Elliott Mufson
Scientific Tracks Abstracts: J Neurol Neurophysiol
The cortical mantle receives a massive cholinergic innervation arising from the nucleus basalis of Meynert (NBM) that is progressively vulnerable during the onset of dementia. However, the role that intraneuronal tau, cortical amyloid and neurotrophic dysfunction play in the unique vulnerability of the cholinergic basal forebrain (CBF) cortical projection network remains unclear. We used biochemical and immunohistochemical procedures to evaluate amyloid levels, cholinergic activity, proNGF/receptors and down stream signaling pathways in the precueus cortex (a default memory network hub) which displays amyloid pathology in preclinical AD in postmortem tissues harvested from no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD cases. Pre-tangle events determined by pS422 immunostaining revealed positive NBM cholinergic neurons and neuropil threads (NT) prior to frank NFT deposition in MCI, which associated with cognitive decline. Despite accumulating amyloid burden, cholinergic enzyme activity was stable in MCI but declined in AD when amyloid levels were elevated compared with MCI precuneus. Precuneus proNGF and p-JNK/JNK ratio protein levels increased only in AD whereas TrkA and p75 NTR receptor levels were unchanged. Interestingly, ventricular proNGF CSF levels marked the progression from NCI to MCI and AD and discriminated NCI from AD in lumbar CSF. Our findings suggest that NBM pretangle cell and NT pathology drive early cognitive decline. Despite amyloid deposition cholinergic activity and proNGF levels remained stable suggesting that this cortical region is resilient to amyloid toxicity early in disease onset. Finally, proNGF expression may be a novel biomarker for the onset of dementia
Elliott Mufson received Ph.D. from the State University of New York in biological psychology followed by a postdoctoral fellowship in Department of Neurology at the Harvard Medical School, Beth Israel Hospital where he was trained in primate neuroanatomy and neurological diseases of the human brain under the direction of Drs. Norman Geshwind, Marcel Mesulam and Deepak Pandya. During this period he produced a series of papers defining the extent and organization of the cholinergic system in the primate brain, a major target for most of the currently available drug for Alzheimer?s disease. During his tenure in Boston, he rose to the rank of Assistant Professor in the Department of Neurology and Associate Director of the Derek Denny Brown Laboratory at the Beth Israel Hospital of the Harvard Medical School. He was then recruited to help established the Sun Health Research Institute located in Sun City Arizona, as its Associate Director where he assisted in the development of one of the largest human brain banks in the country.
