Frontostriatal Network Under-recruitment Underlies Mild Cognitive Impairment in Parkinson's Disease
Abstract & Commentary
By Claire Henchcliffe, MD, DPhil, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidepoint Global.
Synopsis: Multimodal brain imaging demonstrates extensive frontostriatal dysfunction in mild cognitive impairment in early Parkinson's disease.
Source: Ekman U, et al. Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: A cross-sectional study. Lancet Neurol 2012;11:679-687.
Mild cognitive impairment (MCI) is common in parkinson's disease (PD). Unlike dementia, it may occur early in the disease course, and often affects executive function and working memory. Unfortunately, its underlying neural substrate is not well understood, hampering rational development of therapeutics. In this cross-sectional study, drug-naïve subjects with PD were recruited from the Umea project, a longitudinal, population-based cohort of incident patients. Of these, those with PD-MCI were identified based upon scores of ≥ 1.5 SD below mean value in at least two cognitive domains during neuropsychological assessment. Healthy controls without MCI were matched for age and gender. In all, 77 subjects with PD (33 PD-MCI; 44 PD alone) and 24 control subjects were recruited. Certain subjects were further excluded to increase homogeneity of the groups (three with PD-MCI with language or visuospatial deficits as one of two affected domains, 18 with PD alone who scored below criteria on just one cognitive measure, one control subject fulfilling MCI criteria). Imaging comprised functional MRI (fMRI) during a working memory task, and 123I-FP-CIT SPECT scans to evaluate integrity of the nigrostriatal presynaptic dopaminergic system. Overall, cognitive measures were significantly better in the control vs PD group, as well as in the fMRI working memory task. In those with PD both with and without MCI, fMRI blood-oxygen-level-dependent (BOLD) signal demonstrated under-recruitment of frontostriatal regions bilaterally, including right dorsolateral prefrontal cortex, bilateral primary and premotor cortex, occipital cortex, and cerebellum, when compared with control subjects (P < 0.001). Comparing PD-MCI with PD alone, the presence of MCI is associated with further under-recruitment of the anterior cingulate cortex bilaterally (P < 0.001), the right dorsal caudate (P = 0.005), and more weakly with the right dorsolateral prefrontal cortex. Moreover, in the PD-MCI group, right caudate dopamine transporter density measured by 123I-FP-CIT SPECT was less when compared with PD alone (P = 0.08).
Commentary
The concept of PD-MCI is gaining attention and this is the first study to provide information on functional brain activity based upon fMRI. Importantly, the study makes use of recent guidelines for PD-MCI diagnosis, established by a Movement Disorder Society commissioned task force in 2012.1 Similar to previous incident cohorts examined, PD-MCI was found to be high: 43% in this study. PD-MCI is associated with an increased risk of PD dementia (PDD). In the CamPaIGN cohort (in which 17% of incident patients developed dementia within 5 years), baseline semantic fluency and copying a pentagon were significant risk predictors.2 PD-MCI is therefore highly concerning for patient and physician alike, yet we have only limited understanding of the underlying pathophysiology. Moreover, it is likely under-recognized, and there is no established treatment. This study is therefore important in better defining the neural substrate for PD-MCI in early PD. Longitudinal follow-up will be critical in developing a data-driven assessment of prognosis for patients in the clinic. One strength of this study is the use of rigorous inclusion/exclusion criteria, involving both clinical and neuroimaging measures, and the possibility of clinical misdiagnosis (important since it might "enrich" a so-called PD-MCI group with, for example, individuals suffering a Parkinson's Plus syndrome) was addressed by 12-60 months clinical follow-up. Unfortunately, despite the investigators' best attempts to match groups, statistically significant differences between groups existed in the degree of severity of motor symptoms (worse in the PD-MCI vs PD alone group), gender (more men were studied in the total PD and PD-MCI groups), education (higher in the control than total PD group), and mood (Montgomery-Asberg Depression Rating Scale scores were higher in the total PD than control group). In conclusion, it is important to recognize cognitive difficulties, including MCI in PD at all stages, and to openly discuss patient concerns. As yet, it remains to be established whether drugs useful in PDD would be helpful in PD-MCI. Although rivastigmine is well established in providing benefit in PDD, the role of acetylcholinesterase inhibitors and other treatments such as memantine, remain to be established in PD-MCI. PD-MCI therefore remains a critical area of need, but the present study is a significant advance in further defining PD-MCI.
References
1. Litvan I, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guideline. Mov Disord 2012;27:349-356.
2. Williams-Gray CH, et al. The distinct cognitive syndromes of Parkinson's disease: 5-year follow-up of the CamPaIGN cohort. Brain 2009;132:2958-2969.
Multimodal brain imaging demonstrates extensive frontostriatal dysfunction in mild cognitive impairment in early Parkinson's disease.
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