Human Neurochemical Pathology
Laboratory
Head: Dr. Stephen Kish
During 2000/2001, our laboratory continued to divide its time between
studies of subjects who chronically use drugs and investigations of patients
with movement disorders. The involvement of the dopamine and serotonin
neurotransmitter systems offers a link between both groups of conditions.
Our approaches involve investigations of autopsied human brain, positron
emission tomography, clinical pharmacological studies, and review of Canadian
and US databases.
Drug Use
Methamphetamine
Methamphetamine is a widely used drug worldwide. It is commonly assumed
that methamphetamine is preferentially accumulated in the dopamine-rich
striatum of human brain. We (K. Kalasinsky, US medical examiners, S. Kish)
found in an autopsied brain study that methamphetamine levels were homogeneously
distributed throughout the entire brain of both low-dose and high-dose
recreational users of the drug. This suggests we should consider the possibility
that methamphetamine might exert behaviourally significant actions (and
perhaps toxicity) both in dopamine-rich and in dopamine-poor brain areas
of the brain (Forens Sci Int 116:163-169, 2001).
We do not know the cause of the clinically significant and sometimes
long-lasting depression and cognitive impairment following withdrawal
from repeated methamphetamine use. In an examination of autopsied brain
from 20 chronic methamphetamine users, we (US medical examiners, S. Kish)
found that striatal dopamine levels in about one-third of the subjects
were almost as low as those observed in people who have Parkinson's disease,
but the caudate nucleus was affected more than the putamen (ms in preparation).
We suggest that the low brain dopamine explains both the depression and
the cognitive impairment that occurs during drug withdrawal. We also suggest
that treating methamphetamine users with dopaminergic agents during drug
withdrawal might ameliorate this behavioural dysfunction, thereby increasing
retention in a drug rehabilitation setting.
The cause of tolerance to repeated use of methamphetamine, resulting
in dose escalation, is unknown. In study of autopsied human brain, we
(J. Tong, US medical examiners, S. Kish) found that one major index of
dopamine receptor function, dopamine-stimulated adenylyl cyclase activity,
was reduced in brain of chronic methamphetamine users. As the behavioural
effects of methamphetamine are probably due in large part to an action
on the dopamine system, our data suggest the tolerance that can develop
to repeated use of the drug might be due to a down-regulation of dopamine
receptor-linked adenylyl cyclase activity (ms in preparation).
Heroin
Animal data indicate that long-term exposure to heroin might either damage
or cause decreased activity of the brain dopamine system and thereby impair
dopamine-linked behaviour. In a study of autopsied brain of humans who
used heroin, we (US medical examiners, J. Haycock, S. Kish) reported mildly
decreased levels of dopaminergic markers
in the nucleus accumbens, but no evidence of actual damage to brain dopamine
neurons (Neuropsychopharmacol 24:561-7, 2001). Our findings indicate
that heroin is probably not toxic to dopamine neurons in humans who use
the drug, but modestly decreased dopaminergic activity in nucleus accumbens
might explain some of the motivational and affective problems found in
some people who use heroin.
Ecstasy
The question of whether ecstasy can cause death in the normal human is
highly controversial -- people who use ecstasy, and most of the print
media, generally assume that ecstasy-related deaths are actually caused
by co-use of a more toxic drug. In collaboration with medical examiners
and toxicologists in Ontario, New York City, Maryland, Oakland and the
UK, we (S. Kish) have been systematically examining all ecstasy-related
deaths at these centres. Our preliminary findings suggest that almost
all people who use ecstasy also use other toxic drugs of abuse (e.g.,
heroin, cocaine), so the majority of ecstasy-related deaths occur in individuals
who use multiple drugs. We have also found sufficient evidence that ecstasy,
taken alone, can cause death. However, these deaths appear to be rare
when compared with the widespread use of the drug. This strongly suggests
that ecstasy fatalities are likely to occur primarily in people predisposed,
for an as-yet-unknown reason (e.g., analogous to antipsychotic malignant
hyperthermia), to the toxic effects of the drug.
Our ecstasy studies are currently designed to establish, by PET and behavioural
assessments, whether chronic ecstasy exposure does or does not irreversibly
damage brain serotonin neurons in humans.
Movement
Disorders: Parkinson's Disease
What Causes Depression
in Parkinson's Disease?
Parkinson's disease (PD) is a movement disorder commonly associated with
clinically significant depression and cognitive impairment. Recent studies
now confirm clinical impressions that depression in PD affects the quality
of life of the patient more than motor disability. Based on the original
postmortem brain finding of Oleh Hornykiewicz, we (M. Guttman, S. Houle,
J. Warsh, A. Wilson, J. St-Cyr, E. Mundo, J. Blake, S. Kish) are conducting
a PET investigation to establish whether the number of brain serotonin
neurons, inferred from levels of the serotonin transporter, are below
normal in people who are depressed and have PD. This study will make use
of the first reliable radioligand, developed by the CAMH PET Centre, to
measure the serotonin transporter. Our preliminary findings indicate that
striatal binding of the serotonin marker is moderately reduced in non-depressed
patients with PD, and a study has been funded to assess changes with patients
who have PD and are also depressed.
