Table 3 Dopaminergic basis of NMSS Domain 3 (cognitive impairment) pathophysiology in PD
Author | Year | NMSs | Radiotracer | Demographics | Results | Analysis |
|---|---|---|---|---|---|---|
Holthoff et al.105 | 1994 | Cognitive impairment | 18F-DOPA | 7 pairs of twins discordant for PD underwent PET imaging. | Twin groups (PD and control) have significantly reduced 18F-DOPA uptake (p = <0.05). PD twins presented this reduction globally throughout the striatum. The control twins showed impaired 18F-DOPA uptake in at least one striatal region. Verbal memory processing was most impaired in PD twins (p = <0.05), however 6 co-twins also presented similarly significant impairment. | This is an important PET study, first to address genetic susceptibility and in vitro imaging in PD. |
Marie et al.112 | 1999 | Cognitive impairment | 11C-S-NMF | 10 non-demented, non-depressed PD patients underwent frontal executive tests, OA, CAL, and BPP. | A strongly significant correlation was found between right caudate binding and OA performance (r = −0.79, p = <0.02). Somewhat less significant, but converse correlations were observed between putamen binding and CAL performance (r = 0.71, 0 = <0.05; r = 0.64, p = <0.05; left and right putamen respectively). No such significant correlations were noted with BPP. | Data suggests caudate dopaminergic dysfunction may be the cause of PD-executive function impairment. This is another important early study in a small number of patients but its conclusions have been supported in succeeding studies. |
Müller et al.114 | 2000 | Cognitive impairment | 123I-β-CIT | 20 PD patients and 20 healthy controls underwent evaluation with MMSE, DS-F, DS-B, WMS-R, DOT, and RS. | Significant correlations between prefrontal task performance and β-CIT ratios for both the caudate head and putamen were seen (p = <0.05). Reading performance did not correlate however. | This is an early study which has been supported by later studies showing nigrostriatal dopaminergic dysfunction which correlates to the cognitive status in PD patients. The authors scanned and assessed patients in the “on” state but did not present any data on LEDD and whether there are correlations between LEDD and test scores. This could have influenced the results strongly since the authors claim that dopaminergic dysfunction may be the cause for executive function impairment. |
Rinne et al.111 | 2000 | Cognitive impairment | 18F-DOPA | 28 PD patients and 16 healthy controls underwent PET imaging alongside cognitive tests including MMSE and neuropsychological evaluation | There was reduced FDOPA uptake in the putamen (36% of control mean, p = <0.001), caudate (61% of control mean, p = <0.001) in PD patients, and frontal cortex in relation to neuropsychiatric tests in PD patients. | There may be dopaminergic dysfunction in cognitive impairment PD. One of the earliest controlled PET studies addressing cognitive and dopaminergic function in PD. The data has been subsequently replicated in many studies (see below). |
Duchesne et al.116 | 2002 | Cognitive impairment | 123I-β-CIT | 10 PD patients and 10 controls underwent a range of cognitive tests. | The simultaneous processing condition but not the selective or the competitive conditions took significantly more time for patients with PD-OFF than for either the control subjects or the patients with PD-ON. PD patients with PD-OFF took significantly more time than controls (p = <0.01) and PD-ON patients (p = <0.05) for the simultaneous processing condition only (not selective/ competitive conditions). | An older small controlled study, which has been replicated several times suggesting nigrostriatal dopaminergic dysfunction may be implicated in PD cognitive processing, according to the results. |
Ito et al.106 | 2002 | Cognitive impairment | 18F-DOPA | 10 non-demented PD patients, 10 PDD patients and 15 normal controls were recruited. Cognitive tests included MMSE. | PDD had a reduced 18F-DOPA uptake in bilateral striatum, midbrain and anterior cingulate area (p = <0.001). Relative differences in uptake were observed bilaterally in the caudate, anterior cingulate gyrus and ventral striatum between PD and PDD patients (p = <0.001). | The study suggests that PDD is associated with impaired mesolimbic and caudate function, although cognitive assessments could have been more detailed. |
