Metabolic brain networks associated with cognitive function in Parkinson's disease
Introduction
Parkinson’s disease (PD) is a progressive degenerative neurological disorder characterized clinically by its motor manifestations. However, cognitive deficits and behavioral abnormalities are also well documented as part of the illness, with a prevalence of dementia ranging from 24% to 31% (Aasland et al., 2005). The dementia of PD typically includes difficulties in executive and visuospatial functions, as well as memory and language deficits (Bosboom et al., 2004). By contrast, more circumscribed executive deficits, as well as secondary disturbances of memory and visuospatial function, have been described in non-demented PD patients (Green et al., 2002; cf., Zgaljardic et al., 2003, Bosboom et al., 2004 for reviews). Such subtle behavioral/cognitive deficits may have a major impact on the quality of life of PD patients (Schrag et al., 2000).
The best recognized pathological change in PD is the loss of dopaminergic cells of the substantia nigra pars compacta, directly altering the activity of motor cortico-striatopallido-thalamocortical (CSPTC) pathways (Wichmann and DeLong, 2003). The depletion of striatal dopamine has also been suggested as a cause for the cognitive deficits of PD (Green et al., 2002). The direct dopaminergic connections between the ventral tegmental area and the prefrontal cortex may also influence changes in cognition in this disease (e.g., Mattay et al., 2002; cf., Cools, 2006 for review). Nonetheless, the modulation of dopamine systems cannot fully explain the cognitive deficits in PD, and other neurotransmitter systems may be influential (Emre, 2003, Pillon et al., 2003, Bosboom et al., 2004). Moreover, recent postmortem studies in PD suggest a correlation between dementia and cortical Lewy body formation as well as coincident Alzheimer's disease-associated neurofibrillary pathology (Braak et al., 2003, Braak et al., 2005, Kovari et al., 2003).
Positron emission tomography (PET) has been useful in the investigation of cognitive functioning in PD. Functional imaging studies have generally focused upon activation experiments to detect abnormal patterns of neural activity in PD patients during task performance (e.g., Dagher et al., 1999, Nakamura et al., 2001, Owen, 2004). Relevant information has also been obtained through imaging studies conducted in the rest state. For instance, PET imaging has been used to examine the relationship between neuropsychological test performance and the integrity of nigrostriatal dopaminergic projections (e.g., Marié et al., 1999, Brück et al., 2004, Brück et al., 2005, Cheesman et al., 2005). Recently, PET has also been utilized to contrast dopaminergic and cholinergic projection systems in PD patients with and without dementia (Hilker et al., 2005).
PET imaging in the rest state can also provide inferences regarding the status of neural pathways in PD patients. In this regard, 18F-fluorodeoxyglucose (FDG) PET is particularly relevant as a measure of local synaptic activity and the biochemical maintenance processes that dominate the rest state (cf., Jueptner and Weiller, 1995, Eidelberg et al., 1997). Indeed, the effects of pathology on these local cellular functions appear to be greater than other factors that influence the variation in regional brain function that is observed in the resting condition (Ma et al., in press). Moreover, neuropathological processes, even if highly localized, can alter functional connectivity across the entire brain in a disease-specific manner (Eidelberg, 1998, Eckert and Eidelberg, 2005).
Spatial covariance analysis has proven useful as a means of identifying the network abnormalities that are associated with neurological disease (Alexander and Moeller, 1994). Using this network-modeling approach, we have found that PD patients express an abnormal metabolic pattern characterized by increased pallido-thalamic and pontine activity associated with relative reductions in cortical motor regions (Eidelberg et al., 1994, Eidelberg et al., 1997; cf., Carbon et al., 2003a). To date, this PD-related pattern (PDRP) has been detected in eight independent patient populations (Moeller et al., 1999, Feigin et al., 2002, Lozza et al., 2004, Asanuma et al., 2005, Eckert et al., in press) and its expression has been found to be highly reproducible in individual subjects (Ma et al., in press). In addition to accurately discriminating between PD patients and controls (Asanuma et al., 2005, Ma et al., in press), PDRP expression has been found to correlate consistently with Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (Eidelberg et al., 1995, Lozza et al., 2004, Asanuma et al., 2006) and with clinical responses to therapy (e.g., Trošt et al., 2006, Asanuma et al., 2006; cf., Carbon et al., 2003a, Eckert and Eidelberg, 2005).
Similar network approaches can be used to identify potential imaging biomarkers of cognitive functioning in PD (see Carbon and Marié, 2003 for review). Using a covariance mapping approach in the analysis of FDG PET and neuropsychological data, Mentis et al. (2002) identified discrete patterns of resting metabolic activity associated with cognitive and affective functions in non-demented PD patients. In a subsequent FDG PET study, Lozza et al. (2004) used the scaled subprofile model (SSM) and principal components analysis (PCA) (Alexander and Moeller, 1994; cf., Habeck et al., 2005) to characterize a specific metabolic pattern associated with executive functioning in less severely affected patients. Interestingly, their data showed that the patterns associated with motor and cognitive functioning were orthogonal, i.e., statistically independent. This finding supported the notion that the neural pathways mediating these aspects of PD are functionally segregated, at least in the rest state (Wichmann and DeLong, 2003).
In the current study, we utilized a voxel-based adaptation of this approach (Carbon et al., 2003b; cf., Scarmeas et al., 2004) to identify specific spatial covariance patterns relating to cognitive function in non-demented PD patients. To validate these networks as potential metabolic markers of cognitive decline in PD, we determined whether pattern expression predicted performance in a prospective patient cohort. We further explored the potential of these patterns as biomarkers in clinical trials of interventions to improve cognitive function in PD patients. To this end, we evaluated the reproducibility of pattern expression in individual subjects, as well as the effects of routine antiparkinsonian therapies on measurements of network activity.