How Common Is Hereditary
PD?
Although a small number of families have been identified with presumably
rare forms of PD, we do not yet know the percentage of people with PD
who have a hereditary illness, nor do we know the number of genetic defects
involved. Dr. Guttman is collaborating with a team of investigators assessing
genetic abnormalities in PD. A manuscript describing the methodology of
this NIH-funded investigation (Gene PD study) is in press, and a second
manuscript, describing the clinical aspects of the first 200 sib pairs,
has been submitted.
What Is the Impact of
PD on Mortality, Burden to Society and Physician Distribution?
Dr. Guttman and collaborator Dean Naylor have assessed the impact of
PD on mortality, burden to society and physician distribution in Ontario
by using the Ontario Ministry of Health and Long-Term Care database located
at the Institute for Clinical Evaluation Sciences. The sample size of
11 million Ontario residents makes this study unique, and the results
will potentially have an impact on health care delivery to people who
have PD. Contrary to prevailing opinion, and despite marked improvements
in symptomatic treatments, the mortality of PD in Ontario has increased
with an odds ratio of 2.5 compared to age-matched controls. This further
emphasizes the need for neuroprotective therapies in PD. Costs of physician's
services, hospitalization and drug utilization in the PD group were also
increased markedly compared to age-matched controls. Surprisingly, over
50 per cent of PD patients did not receive care from a neurologist during
each year of service (three manuscripts submitted).
New Neuroprotective
Therapies in PD
Dr. Guttman is involved with multicentre clinical trials to assess neuroprotective
strategies in PD. He will establish whether the anti-apoptotic drug TCH
1015 or the drug riluzole slow the progression of PD.
Movement
Disorders: Multiple System Atrophy
The Solubility of *-Synuclein
Is Decreased in Multiple System Atrophy
Multiple system atrophy (MSA) is a disorder of unknown cause, characterized
by degeneration of widespread areas of the brain, including those responsible
for PD. We (Y. Furukawa, M. Guttman, S. Kish) have been examining, in
autopsied brain of people with MSA and with PD, the behaviour of *-synuclein,
a protein involved in one form of hereditary PD. We found that the solubility
of this protein is greatly reduced in brain of people with MSA and, to
a lesser extent, in PD. Our current objective is to establish, in collaboration
with Dr. Yves Briand (Clermont-Ferrand), whether this change might be
explained by a defect in one of the key systems responsible for targeting
proteins for degradation.
Movement
Disorders: Progressive Supranuclear Palsy
Lack of Efficacy of
Pramipexole in Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a Parkinsonian disorder characterized,
like MSA, by degeneration of multiple areas of the brain. Unlike PD, advanced
PSP is not responsive to standard dopaminergic pharmacotherapy. Dr. Guttman
has been the principal investigator of an investigator-initiated multicentre,
placebo-controlled study of the use of pramipexole, a new dopamine agonist
drug, in treating this disorder. Unfortunately, the drug had no beneficial
effect on patients with PSP (ms in preparation).
Movement
Disorders: Huntington's Disease
Lack of Efficacy of
Remacemide and Co-Enzyme Q-10 in Huntington's Disease
Dr. Guttman participated in a large NIH-funded multicentre study to assess
if Remacemide or Co-Enzyme Q-10 would slow the progression of Huntington's
disease (HD). Unfortunately, neither drug was found to have an influence
on disease progression (Neurology, in press).
PHAROS Project
Dr. Guttman, as part of the PHAROS project, will assess subjects at risk
for HD who do not know their gene status. They will be followed clinically
to assess longitudinal changes, to evaluate which symptoms of HD occur
first and to see how this correlates with genetic testing. This project
will identify if neurological, psychiatric or behavioural symptoms are
the first features of this neuropsychiatric disorder.
Movement
Disorders: Dopa-Responsive Dystonia
Tyrosine Hydroxylase
Reduction Is the Critical Factor in the Etiology of Dopa-Responsive Dystonia
Dopa-responsive dystonia (DRD) is a hereditary disorder caused by a defect
in the gene that codes for biopterin, a cofactor of the enzyme tyrosine
hydroxylase. Contrary to the prevailing theory, we (Y. Furukawa, G. Kapatos,
T. Nygaard, S. Kish) found in study of autopsied brain that protein levels
of tyrosine hydroxylase, but not biopterin levels, determined whether
the subject carrying the defective gene would be symptomatic or asymptomatic
(ms in preparation). This suggests that future strategies in the treatment
of DRD should focus on normalizing protein levels of tyrosine hydroxylase.
Movement
Disorders: Diffuse Lewy Body Disease
Gallantamine Project
Dr. Guttman is participating in a placebo-controlled multicentre study
of gallantamine for the treatment of the cognitive impairment of Diffuse
Lewy Body disease.
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