Cortical biopsy in Alzheimer's disease: Diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations
Corresponding Author
Dr Steven T. DeKosky MD
Departments of Psychiatry and Neurology and Alzheimer's Disease Research Center, Western Psychiatric Institute and University of Pittsburgh Medical Center, Pittsburgh, PA
University of Pittsburgh, Alzheimer's Disease Research Center, 3600 Forbes Avenue, Suite 400, Pittsburgh, PA 15213Search for more papers by this authorRobert E. Harbaugh MD
Dartmouth Hitchcock Medical Center, Hanover, NH
Search for more papers by this authorFrederick A. Schmitt PhD
University of Kentucky Medical Center, Lexington, KY
Search for more papers by this authorHelena Chang Chui MD
University of Southern California, Downey, CA
Search for more papers by this authorTeddi M. Reeder BS, RN
Dartmouth Hitchcock Medical Center, Hanover, NH
Search for more papers by this authorAndrew G. Shetter MD
Barrow Neurological Institute, Phoenix, AZ
Search for more papers by this authorHoward J. Senter MD
Western Pennsylvania Hospital, Pittsburgh, PA
Search for more papers by this authorWilliam R. Markesbery MD
University of Kentucky Medical Center, Lexington, KY
Search for more papers by this authorThe Intraventricular Bethanecol Study Group
The following institutions, personnel, and funding agencies were involved in this study: Barrow Neurological Institute, Phoenix, AZ: Philip Carter, MD, James L. Frey, MD, Arthur Schwam, PhD, and Andrew G. Shetter, MD (funding from the Arizona Disease Control Commission). Dartmouth-Hitchcock Medical Center, Hanover, H Colin D. Allen, MD, Lynette Bob, BA, Rita Casey, PhD, Charles M. Culver, MD, Robert E. Harbaugh, MD, and Teddi M. Reeder, BS, RN (funding from the American Health Assistance Foundation and National Institute of Mental Health Grant lROl MH40505-01). The Emory Clinic, Atlanta, GA: Roy A. E. Bakay, MD, David Freides, PhD, Herbert R. Karp, MD, and Suzanne S Mirra, MD (funding from the Veterans Administration Hospital, Decatur, GA). University of Kentucky, Lexington, Ky: Steven T. DeKosky, MD, William R. Markesbery, MD, and Frederick A. Schmitt, PhD (funding from NIA AG05144 and AG05119 and the VA Research Service). University of Minnesota, Minnesota, Minneapolis, MN: Susan Deinard, RN, Donald Erickson, MD, Michael Fuhrman, BS, and David S. Knopman, MD (funding from the Twin Cities Chapter of the Alzheimer's Disease and Related Disorders Association and the University of Minnesota Hospitals). University of Pittsburgh: Steven T. DeKosky, MD (support from NIA AG05133). University of Southern California, Downey, CA: Eileen Bardolph, MD, Helena Chang Chui, MD, Steven Giannotta, MD, Barbara Smith, RNC, Evelyn Teng, PhD, and Bradley Williams, PharmD (funding from the Estelle Doheny Foundation). Western Pennsylvania Hospital, Pittsburgh, PA: Lorraine Klauscher, RN, Rick Kortyna, PAC, Howard J. Senter, MD, and Arthur Vega, PhD (funding from the Western Pennsylvania Guild, The Western Pennsylvania Foundation, and the Western Pennsylvania Hospital
Search for more papers by this authorCorresponding Author
Dr Steven T. DeKosky MD
Departments of Psychiatry and Neurology and Alzheimer's Disease Research Center, Western Psychiatric Institute and University of Pittsburgh Medical Center, Pittsburgh, PA
University of Pittsburgh, Alzheimer's Disease Research Center, 3600 Forbes Avenue, Suite 400, Pittsburgh, PA 15213Search for more papers by this authorRobert E. Harbaugh MD
Dartmouth Hitchcock Medical Center, Hanover, NH
Search for more papers by this authorFrederick A. Schmitt PhD
University of Kentucky Medical Center, Lexington, KY
Search for more papers by this authorHelena Chang Chui MD
University of Southern California, Downey, CA
Search for more papers by this authorTeddi M. Reeder BS, RN
Dartmouth Hitchcock Medical Center, Hanover, NH
Search for more papers by this authorAndrew G. Shetter MD
Barrow Neurological Institute, Phoenix, AZ
Search for more papers by this authorHoward J. Senter MD
Western Pennsylvania Hospital, Pittsburgh, PA
Search for more papers by this authorWilliam R. Markesbery MD
University of Kentucky Medical Center, Lexington, KY
Search for more papers by this authorThe Intraventricular Bethanecol Study Group
The following institutions, personnel, and funding agencies were involved in this study: Barrow Neurological Institute, Phoenix, AZ: Philip Carter, MD, James L. Frey, MD, Arthur Schwam, PhD, and Andrew G. Shetter, MD (funding from the Arizona Disease Control Commission). Dartmouth-Hitchcock Medical Center, Hanover, H Colin D. Allen, MD, Lynette Bob, BA, Rita Casey, PhD, Charles M. Culver, MD, Robert E. Harbaugh, MD, and Teddi M. Reeder, BS, RN (funding from the American Health Assistance Foundation and National Institute of Mental Health Grant lROl MH40505-01). The Emory Clinic, Atlanta, GA: Roy A. E. Bakay, MD, David Freides, PhD, Herbert R. Karp, MD, and Suzanne S Mirra, MD (funding from the Veterans Administration Hospital, Decatur, GA). University of Kentucky, Lexington, Ky: Steven T. DeKosky, MD, William R. Markesbery, MD, and Frederick A. Schmitt, PhD (funding from NIA AG05144 and AG05119 and the VA Research Service). University of Minnesota, Minnesota, Minneapolis, MN: Susan Deinard, RN, Donald Erickson, MD, Michael Fuhrman, BS, and David S. Knopman, MD (funding from the Twin Cities Chapter of the Alzheimer's Disease and Related Disorders Association and the University of Minnesota Hospitals). University of Pittsburgh: Steven T. DeKosky, MD (support from NIA AG05133). University of Southern California, Downey, CA: Eileen Bardolph, MD, Helena Chang Chui, MD, Steven Giannotta, MD, Barbara Smith, RNC, Evelyn Teng, PhD, and Bradley Williams, PharmD (funding from the Estelle Doheny Foundation). Western Pennsylvania Hospital, Pittsburgh, PA: Lorraine Klauscher, RN, Rick Kortyna, PAC, Howard J. Senter, MD, and Arthur Vega, PhD (funding from the Western Pennsylvania Guild, The Western Pennsylvania Foundation, and the Western Pennsylvania Hospital
Search for more papers by this authorAbstract
Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 ± 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22; mean age, 68 ± 2 yr) and autopsied AD brains (n = 11; mean age, 73 ± 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to {3H}quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [3H}pirenzepine binding as an index of Ml cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in {3H}quinuclidinyl benzilate binding or {3H}pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or ChAT activity in the biopsy specimens. The correlation of cortical ChAT activity with degree of dementia, although considerably weaker than those of cortical synaptic density with dementia, is the first demonstration of such a relationship in biopsied patients, and suggests another reason why the AD brain may be unresponsive to presynaptic cholinergic manipulations or attempts at enhancement.
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