Charles H. Markham

MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects.

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinsons disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

Ocular counterrolling as an indicator of vestibular otolith function

Sixteen normal subjects, 8 patients with unilateral vestibular nerve section, and 11 patients with acoustic neuromas underwent dynamic ocular counterrolling (OCR) testing. Both eyes were photographed at every 10° as the subject was tilted about the naso-occipital axis at a constant velocity of 3°/sec. Normal subjects differed from patients in four characteristics: (1) The binocular OCR patterns of normal subjects were consistent from one trial to the next. (2) The two eyes were mostly conjugate in movement. (3) The patterns were smooth. (4) OCR was approximately symmetric to right and left tilts. In the patients, patterns were abnormal when tilted to the side opposite the lesion. In quantified measures of the four characteristics, differences between the normal group and the group of patients with unilateral vestibular nerve sections were significant in consistency and total scores. In the patients with acoustic neuromas, OCR abnormalities corresponded to the size and location of the tumors and the extent to which they impinged on the utricular nerve and brainstem.

Sleep in patients with Parkinson's disease and normal subiects prior to and following levodopa administration

Six patients with parkinsonism and 4 spouse control subjects were studied in the sleep laboratory prior to administration of levodopa and during initial, short‐term, long‐term, and chronic usage. The parkinsonian patients had a significant amount of sleeping difficulty, taking much longer to fall asleep and awakening frequently for long periods during the night, as compared with spouse control subjects and a normal, elderly control group. Values for rapid eye movement (REM) sleep were similar to those of both control groups, while Stage 3 sleep was decreased. Three of the 6 patients showed a decrease in REM sleep with initial drug administration at the 1.0 Gm. per day dosage level. One had a marked increase in REM sleep for about the first 2 weeks of drug administration. However, REM sleep values for all patients with long‐term and chronic drug administration were similar to base‐line values. In the spouse control subjects, other than a slight increase in REM sleep with initial drug administration which was not maintained with long‐term use, no changes were noted in REM sleep, even during withdrawal of the drug. In both patients and control subjects, values for sleep induction and sleep maintenance were essentially unaltered by the administration of levodopa. Biochemical implications of these data are discussed. In addition, the clinical implications in terms of evaluating and treating the moderately severe insomnia in parkinsonian patients are described.

Selective loss of subpopulations of ventral mesencephalic dopaminergic neurons in the monkey following exposure to MPTP.

Tyrosine hydroxylase immunohistochemical examination of the mesencephalon of severely parkinsonian MPTP-treated macaque fascicularis monkeys revealed a marked loss of substantia nigra pars compacta (SNc) neurons in both medial and central portions of the nucleus with a relative sparing of neurons in the dorsal-most portions of the substantia nigra. These animals also sustained 20-65% loss of neurons in the substantia nigra pars lateralis area, ventral tegmental area (A-10), and the retrorubral area (A-8 cell group, and the parabrachialis pigmentosus region). These animals all had extreme striatal dopamine depletions. A monkey which received several small doses of MPTP and yet remained asymptomatic for a motor disorder (although it had demonstrable behavioral performance deficits) had only a loss of ventral SNc neurons, with no appreciable cell loss in associated ventral mesencephalic dopamine areas and no loss of striatal dopamine. These data suggest that the effects of MPTP are not as selective as originally thought and, more importantly, indicate that MPTP-induced parkinsonism in the primate may be more analogous to idiopathic Parkinsons disease, where cells other than SNc cells are affected. Furthermore, the present findings suggest that only certain mesencephalic dopamine neurons are susceptible to MPTP-induced damage. The unique characteristics of these neurons need to be elucidated.

Parkinson's disease: sensory and motor problems in arms and hands.

Fifteen undemented patients with Parkinsons disease (PD) and 15 age-matched controls were given a battery of tests to assess sensorimotor integration in the arms. PD patients made more errors (p < 0.01) than controls, particularly in tests of proprioception. Age was not related to errors. Compared with controls, two-point discrimination thresholds were significantly higher (p <0.02) on the index finger of PD patients, but not on the forearm. Results confirm the sensorimotor deficits found earlier in an orofacial study, and imply that PD involves a generalized dysfunction of sensorimotor integration and proprioception, probably a result of impaired basal ganglia function in processing and integrating sensory input to organize and guide movement.

Neural-Targeted Gene Therapy for Rodent and Primate Hemiparkinsonism

Expression of the rate-limiting enzyme for catecholamine biosynthesis, tyrosine hydroxylase (TH), via retroviral and plasmid expression vectors improved the efficacy of conditionally immortalized nigral neural cells in ameliorating rodent and nonhuman primate models of Parkinsons disease through neural transplantation. No improvement in rotational behavior occurred when sham transplants or nondopaminergic transplants were performed. Transplantation of the temperature-sensitive immortalized parental nigral neural line with a TH expression vector resulted in improvement for at least 2 months. Improvement was accompanied by HPLC evidence of increased L-DOPA production and immunocytochemical evidence of TH in the transfected cells increased over that of the parental line. No tumor formation was detected. These results suggest that: (1) temperature-sensitive immortalized neural cells may be genetically engineered successfully to improve their efficacy for the treatment of parkinsonism; and (2) a change in L-DOPA production, as opposed to growth factor production or other factors, is likely to account for the observed improvement, since the parental and derived lines differ by a single gene.

