BioSketch for Dr. William R. Kennedy
|University of Illinois, Urbana||B.S.||1951|
|University of Wisconsin, Madison||M.S,||1952||Biochemistry|
|Marquette University, Milwaukee||M.D.||1958||Medicine|
|Mayo Foundation, Rochester||Residency||1964||Internal Medicine - Neurology|
The two major goals of the current research in the Kennedy laboratory are:
- to devise new methods to detect minimal dysfunction of peripheral and autonomic nerves in skin, muscle or internal organs and,
- to validate the new methods by quantifying the innervation of skin and the gastrointestinal tract in healthy subjects and in patients with peripheral neuropathy who are tested by the devices.
I formed a team to invent and develop new medical devices with mechanical and electrical engineers in our University and from small Minnesota businesses. The devices are supplementary to the neurological examination in our special niche of peripheral neuropathy, especially neuropathy associated with diabetes, cancer, cancer chemotherapy and aging. They are designed to provide objective, sensitive quantification of selected nerve functions of touch, flutter and sweating on the extremities as is required for earlier diagnosis when the neuropathology is potentially reversible, to follow the progression or reversal of neuropathy and to evaluate the many new therapies coming to market. I devised 1) a method to quantify touch sensitivity at low micrometer levels on the finger pads, 2) to quantify slow vibration-like flutter stimuli to the feet and toes and, 3) a sensitive sweat test (SST) that measures rate of secretion and volume of each of > 200 SGs plus SG number, size and distribution to detect early autonomic neuropathy of sudomotor nerves to sweat glands. The devices are shared with select colleagues at other institutions for trial use.
This laboratory also developed methods to quantify the cutaneous epidermal nerve fibers in skin biopsies, in skin blisters and in the mucosal layer of the stomach, rectum and colon using immunohistochemistry with 2, 4 or more antibodies as needed imaged by confocal microscopy. These methods are used for diagnosis of peripheral neuropathy of many etiologies, in diabetic gastroparesis, idiopathic childhood constipation and to validate the results obtained by the medical devices. Over several decades the laboratory has studied 7 general areas. These are commented upon below with a sampling of publications in the areas.
Positions and Honors
|1968-1971||Associate Professor, Department of Neurology, University of Minnesota|
|1964-1968||Assistant Professor, Department of Neurology, University of Minnesota|
|1968-Present||Full Member, University of Minnesota Graduate School Faculty.|
|1964-1995||Professor, Department of Neurology, University of Minnesota|
|1990-present||Professor & Head of Kennedy Research Laboratories, University of Minnesota|
|2004||American Academy of Neurology, Honorary Member|
|2006||Selected as a “Giant of Neurology” American Academy of Neurology Foundation|
|2007||American Neurological Association, Honorary member|
|2010||American Association of Electrodiagnostic Medicine highest honor, the “Lifetime Achievement Award”|
American Medical Association (AMA) Special acclaim as representative of the specialty of Neurology to the AMA House of Delegates for 25 years
AMA Council of Scientific Affairs. Elected for three 3 year terms
American Association of Electrodiagnostic Medicine “Researcher of the Year award”.
American Academy of Neurology voted the paper by Kennedy, Alter & Sung "Progressive proximal spinal and bulbar muscular atrophy of late onset." (now called Kennedy’s Disease) among the 15 most influential papers published during the first 50 years of the journal Neurology. The paper was reprinted for the AAN golden anniversary in Neurology 50:671-680, 1998.
Honored as the “Lambert lecturer” at the 50th annual celebration meeting of the American Association of Electrodiagnostic Medicine.
Honored as the “Caruso Lecturer” Italian Society on Clinical Neurophysiology, Turin, Italy.
American Clinical Neurophysiology Society. Lifetime award as the Robert S. Schwab lecturer.
1. AN IMPORTANT EARLY PUBLICATION:
Spinal and Bulbar Muscular Atrophy (Kennedy’s Disease) was recognized in 1998 by the American Academy of Neurology as one of the 15 most influential studies in the academy's then 50-year history. It was reprinted in the golden anniversary edition 1998;50:583. It not only established that KD as a distinct disease with near normal life expectancy, it distinguished it from Amyotrophic Lateral Sclerosis (ALS) that has a 3 to 5 year prognosis after diagnosis. It showed KD is sex-linked or "X-linked," caused by a defective gene on the X chromosome. It was later recognized as discovery of the first disease with a trinucleotide “CAG” repeat.
- Kennedy WR, Alter M, Sung JH, Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968 Jul;18(7):671-80. PMID: 4233749
2. SKIN BIOPSY In 1993 we published the landmark paper for 3-dimensional imaging of human epidermal nerve fibers (ENFs) by triple immunostaining and confocal microscopy in 3 mm skin biopsies. This paper led to papers on the ENF deficiency in diabetic neuropathy and paved the way to better understanding of painful small fiber sensory neuropathy. Skin biopsy is now the ‘gold standard’ for quantifying peripheral neuropathy. We later devised, patented and published a method to isolate and quantify ENFS in the roof of a skin blister. These methods are widely used in humans and mice.
