Two Distinct Parkinson’s Networks Identified
The disease that causes tremors, rigidity and slowed movements in a million Americans also targets another brain network that regulates cognitive thought and the ability to carry out everyday tasks.
David Eidelberg, MD, head of the Center for Neurosciences at The Feinstein Institute for Medical Research, and his colleagues measured and quantified this network of brain regions during a five-year study of newly diagnosed Parkinson’s patients who agreed to be followed several times over the course of the study. This is the first longitudinal study of Parkinson’s disease using a brain scan to follow these Parkinson’s network over time.
The technology is now precise enough to diagnose the two brain networks — one that regulates movement and the other cognition — in individuals, and Dr. Eidelberg said that it could be used to assess the degenerative disease process and the person’s response to treatments. The study also shows that the standard drugs used to treat Parkinson’s alter the areas that are involved in movement but not those that regulate cognition.
The network that grows abnormal over time includes an called the pre-frontal cortex, known as the brain’s executive secretary; organizing, planning and carrying out tasks in order of importance. It’s the same region that is hard-hit in mild cognitive impairment, the precursor to Alzheimer’s dementia. But Eidelberg said that the symptoms in the two diseases are quite different. But thinking that medicines used for Alzheimer’s might help normalize this network, the scientists gave Parkinson’s patients eight weeks of treatment. It didn’t work.
“We really don’t know precisely what’s going on in this newly-identified network, but we can begin to ask questions and figure it out,” said Dr. Eidelberg.”We don’t even know whether this network can be fixed.”
In 1999, the researchers recruited 15 patients with early stage Parkinson’s and signed them on to get brain scans at different points throughout the study. Some were on medicines and some were not. The first networks to be identified were no surprise: The basal ganglia, thalamus and brain stem that regulate movement. The scans they used measured glucose metabolism — the brain’s fuel — and identified areas in this motor network that showed decreased metabolic activity and some areas that had increased metabolic activity. Over time, the cognitive network became apparent. And as the disease progressed and symptoms worsened, this network also took its toll.
“The circuits are like a fingerprint of the disease,” Dr. Eidelberg said. “As the disease gets worse, the fingerprint is much easier to identify.” The circuits are the same in all Parkinson’s patients, he added. They are now testing other treatments, including deep brain stimulation, to see if it can impact on the cognitive network. “The cognitive problems are real and have to be addressed,” he added. “The medicines for Parkinson’s don’t seem to do anything to alter these networks and we need new ones to target these symptoms.”
He said that the networks could be used as biomarkers to diagnose the disease. The scientists have also developed mathematical computer models to determine how fast the disease will progress. “These scanning techniques may be helpful in determining what treatments work and what don’t.”
Brain. 2007 Jul;130(Pt 7):1834-46. Epub 2007 Apr 30.
Changes in network activity with the progression of Parkinson’s disease.
Center for Neurosciences, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA.
Parkinson’s disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features. The time at which these abnormalities appear is unknown, as is their relationship to concurrent clinical and dopaminergic indices of disease progression. In this longitudinal study, 15 early stage PD patients (age 58.0 +/- 10.2 years; Hoehn and Yahr Stage 1.2 +/- 0.3) were enrolled within 2 years of diagnosis. The subjects underwent multitracer PET imaging at baseline, 24 and 48 months. At each timepoint they were scanned with [18F]-fluorodeoxyglucose (FDG) to assess longitudinal changes in regional glucose utilization and in the expression of the PD-related motor (PDRP) and cognitive metabolic covariance patterns (PDCP). At each timepoint the subjects also underwent PET imaging with [18F]-fluoropropyl betaCIT (FP-CIT) to quantify longitudinal changes in caudate and putamen dopamine transporter (DAT) binding. Regional metabolic changes across the three timepoints were localized using statistical parametric mapping (SPM). Longitudinal changes in regional metabolism and network activity, caudate/putamen DAT binding, and Unified Parkinson’s Disease Rating Scale (UPDRS) motor ratings were assessed using repeated measures analysis of variance (RMANOVA). Relationships between these measures of disease progression were assessed by computing within-subject correlation coefficients. We found that disease progression was associated with increasing metabolism in the subthalamic nucleus (STN) and internal globus pallidus (GPi) (P < 0.001), as well as in the dorsal pons and primary motor cortex (P < 0.0001). Advancing disease was also associated with declining metabolism in the prefrontal and inferior parietal regions (P < 0.001). PDRP expression was elevated at baseline relative to healthy control subjects (P < 0.04), and increased progressively over time (P < 0.0001). PDCP activity also increased with time (P < 0.0001). However, these changes in network activity were slower than for the PDRP (P < 0.04), reaching abnormal levels only at the final timepoint. Changes in PDRP activity, but not PDCP activity, correlated with concurrent declines in striatal DAT binding (P < 0.01) and increases in motor ratings (P < 0.005). Significant within-subject correlations (P < 0.01) were also evident between the latter two progression indices. The early stages of PD are associated with progressive increases and decreases in regional metabolism at key nodes of the motor and cognitive networks that characterize the illness. Potential disease-modifying therapies may alter the time course of one or both of these abnormal networks.
PMID: 17470495 [PubMed – in process]