Autosomal dominant parkinsonism
associated with variable synuclein
and tau pathology
Z.K. Wszolek, MD; R.F. Pfeiffer, MD; Y. Tsuboi, MD; R.J. Uitti, MD; R.D. McComb, MD; A.J. Stoessl, MD;
A.J. Strongosky, BS; A. Zimprich, MD; B. Müller-Myhsok, MD; M.J. Farrer, PhD; T. Gasser, MD;
D.B. Calne, MD; and D.W. Dickson, MD
Abstract—Since the original 1995 report of a parkinsonian kindred, four individuals have been affected (mean age at
onset, 65 years). All four had cardinal signs of Parkinson disease (PD) and good response to levodopa. Four autopsies
showed neuronal loss and gliosis in the substantia nigra. Lewy bodies (LB) limited to brainstem nuclei were detected in
one case, diffuse LB in the second, neurofibrillary tangles (NFT) without LB in the third, and neither NFT nor LB in the
fourth. Genetic studies suggested linkage to the PARK8 locus on chromosome 12.
NEUROLOGY 2004;62:1619–1622
Since 1992, we have followed a parkinsonian kin-
dred, Family D, also called the Western Nebraska
kindred.1 Phenotype is characterized by late-onset,
levodopa-responsive parkinsonism. Since our initial
report in 1995, we have added 8-year follow-up infor-
mation on this family, during which progress was
made in clinical, pathologic, and genetic
investigations.
Methods. Institutional review boards approved all studies. For
three new autopsies, brain sections were examined with
hematoxylin-eosin, thioflavine-S fluorescence, and antibodies to
tau and
-synuclein. For linkage analysis, PARK8 markers on
chromosome 12 were used with a model of age-dependent pen-
etrance estimates; FASTMAP was used for multipoint calcula-
tions and MLINK for two-point analysis.2
Results. Family D pedigree has 190 members, with 22
affected (figure 1). Eighteen affected members were in-
cluded in the previous report1; four (III-24, IV-5, IV-15,
and IV-24) were affected in the interim. Family D is most
likely of English extraction and genealogically unrelated to
kindreds known to others and us in the United Kingdom
(D. Nicholl, personal communication, April 2003).
In the four newly diagnosed cases, symptoms developed
at a mean age of 70.5 years (mean for all 22 affected, 65
years). Mean survival is 13 years in all affected members.
The most common initial presentation includes bradykine-
sia (64%) and unilateral resting hand tremor (43%). Re-
sponse to levodopa therapy has been excellent, and typical
motor complications have developed in half those receiving
treatment.
During the study period, five family members died.
Three (III-20, III-21, and IV-20) donated their brains for
research; we retrieved glass slides and paraffin-embedded
blocks from an autopsy of a fourth (III-14). All four pa-
tients had typical parkinsonism, and one (III-21) had a
supranuclear gaze palsy (SNGP). Three of the four were
alive after development of levodopa and had beneficial re-
sponses to treatment. Pathologic examinations (table) were
made independently by two neuropathologists.
III-14 (1903–1955). Pathologic examination showed
neuronal loss (NL) and gliosis with abundant extracellular
pigment in the substantia nigra (SN). Lewy bodies (LB)
and Lewy neurites were seen in the brainstem, whereas no
neurofibrillary tangles (NFT), senile plaques (SP), or amy-
loid deposits were identified (figure 2A). The final patho-
logic diagnosis was brainstem LB disease (LBD).
III-20 (1909–1998). There was nearly total loss of pig-
mentation of the SN and locus ceruleus (LC) in conjunction
with marked NL and gliosis with extraneuronal melanin.
