The effect of age on motor deficits and cerebral glucose metabolism of Parkinson's disease

Lee MS, Lyoo CH, Ryu YH, Lim HS, Nam CM, Kim HS, Rinne JO. The effect of age on motor deficits and cerebral glucose metabolism of Parkinson’s disease.
Acta Neurol Scand: 2011: 124: 196–201.
© 2010 John Wiley & Sons A/S. Background – No systematic study has been made to separate age‐related clinical deterioration and dysfunctional brain areas from those associated with Parkinson’s disease (PD). Methods – This study included 73 de novo patients with PD and 43 age‐matched controls. All subjects underwent [¹⁸F]‐fluorodeoxy glucose (FDG) positron emission tomography studies. The severity of parkinsonian motor deficit was measured using unified PD rating scale (UPDRS) motor scores. Multiple linear regression analysis was used to identify those parkinsonian motor deficits for which severity was correlated with the age of the patients and to locate brain areas in which normalized FDG uptake values were inversely correlated with the age of the subjects. Results – Patient age was positively correlated with total UPDRS motor scores and with subscores for bradykinesia and axial motor deficits, but not with subscores for tremor and rigidity. In the control group, an age‐related decline in glucose uptake was found only in the cingulate cortex. However, in the patient group, an inverse correlation between age and glucose uptake was observed in the prefrontal, cingulate, orbitofrontal, perisylvian areas, caudate, and thalamus. Conclusions – In PD, widespread age‐related decline in cerebral function may exaggerate the deterioration associated with bradykinesia and the axial motor deficits associated with nigral neuronal loss.     

Striatal subregional 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD.     

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11C]UCB-J and [18F]FDG PET Study

Background

Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor.

Objective

The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease.

Method

Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET and [¹¹C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level.

Results

We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density.

Conclusion

Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [¹⁸F]FDG PET and [¹¹C]UCB-J PET in Lewy body patients. The magnitude of reduced [¹⁸F]FDG uptake was greater than the corresponding decline in [¹¹C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Distinct patterns of regional cerebral glucose metabolism in Parkinson's disease with and without mild cognitive impairment

There is no consensus with regard to the clinical and neuroimaging characteristics of prodromal dementia in Parkinson's disease (PD). To delineate functional neuroimaging features of PD with mild cognitive impairment (PDMCI) and with no cognitive impairment (PDNC), we compared regional cerebral glucose metabolism (CMRglc) amongst 13 patients with PDMCI, 27 with PDNC, and 13 healthy controls. The PDNC patients had limited areas of hypometabolism in the frontal and occipital cortices. In the PDMCI patients, there were extensive areas of hypometabolism in the posterior cortical regions, including the temporo‐parieto‐occipital junction, medial parietal, and inferior temporal cortices. The present results suggest that posterior cortical dysfunction is the primary neuroimaging feature of PD patients at risk for dementia. © 2009 Movement Disorder Society     

Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson's disease

Summary The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on striatal uptake of 6-[¹⁸F]fluoro-L-dopa (FDOPA) was studied with PET both without and with entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k₃R₀), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (K_i) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the K_i remained virtually unchanged.Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.     

轻度认知障碍^18F-FDG PET显像的研究进展

轻度认知障碍(MCI)的病理改变与早期或临床前期阿尔茨海默病(AD)相似,MCI患者已经成为预测AD是否发生、有效延缓或早期干预治疗AD的最适群体,FDG PET脑功能显像可反映局部脑内葡萄糖代谢率,为MCI的病理学研究及临床诊断提供一种新的可靠工具.正确认识MCI与正常脑老化、AD脑葡萄糖代谢的不同、FDG PET图像特征及影响因素、对于预测病程及早期干预治疗、检测治疗效果、预防AD的发生及提高老年人生活质量有着重要的意义.     

Progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease using [18F]CFT PET

The aim of this study was to investigate the progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease (PD). We studied 12 patients with early PD and 11 healthy controls with a dopamine transporter ligand 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT) positron emission tomography (PET). The PET scan was carried out twice with an average interval of 2.2 years. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. At the first PET scan in PD patients, the [(18)F]CFT uptake in the anterior putamen was 1.92 +/- 0.67, which was 45% of the control mean, and in the posterior putamen 1.02 +/- 0.55, being only 27% of the control mean. For the caudate nucleus the corresponding figure was 2.55 +/- 0.58 (71% of the control mean). The uptake ratios had declined significantly by the time of the second PET scan and the absolute annual rate of decline of the tracer uptake was 0.23 +/- 0.14 (P < 0.001) in the anterior putamen, 0.13 +/- 0.13 (P = 0.005) in the posterior putamen, and 0.20 +/- 0.15 (P < 0.001) in the caudate nucleus. There was a statistically significant difference of the decline in the tracer uptake between the anterior and posterior putamen (P = 0.033). When the rate of progression was calculated compared to the normal control mean, the rate of annual decline was 5.3% in the anterior putamen, 3.3% in the posterior putamen, and 5.6% in the caudate nucleus, without significant changes among striatal subregions (P = 0.10). When ipsi- and contralateral sides were analyzed separately, the absolute decline of [(18)F]CFT uptake in the putamen was higher in the side ipsilateral to the predominant symptoms than in the contralateral side (P = 0.035 for anterior putamen and P = 0.026 for posterior putamen). In the caudate nucleus the absolute decline was not different between ipsi- and contralateral sides (P = 0.76). In healthy controls, no significant decline of [(18)F]CFT uptake was detected. The results are suggestive of slower progression in the posterior putamen, where the disease is more advanced, but studies to follow up the same patient at several time points are needed to resolve this question. Synapse 48:109-115, 2003.     

