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The Role of Cholesterol, Dementia, and Gene Therapy Highlighted in Noteworthy Parkinson Disease Research

Serum cholesterol, dementia, and gene therapy were the focus of noteworthy research papers on Parkinson disease (PD) highlighted for Neurology Today by three experts: Marc Wasserman, MD, a general neurologist in Phoenix, AZ; Anna Hohler, MD, assistant professor of neurology at Boston University; and Rajesh Pahwa, MD, professor of neurology and director of the Parkinson Disease and Movement Disorder Center at the University of Kansas Medical Center in Kansas City.

CHOLESTEROL AS PD RISK FACTOR

The correlation between high serum cholesterol and heart disease is well-documented, but the evidence for a relationship between cholesterol and neurodegenerative disease is mixed. Gang Hu, MD, PhD, of the National Public Health Institute in Helsinki, Finland, and colleagues examined this association, using data gathered on 50,926 people in six independent cross-sectional surveys conducted between 1972 and 1997.

The participants, who ranged in age from 25 to 74 years, had no history of PD or stroke at baseline. Over a mean follow-up period of 18.1 years, 625 people (1.2 percent) developed PD.

PD risk increased with rising cholesterol levels among people aged 25 to 54 at baseline, but not in older subjects. For both sexes combined, the hazard ratio for PD ranged from 1.00 among people with a serum cholesterol less than 5 mmol/L to 1.86 for those with cholesterol levels greater than mmol/L (p for trend = 0.002).

“The present study is, to our knowledge, the first large prospective study to find that high total cholesterol may increase PD risk,” the authors wrote in the May 20, 2008, Neurology. Interestingly, they also noted that a decline in serum cholesterol in midlife is sometimes a harbinger of PD or Alzheimer disease. They also warned that a shared genetic and environmental background of PD and high cholesterol risk could not be excluded.

“There seems to be a correlation between lipid function and several neurological diseases, including strokes and Alzheimer disease, so it is not surprising that Parkinson disease might also be involved,” said Dr. Wasserman, MD, who chose this paper. “Further research into the causes and treatment of Parkinson disease as related to cholesterol would certainly be warranted and valuable.”

DEMENTIA AND PD

It is also known that people with PD have a higher than average risk of dementia. Dag Aarsland, MD, and colleagues at Stavanger University Hospital in Norway found that of 233 patients they followed for 12 years, 140 (60 percent) had developed dementia by the end of the study period.

At baseline, the patients were, on average, 75 years old, and 62 (27 percent) already had dementia. By year 12, dementia had developed in 78 more. In the April 22, 2008, issue of Neurology, the authors explained that a 70-year-old man with PD but no dementia has a life expectancy of eight years, of which five would continue to be dementia-free. If this patient already has dementia, his life expectancy would be 4.2 years. A female PD patient of the same age has a life expectancy of 11 years, of which 7.2 would be dementia-free. The presence of dementia already would curtail her life expectancy to 5.7 years. In an earlier study comparing the incidence of dementia in PD patients to that of an age-matched, healthy control group, these authors found that those with PD had a 5.9-fold increase in risk of developing dementia. They concluded that the possibility of dementia should be considered when making long-range plans for people with PD.

“This is another reminder that neurologists must carefully assess non-motor factors when evaluating PD patients,” Dr. Hohler told Neurology Today. “Dementia can significantly impact activities of daily life, as well as rates of institutionalization and mortality in people with PD. Dementia also increases caregiver stress and can accelerate caregiver burnout.”

GENE THERAPY

Instratriatal infusion of an adeno-associated viral (AAV) vector containing human aromatic L-amino acid decarboxylase (hAADC) results in robust gene expression and conversion of levodopa to dopamine in a primate model of PD, Jamie L. Eberling, PhD, and colleagues of the Lawrence Berkeley National Laboratory in Berkeley, CA, reported in the May 20, 2008, issue of Neurology.

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DR. ANNA HOHLER: “Dementia can significantly impact activities of daily life, as well as rates of institutionalization and mortality in people with PD. Dementia also increases caregiver stress and can accelerate caregiver burnout.”

Encouraged by these findings, they conducted a phase I safety trial of hAADC gene therapy in five people with PD. At baseline, each patient had had PET scans with the tracer, fluoro-1-m-tyrosine (FMT). The patients then received bilateral intraputaminal infusions of the AAV-hAADC vector, followed by repeat PETs with FMT at one and six months.

The follow-up scans showed an average 30 percent increase in tracer uptake, suggesting sustained gene expression and activity. In general, the procedure and the therapy were well-tolerated. Three patients had their doses of levodopa reduced six months after surgery due to increased duration and extent of benefit. All in all, the authors observed modest benefits in the Unified Parkinson Disease Rating Scale (UPDRS) and motor activity, but they warned that these results must be interpreted with caution due to the study's small size, open-label design, and lack of a control group.

Similar findings were obtained in a phase I trial involving the gene delivery of the neurotrophic factor neurturin, as reported in the May 2008 issue of The Lancet Neurology.

William J. Marks, MD, of the University of California-San Francisco, and colleagues administered intraputaminal injections of AAV serotype 2-neurturin (CERE-120) to 12 patients who had had PD for at least five years. The patients did well, with no clinically significant adverse events at one year. They also showed a mean improvement of 14 points on the off-medication motor Unified Parkinson's Disease Rating Scale (UPDRS) subscore (p=0.000121), and a mean increase of 2.3 hours in time without troublesome dyskinesia (p=0.0250).

Unfortunately, a phase 2 study reported in November did not show any appreciable difference in UPDRS improvement between patients treated with CERE-120 and a control group, said Rajesh Pahwa, MD, professor of neurology and director of the Parkinson Disease and Movement Disorder Center at the University of Kansas Medical Center in Kansas City. Thus, he warned, while the earlier studies appeared to be important milestones in the treatment of PD, longer-term research is always necessary to confirm initial findings.

REFERENCES

• Hu G Antikainen R, Tuomilehto J, et al. Total cholesterol and the risk of Parkinson disease. Neurology 2008;70(21);1972–1979.
    • Buter TC, Hout VD, Aarsland D, et al. Dementia and survival in Parkinson disease: A 12-year population study. Neurology 2008;70:1017–1022.
    • Eberling JL, Jagust WH, Aminoff MJ, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 2008;70:1980–1983.
    • Marks WJ Jr, Ostrem JL, Bartus RT, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: An open-label, phase I trial. Lancet Neurol 2008;7:400–408.