SP were seen in frontal, temporal, parietal, and entorhinal
cortices and in amygdala and hippocampus. NFT were
seen only in the subthalamic nucleus, midbrain tectum,
and pontine tegmentum. Immunohistochemical evaluation
From the Department of Neurology (Drs. Wszolek, Tsuboi, and Uitti, and A.J. Strongosky) and the Department of Neuroscience (Drs. Farrer and Dickson),
Mayo Clinic, Jacksonville, FL; the Department of Neurology (Dr. Pfeiffer), University of Tennessee Health Science Center, Memphis, TN; the Department of
Pathology and Microbiology (Dr. McComb), University of Nebraska Medical Center, Omaha, NE; the Department of Neurology (Dr. Stoessl), University of
British Columbia, Vancouver, British Columbia, Canada; the Department of Neurology (Drs. Zimprich and Gasser), Klinikum Grosshadern, Ludwig-
Maximilians-Universitie, Munich, Germany; the Computational Genetics Group (Dr. Müller-Myhsok), Max-Planck-Institute of Psychiatry, Munich, Ger-
many; and the Pacific Parkinson’s Research Centre (Dr. Calne), University Hospital, Vancouver, British Columbia, Canada.
Supported in part by the National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the M. K. Udall Parkinson’s Disease
Research Center of Excellence grant, the Canadian Institutes for Health Research, and the Pacific Parkinson’s Research Institute. T.G. and A.Z. were also
supported in part by the Deutsche Forschungsgemeinschaft (Ga 402/9-1) and the Bundesministerium für Forschung und Bildung (BMBF, Grant No.
01GS0116).
Presented in part at the 7th International Congress of Parkinson’s Disease and Movement Disorders; Miami, Florida; November 10 to 14, 2002 and at the
55th annual meeting of the American Academy of Neurology; Honolulu, Hawaii; March 29 to April 15, 2003.
Received July 1, 2003. Accepted in final form December 23, 2003.
Address correspondence and reprint requests to Dr. Zbigniew K. Wszolek, Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL
32224.
Copyright © 2004 by AAN Enterprises, Inc. 1619

showed LB and Lewy neurites (figure 2B). The final patho-
logic diagnosis was diffuse LBD.
III-21 (1911–2000). The SN and LC showed decreased
pigmentation with NL, gliosis, and extraneuronal melanin
being most pronounced in ventral and lateral locations. NFT
and a few tau-positive glia were present in the basal fore-
brain, striatum, subthalamic nucleus, and brainstem nuclei
(figure 2C). Only a few cortical SP, but no LB or Lewy neu-
Table Immunohistochemical findings of four affected individuals from Family D
Pedigree no.
III-14 III-20 III-21 IV-20
Tau inclusion LB Tau inclusion LB Tau inclusion LB Tau inclusion LB
Cortex        
Cingulate gyrus NA    NA   
Amygdala NA NA NA  NA   
Caudate/putamen        
Basal nucleus        
Subthalamic nucleus NA NA  NA    
Red nucleus        
Substantia nigra        
Midbrain tectum        
Locus ceruleus NA NA NA     
Pontine tegmentum        
Pontine base        
Medullary tegmentum        
Inferior olive        
Dentate nucleus NA NA NA NA    
Cerebellar white matter        
Braak NFT stage 1 3 2 1
Pathologic diagnosis BLBD DLBD Neurodegenerative
disorder with
tauopathy
Focal gliosis
(substantia nigra,
thalamus, and
hypothalamus)
BLBD  brainstem-type Lewy body disease; DLBD  diffuse Lewy body disease; LB  Lewy bodies; NA  not available; NFT  neu-
rofibrillary tangle;   positive;   negative.
Figure 1. Pedigree of Family D (western
Nebraska). Squares represent males, cir-
cles represent females. Solid squares or
circles represent affected subjects. A diag-
onal line through a square or a circle
indicates a deceased person. An arrow
indicates proband. A plus sign indicates
the presence of mild postural and action
tremor without any other symptoms or
signs of parkinsonism. (III-10 was re-
peatedly examined during 5 years before
his death at age 92 in 1998. III-9 died of
heart attack at age 78 in 1979, before
initiation of our studies on this family in
1992, and information about her is
based on newly available medical and
historical records; although she did not
have parkinsonian features, typical par-
kinsonism developed in one of her
daughters, IV-5.) An asterisk indicates
the presence of supranuclear gaze palsy
(vertical gaze palsy developed in III-21 at
age 83 years, 5 years from the onset of
symptoms, no other atypical clinical fea-
tures were documented, and a good re-
sponse to carbidopa-levodopa therapy
was sustained). A caret indicates an
autopsy.
1620 NEUROLOGY 62 May (1 of 2) 2004