Selective diplopia in Parkinson's disease: A special subtype of visual hallucination?

Diplopia is sometimes reported by patients with Parkinson's disease (PD) without apparent oculomotor disorders. We assessed clinical features and associated oculomotor and perceptual performance in 14 patients (6 male, 8 female) with PD with a peculiar type of selective diplopia. Duplication of images was confined to single objects or persons, occurred repetitively, and lasted few seconds in all subjects. Frequency of episodes ranged from several episodes per day to three episodes per year. In six of seven subjects undergoing comprehensive ophtalmological examination, subtle ocular disorders (heterophoria, strabism, etc.) were found. Nine of 14 patients were suffering from current or previous visual hallucinations and 3 more patients developed hallucinations within 3 years of diplopia onset. Selective diplopia of isolated single objects and persons in PD is possibly related to hallucinosis and minor ocular disturbances seem to be a triggering factor for this peculiar type of misperception.     

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.     

Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early‐stage PD patients and in seven healthy matched‐control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [¹¹C]DASB. Depressed PD patients displayed a wide‐spread increase (8–68%) in [¹¹C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [¹¹C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[¹¹C]DASB findings in major depression, the present preliminary data suggest that increased [¹¹C]DASB binding, possibly reflecting greater serotonin transporter density (up‐regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society     

Brain energization in response to deep brain stimulation of subthalamic nuclei in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in a subgroup of medically refractory patients with Parkinson''s disease (PD). Here, we compared resting-state ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography images in the stimulator off (DBS_OFF) and on (DBS_ON) conditions in eight PD patients in an unmedicated state, on average 2 years after bilateral electrode implantation. Global standardized uptake value (SUV) significantly increased by ∼11% in response to STN-DBS. To avoid any bias in the voxel-based analysis comparing DBS_ON and DBS_OFF conditions, individual scan intensity was scaled to a region where FDG-SUV did not differ significantly between conditions. The resulting FDG-SUV ratio (FDG-SUVR) was found to increase in many regions in response to STN-DBS including the target area of surgery, caudate nuclei, primary sensorimotor, and associative cortices. Contrary to previous studies, we could not find any regional decrease in FDG-SUVR. These findings were indirectly supported by comparing the extent of areas with depressed FDG-SUVR in DBS_OFF and DBS_ON relatively to 10 normal controls. Altogether, these novel results support the prediction that the effect of STN-DBS on brain activity in PD is unidirectional and consists in an increase in many subcortical and cortical regions.     

Functional integration changes in regional brain glucose metabolism from childhood to adulthood

The aim of this study was to investigate the age‐related changes in resting‐state neurometabolic connectivity from childhood to adulthood (6–50 years old). Fifty‐four healthy adult subjects and twenty‐three pseudo‐healthy children underwent [¹⁸F]‐fluorodeoxyglucose positron emission tomography at rest. Using statistical parametric mapping (SPM8), age and age squared were first used as covariate of interest to identify linear and non‐linear age effects on the regional distribution of glucose metabolism throughout the brain. Then, by selecting voxels of interest (VOI) within the regions showing significant age‐related metabolic changes, a psychophysiological interaction (PPI) analysis was used to search for age‐induced changes in the contribution of VOIs to the metabolic activity in other brain areas. Significant linear or non‐linear age‐related changes in regional glucose metabolism were found in prefrontal cortices (DMPFC/ACC), cerebellar lobules, and thalamo‐hippocampal areas bilaterally. Decreases were found in the contribution of thalamic, hippocampal, and cerebellar regions to DMPFC/ACC metabolic activity as well as in the contribution of hippocampi to preSMA and right IFG metabolic activities. Increases were found in the contribution of the right hippocampus to insular cortex and of the cerebellar lobule IX to superior parietal cortex metabolic activities. This study evidences significant linear or non‐linear age‐related changes in regional glucose metabolism of mesial prefrontal, thalamic, mesiotemporal, and cerebellar areas, associated with significant modifications in neurometabolic connectivity involving fronto‐thalamic, fronto‐hippocampal, and fronto‐cerebellar networks. These changes in functional brain integration likely represent a metabolic correlate of age‐dependent effects on sensory, motor, and high‐level cognitive functional networks. Hum Brain Mapp 37:3017–3030, 2016. © 2016 Wiley Periodicals, Inc .     