- Kennedy WR, Wendelshafer-Crabb G. The innervation of human epidermis. J. Neurol. Sci. 1993;115:184-190.
- Kennedy WR, Wendelschafer-Crabb G, Johnson T Quantitation of epidermal nerves in diabetic neuropathy.. Neurology. 1996 Oct;47(4):1042-8. PMID: 8857742
- Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999 May;81(1-2):135-45. PMID: 10353501
- Kennedy WR, Wendelschafer-Crabb G, Walk D. J. Use of skin biopsy and skin blister in neurologic practice. Clin Neuromuscul Dis. 2000 Jun;1(4):196-204. PMID: 19078588
- Vanhove GF, Kennedy WR, Sutton MA, Tobias J, Bley K, Wendelschafer-Crabb G, Simone D, Selim M. A. Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, Wendelschafer-Crabb G, Simone DA, Selim MM. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain. 2010 Jun;11(6):579-87. PMID: 20400377.
- Selim MM, Wendelschafer-Crabb G, Hodges JS, Simone DA, Foster SX, Vanhove GF, Kennedy WR. Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements. Pain. 2010 Dec;151(3):575-81. PMID: 208515185.
- Wendelschafer-Crabb G, Salem M, Kennedy WR, Waller L. Analysis of spatial structure. of epidermal nerve entry points based on replicated data. Myllymaki M, Sarkka A, J Microsc. 2012; 247:228-39. PMID: 22906010
3. MEDICAL DEVICES
We formed the hypothesis that the neurological examination must become more objective, quantitative and more sensitive if we are to diagnose neurological disease early when it is most susceptible to treatment, if medications are helping or harming our patients, or to determine the effects of new pharmaceuticals as they become available. Our approach is to devise fast, simple highly sensitive quantitative tests of specific functions. Our 1st medical device measures the threshold of finger pad touch sensation at the micron level. The 2nd quantifies the changes of sweating rate and volume of each of >200 of single sweat glands to disease. A 3rd will measure foot vibratory sensation. The 1st and 2nd have been adapted to the mouse.
- Kennedy WR, Selim MM, Brink TS, Hodges JS, Wendelschafer-Crabb G, Foster SX, Nolano M, Provitera V, Simone DA. A new device to quantify tactile sensation in neuropathy. Neurology. 2011 May 10;76(19):1642-9. PMID: 21555731
- Boyette-Davis JA, Eng C, Wang XS, Cleeland CS, Wendelschafer-Crabb G, Kennedy WR, Simone DA, Zhang H, Dougherty PM. Subclinical peripheral neuropathy is a common finding in colorectal cancer patients prior to chemotherapy. Clin Cancer Res. 2012 Jun 1;18(11):3180-7. PMID: 22496202
4. SWEAT GLAND (SG) STRUCTURE AND INNERVATION (Early basic work that led to development of the sweat device in II above.)
SGs are innervated by unmyelinated autonomic sudomotor nerve fibers. In a series of papers we described the normal microscopic and electron microscopic structure of SG innervation in humans and mice, their aggregate and individual SG density, distribution and the individual sweating rate and the changes produced during diabetic and chemotherapy induced neuropathy and during iontophoresis of an agonist.
- Kennedy WR, Sakuta M, Sutherland D, Goetz FC.The sweating deficiency in diabetes mellitus: methods of quantitation and clinical correlation. Neurology. 1984 Jun;34(6):758-63. PMID: 6539438
- Quick DC, Kennedy WR, Yoon KS. Ultrastructure of the secretory epithelium, nerve fibers, and capillaries in the mouse sweat gland. Anat Rec. 1984 Apr;208(4):491-9. PMID: 6731858
- Kennedy WR, Sakuta M, Quick DC. Rodent eccrine sweat glands: a case of multiple efferent innervation. Neuroscience. 1984 Mar;11(3):741-9.PMID: 6717807
- Kennedy WR, Wendelschafer-Crabb G, Brelje TC Innervation and vasculature of human sweat glands: an immunohistochemistry-laser scanning confocal fluorescence microscopy study.. J Neurosci. 1994 Nov;14(11 Pt 2):6825-33. PMID: 7525893
- Provitera V, Nolano M, Caporaso G, Stancanelli A, Santoro L, Kennedy WR. Evaluation of sudomotor function in diabetes using the dynamic sweat test. Neurology. 2010 Jan 5;74(1):50-6. PMID: 20038772.
- Kennedy WR, Selim M, Wendelschafer-Crabb G, Blaes A, Suter F, Nolano M, Provitera V. A device to quantify sweat in single sweat glands to diagnose neuropathy. J Medical Devices. 2013;7:030941-1-2.
5. GASTROINTESTINAL TRACT (Related work in techniques the relate to peripheral neuropathy research, although developed in the GI tract).