An examination of male‐female differences in progression and mortality of Parkinson's disease

We conducted disability and mortality studies to determine if the male preponderance usually found in Parkinsons disease (PD) was reflected in different courses of the disease in the 2 sexes. We analyzed longitudinal disability score in 47 men and 23 women with PD followed for 6 years at UCLA. We found no significant differences between the sexes in mean disability scores in any of the 6 years. Mean dopa dosage was significantly higher in men, possibly reflecting their generally larger body mass. Choreoathetosis, dementia, or other side effects did not differ between the 2 groups. We obtained observed to expected mortality ratios in 239 men and 132 women followed for 3,831 person-years from records of 4 medical centers. Using the sex-specific US Life Tables to calculate expected mortality, we found the observed to expected ratio for the men was 1.7457 and for the women 2.4740, a significantly greater excess in female mortality. Analyses of mortality using tables which are not sex-specific will fail to uncover the decreased longevity in women with PD. We conclude that, despite the male preponderance in PD, men and women acquire it at the same age, have the same progression and duration of disease, and die at the same age; whereas, in the general population, women have a longer life expectancy than men. It is not known what factors protect women from incurring PD and what lowers their life expectancy to that of men when they do have the disease.

Effect of age at onset on progression and mortality in Parkinson's disease

We examined longitudinal disability scores in 54 patients with Parkinsons disease followed for 6 years at UCLA. We sorted data into 3 groups based on age at onset of symptoms: group A, onset under 50 years; group B, 50 to 59 years; group C, 60 years or older. There were no significant differences between groups initially. All 3 groups improved dramatically when levodopa was given, but group A showed significantly less disability in years 4, 5, and 6 than did group C. The groups did not differ with respect to side effects. To determine if age at onset affected mortality, we sorted records from 4 geographically diverse centers into the same 3 groups. Results on 359 patients followed for 3,314 person-years, covering a period of 17 years after onset of symptoms, showed that group A had the most favorable observed-to-expected mortality ratio, 1.82, compared with 2.17 and 2.20 for groups B and C respectively, but the difference was not statistically significant. Results from the disability analyses indicate that patients with onset of Parkinsons disease under 50 years of age may have a more favorable prognosis than those whose symptoms begin in later years.

Production of a Parkinson-like syndrome in the cat with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Behavior, histology, and biochemistry

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent dopaminergic neurotoxin, was administered to cats systemically for 5 to 7 days. This treatment produced a behavioral syndrome characterized by akinesia, ataxia, bradykinesia, and feeding difficulties, lasting for several weeks. During this period of severe behavioral impairment, caudate and nucleus accumbens dopamine and norepinephrine concentrations were quite depleted. Behavioral recovery ensued over the next several weeks as did some recovery of striatal catecholamines. MPTP destroyed the majority of substantia nigra pars compacta neurons while affecting a much lesser number of locus ceruleus and ventral tegmental neurons. These results demonstrated for the first time that MPTP can cause long-lasting deficits in nigrostriatal functioning in the cat and may provide a means for studying the apparently selective neurotoxic effects of MPTP as well as for understanding the pathophysiology of Parkinsons disease.

Convergence of labyrinthine influences on units in the vestibular nuclei of the cat. I. Natural stimulation.

Abstract Neurons in the vestibular nuclei were examined by extracellular recording in cats with high cervical spinal cord transections and were physiologically identified by their response to angular acceleration stimulation in the plane of the horizontal canal. Units which responded to horizontal canal stimulation were then tested firstly by slow constant velocity tilts and statically maintained positions in space (otolithic tests) and then by angular accelerations (canicular tests) in the plane of the left anterior-right posterior canals and in the plane of the left posterior-right anterior canals. In this way the extent of convergence from various vestibular sensory regions onto horizontal canal neurons was determined. In some cats an attempt was made to eliminate input from vestibular sensory regions contralateral to the recording site by making a midline section of the floor of the fourth ventricle from the aqueduct to the obex. Approximately one-third of the units in both sectioned and non-sectioned animals responded solely to horizontal canal stimulation. The remaining two-thirds exhibited convergence from other sensory regions in varying degrees of complexity — most responded to only one other sensory region, but some responded to stimulation of 2 or 3 other sensory regions. Approximately half of all units in both sectioned and non-sectioned animals responded to otolithic stimulation. Likewise, approximately half of all units responded to stimulation of at least on vertical canal, however, midline sectioning appeared to reduce this proportion. It is suggested that vestibular convergence is due to neural interaction within the vestibular nuclei rather than being due to spread of stimulation or being instances of unusual modes of operation of particular vestibular receptors. The comparatively negligible effect of midline section may be consistent with the hypothesis that vestibular commissural fibers convey ‘mirror image’information from vestibular receptors on the contralateral side, and that this information, in the animal with bilaterally intact labyrinths, has an enhancing or ‘sharpening’ effect.