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.     

Visual hallucinations in Parkinson's disease: Theoretical models

One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson's disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson's disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading hypothetical frameworks for visual hallucinations in Parkinson's disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention. © 2014 International Parkinson and Movement Disorder Society     

Monosymptomatic resting tremor and Parkinson's disease: a multitracer positron emission tomographic study.

We sought to elucidate the relationship between monosymptomatic resting tremor (mRT) and Parkinson's disease (PD). We studied eight mRT patients (mean Hoehn and Yahr [H&Y], 1.1 +/- 0.4), eight patients with PD (mean H&Y, 1.5 +/- 0.8), who showed all three classic parkinsonian symptoms, and seven age-matched healthy subjects. Subjects underwent cerebral magnetic resonance imaging (MRI) and multitracer positron emission tomography (PET) with 6-[(18)F]fluoro-L-dopa (F-dopa), [(18)F]fluorodeoxyglucose (FDG), and [(11)C]raclopride (RACLO). PD and mRT patients did not show significant differences in F-dopa-, RACLO-, or FDG-PET scans. In F-dopa- and RACLO-PET, significant differences between the pooled patient data and control subjects were found for the following regions: anterior and posterior putamen ipsilateral and contralateral to the more affected body side, and ipsilateral and contralateral putaminal gradients of the K(i) values. Furthermore, we found a difference for the normalized glucose values of the whole cerebellum between the control group (0.94 +/- 0.06) and PD patients (1.01 +/- 0.04; P < 0.05) but not for the mRT group (0.97 +/- 0.03). Our findings indicate that monosymptomatic resting tremor represents a phenotype of Parkinson's disease, with a nearly identical striatal dopaminergic deficit and postsynaptic D2-receptor upregulation in both patient groups. We suggest that the cerebellar metabolic hyperactivity in PD is closer related to akinesia and rigidity rather than to tremor.     

Visual form discrimination from texture cues: A PET study

With the purpose of localising the cerebral cortical areas participating in the discrimination of visual form generated exclusively by texture cues, we measured changes in regional cerebral blood flow (rCBF) with positron emission tomography (PET) and ¹⁵O-butanol as the tracer. The subjects performed two odd-one-out discrimination tasks: a form-from-texture discrimination task (in which a visual form was defined by differences in texture) and its reference task, the discrimination of texture. During task performance, activated fields were present bilaterally in the primary visual cortex and its immediate extrastriate cortex, the right lateral occipital gyrus, bilaterally in the fusiform and superior temporal gyri and posterior parts of the superior parietal lobules, along the medial bank of the right intraparietal sulcus, and in the right supramarginal gyrus. Other fields were found in the cingulate and prefrontal cortex. The findings demonstrate that the discrimination of visual form as defined by texture engages cortical fields that are widely distributed in the human brain. In the visual cortex, the activated fields are present in both the occipito-temporal and occipito-parietal visual areas. These results suggest that the perception and discrimination of forms in the visual system requires the joint activation of neuronal populations in the visual cortex. Hum. Brain Mapping 6:115–127, 1998. © 1998 Wiley-Liss, Inc.     

Visual hallucinations as REM sleep behavior disorders in patients with Parkinson's disease.

To clarify whether visual hallucinations in patients with Parkinson's disease (PD) are related to rapid eye movement (REM) sleep, nocturnal polysomnographic variables were compared between a group with hallucinations (hallucinators, n = 14) and a group without hallucinations (nonhallucinators, n = 8). A multiple sleep latency test (MSLT) was performed on 3 hallucinators, and the content of dreams during daytime REM sleep was investigated. The efficacy of clonazepam, a standard treatment choice for REM sleep behavior disorders, was investigated in 8 hallucinators. Nocturnal polysomnograms of the hallucinators showed a higher amount of stage 1-REM sleep with tonic electromyogram (stage 1-REM) than the nonhallucinators, and the reported occurrences of nocturnal hallucinations corresponded with the periods of stage REM or stage 1-REM in most hallucinators. The frequency of sleep onset REM periods (SOREMP) on the MSLT were pathologically high in the hallucinators, and the content of the dreams during the MSLT period was quite similar to their hallucinations. During clonazepam treatment, the frequency of hallucinatory symptoms decreased in 5 of 8 hallucinators. These results indicate that visual hallucinations in PD are likely to be related to a REM sleep disorder manifested as the appearance of both stage 1-REM during the night and SOREMP in the daytime.