- Wendelschafer-Crabb G, Neppalli V, Jessurun J, Hodges J, Vance K, Saltzman D, Acton R, Kennedy WR. Mucosal nerve deficiency in chronic childhood constipation: a postmigration defect? J Pediatr Surg. 2009 Apr;44(4):773-82. PMID: 19361639
- Selim MM, Wendelschafer-Crabb G, Redmon JB, Khoruts A, Hodges JS, Koch K, Walk D, Kennedy WR. Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy? Neurology. 2010 Sep 14;75(11):973-81. PMID: 20837965
- Azan G, Low W, Wendelschafer-Crabb, Kennedy WR. Evidence for Neural Progenitor Cells in the Human Adult Enteric Nervous System. Cell and Tissue Research. 2011; 344:217-225. COVER
6. DERMATOLOGY INCLUDING SCALP
- Hordinsky M, Kavand S, Crabb C, Hurliman E, Bohjanen K, Kane K, Kennedy WR. Dermatomyositis and scalp pruritus is associated with small fiber neuropathy. 7th World Congress for Hair Research. Edinburgh, Scotland. May 4-6, 2013. Abstr542-0016-00348.
- Hordinsky M, Kavand S, Kennedy WR Crabb C, Pierre-Louise M, Kane K, Doche L, Ericson M. "Small fiber neuropathy in symptomatic lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA). 7th World Congress for Hair Research. Edinburgh, Scotland. May 4-6, 2013. Abstr 542-0004-00266.
- McAdams B, Wendelschafer-Crabb G, Kennedy WR. Multiple synaptic vesicle- associated proteins colocalize in mechanoreceptors and free nerve endings in skin. Soc Neurosci Ann Meeting 2013, San Diego, CA.
- Panoutsopoulou I, Wendelschafer-Crabb G, Hordinsky M, Wilcox G, Kennedy WR. Langerhans’ cell (LC) migration and sensory re-innervation of psoriatic and normal epidermis. 2008 IID meeting May 14-17, Kyoto, Japan.
- Groth D, Crabb G, Kennedy W, Bemmels H, Hordinsky MK. Neurogenic inflammation in active alopecia areata (AA). 8th World Congress for Hair Research, JeJu Island, Korea. May 15, 2014.
- Poss K, Hurliman E, Wendelschafer-Crabb G, Kennedy WR, McAdams B, Foster S, Hordinsky M Regional differences in scalp innervation: A pilot study of the healthy scalp. Society of Investigative Dermatology, Scottsdale AZ. May 11-14, 2016.
- Aschenbeck K, Hordinsky M, Kennedy WR, Wendelschafer-Crabb G, Ericson M, Kavand S, Bertin A, Dystra D, Panoutsopoulou I. Onabotulinum toxin injections for the treatment of psioriasis vulgaris: efficacy and effects on neuropeptide expression. Society of Investigative Dermatology, Scottsdale AZ. May 11-14, 2016.
- Dodd E, Hurliman E, Miller D, Wendelschafer-Crabb G, Kennedy WR, Hordinsky M. Topical gabapentin solution for the treatment of symptomatic scalp in cicatricial alopecias. Society of Investigative Dermatology, Scottsdale AZ. May 11-14, 2016.
7. THE MUSCLE SPINDLE
- Kennedy, W.R.: "Innervation of muscle spindles in amyotrophic lateral sclerosis." Mayo Clinic Proc. 46:245-257, 1971.
- Sahinen, F.M. and Kennedy, W.R.: "The distribution of muscle spindles in the human first dorsal interosseus." Anat Rec. 173:151-156, 1972.
- Kennedy, W.R., Poppele R.E. and Staley, N.A.: "Isolation of viable human muscle spindles for electron microscope and physiologic study." Anat. Rec. 179:453-462, 1974.
- Kennedy, W.R.: "The innervation of muscle spindles in a case of hypertrophic polyneuropathy." Neurology. 24:788-794, 1974.
- Kennedy, W.R., Webster, H.F. and Yoon, K.S.: "Human muscles spindles: microfilaments in the group IA sensory nerve endings." Anat. Rec. 180:521-526, 1974.
- Kennedy, W.R., Webster, H.F. and Yoon, K.S.: "Human muscles spindles: fine structure of the primary sensory ending." J. Neurocytol. 4:675-695, 1975.
- Miyoshi, T., Kennedy, W.R. and Yoon, K.: "Morphometric comparison of capillaries in muscle spindles, nerve, and muscle." Arch Neurol. 36:547552, 1979.
- Miyoshi, T. and Kennedy, W.R.: "Microvasculature of rabbit muscle spindles." Arch Neurol. 36:471-475, 1979.
- Kennedy, W.R. and Yoon, K.S.: "Permeability of muscle spindle capillaries and capsule." Muscle Nerve. 2:101-108, 1979.
- Poppele, R.E., Kennedy, W.R. and Quick, D.C.: "A determination of static mechanical properties of intrafusal muscle in isolated cat muscle spindles." Neurosci. 4:401-411, 1979.
- Quick, D.C., Kennedy, W.R. and Poppele, R.E.: "Anatomical evidence for multiple sources of action potentials in the afferent fibers of muscle spindles." Neurosci. 5:109-115, 1980.
Link to expanded list: Publications