Section snippets
Pattern identification
To identify cognitive-related spatial covariance patterns in PD (PDCPs), we studied 15 non-demented patients (9 men and 6 women; 14 right handers and 1 left hander; age 58.6 ± 9.5 years [mean ± SD]; disease duration 11.0 ± 4.6 years; off-state UPDRS motor ratings 34.3 ± 18.2; MMSE 28.3 ± 2.1) with FDG PET and neuropsychological evaluation. A diagnosis of PD was made if the patients had “pure” parkinsonism without a history of known causative factors such as encephalitis or neuroleptic treatment, and did
Neuropsychology and behavior
The results of neuropsychological evaluation and behavioral assessment are presented in Table 1. All the means are within two standard deviation of their respective normative mean, except for two executive tests: Trail Making Test B (identification and validation samples, and the combined sample) and Wisconsin Card Sorting Test: Categories Achieved (identification sample and the combined sample).
Pattern identification
Spatial covariance analysis was performed on the FDG PET scans of the original PD group (n = 15). The
Discussion
In this study, we applied network analysis to FDG PET data from non-demented PD patients to identify a novel spatial covariance pattern associated with cognitive function in this disorder. Significant correlations between PDCP expression and performance on tests of memory and executive functioning were replicated in a larger group of patients. Additionally, test–retest studies demonstrated that measurements of PDCP activity in individual subjects were stable over an 8-week follow-up period.
Acknowledgments
This work was supported by NIH NINDS R01 35069 (D.E.) and the General Clinical Research Center at the North Shore-Long Island Jewish Health System (NIH RR MO1 018535). The authors would like to thank Mr. Aaron Edelstein and Ms. Shivani Rachakonda for assistance in data management and analysis. We are grateful to Ms. Toni Flanagan for editorial assistance and manuscript preparation.
References (76)
- et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003) - et al.
Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus
Neurosci. Lett.
(2001) - et al.
Cortical 6-[18F]fluoro-l-dopa uptake and frontal cognitive functions in early Parkinson's disease
Neurobiol. Aging
(2005) - et al.
Caudate nucleus: influence of dopaminergic input on sequence learning and brain activation in Parkinsonism
NeuroImage
(2004) Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinson's disease
Neurosci. Biobehav. Rev.
(2006)- et al.
Neuroimaging and therapeutics in movement disorders
NeuroRx
(2005) - et al.
“ Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Review: does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI
NeuroImage
(1995) - et al.
Relationships between striatal dopamine denervation and frontal executive tests in Parkinson's disease
Neurosci. Lett.
(1999) - et al.
Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance
NeuroImage
(2004)
Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease
NeuroImage
A systematic review of prevalence studies of dementia in Parkinson's disease
Mov. Disord.
Manual of Directions and Scoring
Application of the scaled subprofile model to functional imaging in neuropsychiatric disorders: a principal component approach to modeling brain function in disease
Hum. Brain Mapp.
The metabolic pathology of dopa-responsive dystonia
Ann. Neurol.
Network modulation in the treatment of Parkinson's disease
Brain
Beck Depression Inventory: Manual
Conceptual processing during the conscious resting state. A functional MRI study
J. Cogn. Neurosci.
Measurement error
BMJ
Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study
Arch. Neurol.
Cognitive dysfunction and dementia in Parkinson's disease
J. Neural Transm.
Cognitive status correlates with neuropathologic stage in Parkinson disease
Neurology
Hippocampal and prefrontal atrophy in patients with early non-demented Parkinson's disease is related to cognitive impairment
J. Neurol. Neurosurg. Psychiatry
Functional imaging of cognition in Parkinson's disease
Curr. Opin. Neurol.
Functional brain imaging in Parkinson's disease
Adv. Neurol.
Learning networks in health and Parkinson's disease: reproducibility and treatment effects
Hum. Brain Mapp.
Lateralisation of striatal function: evidence from 18F-dopa PET in Parkinson's disease
J. Neurol. Neurosurg. Psychiatry
Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET
Brain
Mapping the network for planning: a correlational PET activation study with the Tower of London task
Brain
California Verbal Learning Test: Adult Version
Motor and nonmotor domains in the monkey dentate
Ann. N. Y. Acad. Sci.
An Introduction To The Bootstrap
Functional brain networks in movement disorders
Curr. Opin. Neurol.
The metabolic topography of parkinsonism
J. Cereb. Blood Flow Metab.
Assessment of disease severity in parkinsonism with fluorine-18-fluorodeoxyglucose and PET
J. Nucl. Med.
Metabolic correlates of pallidal neuronal activity in Parkinson's disease
Brain
What causes mental dysfunction in Parkinson's disease?
Mov. Disord.
Cited by (297)
Refining the clinical diagnosis of Parkinson's disease
2024, Parkinsonism and Related DisordersFunctional Brain Networks to Evaluate Treatment Responses in Parkinson’s Disease
2023, NeurotherapeuticsRole of Arterial Spin Labeling (ASL) Images in Parkinson's Disease (PD): A Systematic Review
2023, Academic RadiologyImpaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction
2023, Psychological MedicineAssociation of Parkinson's disease to Parkinson's plus syndromes, Lewy body dementia, and Alzheimer's dementia
2024, Health Science Reports