impairment (NCI), and collected their cerebrospinal fluid (CSF), blood, and urine. From this strategy, we found compelling evidence of altered lipids in brain-derived CSF membranes from participants with Alzheimer’s disease. We are following these participants longitudinally, for which they have all consented, to assess clinical and chemical changes. Over fifty study participants have already been re-assessed 3-4 years after their initial visit. If our hypothesis that membrane damage of neurons drives early Alzheimer’s pathology is confirmed, treatments can measure improvement to CSF membrane composition as an outcome. We collaborate on these studies with Dr. Fonteh and colleagues at HMRI, and Drs. Chui, Zlokovic and colleagues at the USC Alzheimer’s Disease Research Center, whose expertise in blood-brain-barrier and vascular dementia is invaluable.
Fonteh AN, Harrington RJ, Tsai A, Liao P, Harrington MG. Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects. Amino Acids. 2007 Feb;32(2):213-24. Epub 2006 Oct 10. PubMed PMID: 17031479.
Harrington, M. G., Chiang, J., Pogoda, J. M., Gomez, M., Thomas, K., Marion, S. D., Miller K.J., Siddarth, P., Yi X Zhou F., Lee., S., Arakaki, X., Cowan, R.P., Tran, T., Charleswell, C., Ross, B.D., & Fonteh, A. N. (2013). Executive function changes before memory in preclinical Alzheimer’s pathology: a prospective, cross-sectional, case control study. PLoS One, 8(11), e79378. PMID: 24260210
Fonteh, A. N., Chiang, J., Cipolla, M., Hale, J., Diallo, F., Chirino, A., Arakaki, X., & Harrington, M. G. (2013). Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res, 54(10), 2884-2897. PMID: 23868911
Fonteh, A. N., Cipolla, M., Chiang, J., Arakaki, X., & Harrington, M. G. (2014). Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One, 9(6), e100519. PMID: 24956173
Montagne A., Barnes S.R., Sweeney M.D., Halliday M.R., Sagare A.P., Zhao Z., Toga A.W., Jacobs R.E., Liu C.Y., Amezcua L., Harrington M.G., Chui H.C., Law M., Zlokovic B.V. (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron, 85, 296-302
Complete List of Published Work in Dr. Harrington’s Bibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/michael.harrington.1/bibliography/44075935/public/?sort=date&direction=descending