Brück et al.99 | 2005 | Cognitive impairment | 18F-DOPA | 21 non-demented PD patients and 24 healthy controls underwent imaging and multiple cognitive tests including MMSE, CERAD, WAIS-R. | PD patients had, as was expected based on previous work, decreased striatal 18F-DOPA uptake compared to controls, however much of the cortex showed increased uptake. DLPFC 18F-DOPA uptake correlated with VIG reaction time (p = 0.013) and both the MFC and AC showed negative correlation with classic Stroop effect (p = 0.01). No significant correlations were found between cognitive testing and striatal uptake. | This is an important study showing increased cortical DaT uptake and a possible compensatory dopaminergic role in the brain network. |
Cheesman et al.107 | 2005 | Cognitive impairment | 18F-DOPA | 16 non-demented, non-depressed PD patients evaluated using TOL-SPT, VWMT. | Significant positive covariation was found between the right caudate and TOL score as determined by statistical paramertric mapping (p = 0.031). Similar covariation was seen between the left anterior putamen and performance in VWMT testing (p = 0.012). | A link between striatal dopaminergic defect and early executive function impairment in PD could be suggested on the basis of this study. But no control group was used. Surprisingly, PD motor patterns did not correlate with putamen DaT binding. |
Cropley et al.104 | 2008 | Cognitive impairment | 18F-DOPA, 11C-NNC 112 | 15 non-demented non- depressed PD patients and 14 healthy controls. MMSE, DRS-2, WCST, and BDI were conducted. | No significant regional differences were observed between patients and controls with regards to D1-receptor density and in overall frontostriatal performance. | Analysis suggests that decreases in putaminal Ki predicted WCST performance in PD. This is an multimodal imaging study and as such, draws importance to advance in DA receptor basis of frontal cognition. |
Jokinen et al.103 | 2009 | Cognitive impairment | 18F-DOPA | 19 treated PD patients and 21 healthy controls took part with 12 undergoing cognitive tests including CERAD, WMS-R, WAIS-R, MMSE. | A positive correlation was found between the 18F-DOPA uptake of left ventral caudate and verbal memory (r = 0.72, p = 0.009), right ventral caudate and visual memory (r = 0.61, p = 0.037), and right ventral caudate and CERAD (r = 0.77, p = 0.003). | The analysis points towards reduced dopaminergic activity being able to impair cognitive performance tests. This is a powerful PET study with the use of controls. |
Arnaldi et al.109 | 2012 | Cognitive impairment | 123I-FP-CIT | 30 de novo, drug naïve PD patients underwent MMSE, ADL, GDS and other neuropsychiatric assessments. | Verbal memory and language task performance were significantly impaired in the posterior parieto-temporal region of the less affected side and was predicted by Dat uptake (r = 0.42, p = 0.0005). DaT caudate uptake in the less affected hemisphere combined with UPDRS-III score predicted decline in both executive (r = 0.54, p = 0.0001) and visuospatial (r = 0.56, p = 0.0001) function. | A dysfunctional dopaminergic basis is therefore proposed for some level of cognitive decline in PD. The strength of this study is the assessment in a reasonable drug naïve PD population supporting the role of dysfunctional dopaminergic basis and cognitive decline in PD. |
Niethammer et al.108 | 2013 | Cognitive impairment | 18F-DOPA, 123I-FP-CIT | 17 RH non-demented PD patients underwent imaging including PDCP. | The authors find a strong inverse correlation between PDCP scores and DaT binding in the caudate nucleus (r = −0.67, p = <0.005)) and putamen (r = −0.51, p = <0.05). | They therefore suggest there to be dopaminergic loss between caudate and the cognitive-network in PD. This is an interesting study but does not add any substantial new information. |
Pellecchia et al.115 | 2015 | Cognitive impairment | 123I-FP-CIT | 34 de novo, drug-naïve PD patients separated into those with (n = 15) and without (n = 19) MCI underwent neuropsychological battery. | DAT availability in average striatum, caudate, and putamen (more and less affected) was lower in MCI and in non-MCI patients with PD but not significantly different. | There’s some suggestions of striatal DA depletion contributing to cognitive defect in PD. This is an interesting study in drug naïve PD and addressing MCI vs. non-MCI PD. Supports a subtype concept and also a non-dopaminergic origin of MCI even in early PD. |
