Brain and Systemic Inflammation in De Novo Parkinson's Disease

Objective

To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD).

Background

Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression.

Methods

We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with ¹⁸F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented.

Results

Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased ¹⁸F-DPA-714 signal in PD subjects. ¹⁸F-DPA-714 signal correlated with several cognitive measures and some chemokines.

Conclusions

¹⁸F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease

Background

Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [¹²³I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density.

Objectives

To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD.

Methods

We assessed clinical features, the peripheral immune profile, and striatal [¹²³I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort).

Results

A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: β = −0.01, p < 0.001; PPMI-cohort: β = −0.05, p = 0.05) and the putamen (primary-cohort: β = −0.05, p = 0.02; PPMI-cohort: β = −0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: β = +0.09, p < 0.05; PPMI-cohort: β = +0.11, p = 0.02) and the putamen (primary-cohort: β = +0.09, p < 0.05, PPMI-cohort: β = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: β = −0.05, p = 0.02; PPMI-cohort: β = 0, p = 0.94; putamen; primary-cohort: β = −0.04, p = 0.08; PPMI-cohort: β = −0.01, p = 0.73).

Conclusions

Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration—[18F]FDG‐PET

In Parkinson's disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [¹⁸F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinson's disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty‐two Parkinson's patients (10 demented) and seven controls underwent FDG‐PET. A metabolic index (mean relative uptake in typically affected regions) was calculated for each patient and compared with scores for cognition [Minimental State Examination (MMSE)], motor performance [Unified Parkinson's Disease Rating Scale (UPDRS III)” and behavior (Neuropsychiatric Inventory). In stepwise linear regression analysis, MMSE (P < 0.001) score showed the only significant effect. Estimated sensitivity and specificity for DSM‐IV diagnosis of dementia were high for the metabolic index (MI), with 91 and 100%. Taken together, the presented data indicate that cerebral hypometabolism in Parkinson's disease is primarily associated with cognitive impairment. © 2009 Movement Disorder Society     

Dopaminergic innervation of the human striatum in Parkinson's disease.

In Parkinson's disease (PD), dopaminergic input to the caudate nucleus and a band of putaminal tissue abutting the external globus pallidus seems well preserved on immunohistochemical staining for the dopamine transporter. Counting of dopaminergic terminals showed that terminal density in these regions in PD was the same as that in controls, which indicates that input is truly preserved and not a consequence of a compensatory upregulation of metabolism in a reduced pool of surviving terminals. When the branching pattern of dopaminergic axons coursing through the globus pallidus was examined, we found no evidence for increased axonal sprouting in PD that might have contributed to preservation of dopaminergic input to the putamen or caudate nucleus. Although terminal counting indicated that anatomic input was preserved to parts of the striatum, dopamine uptake site density in these regions was reduced significantly. This suggests that the impact of disease in these areas is more profound than was thought previously.     

Memory Phenotypes In Early,De Novo Parkinson's Disease Patients with Mild Cognitive Impairment

Background

Memory deficits in mild cognitive impairment related to Parkinson's disease (PD-MCI) are quite heterogeneous, and there is no general agreement on their genesis.

Objectives

To define memory phenotypes in de novo PD-MCI and their associations with motor and non-motor features and patients’ quality of life.

Methods

From a sample of 183 early de novo patients with PD, cluster analysis was applied to neuropsychological measures of memory function of 82 patients with PD-MCI (44.8%). The remaining patients free of cognitive impairment were considered as a comparison group (n = 101). Cognitive measures and structural magnetic resonance imaging-based neural correlates of memory function were used to substantiate the results.

Results

A three-cluster model produced the best solution. Cluster A (65.85%) included memory unimpaired patients; Cluster B (23.17%) included patients with mild episodic memory disorder related to a “prefrontal executive-dependent phenotype”; Cluster C (10.97%) included patients with severe episodic memory disorder related to a “hybrid phenotype,” where hippocampal-dependent deficits co-occurred with prefrontal executive-dependent memory dysfunctions. Cognitive and brain structural imaging correlates substantiated the findings. The three phenotypes did not differ in terms of motor and non-motor features, but the attention/executive deficits progressively increased from Cluster A, through Cluster B, to Cluster C. This last cluster had worse quality of life compared to others.

Conclusions

Our results demonstrated the memory heterogeneity of de novo PD-MCI, suggesting existence of three distinct memory-related phenotypes. Identification of such phenotypes can be fruitful in understanding the pathophysiological mechanisms underlying PD-MCI and its subtypes and in guiding appropriate treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Position Emission Tomography/Single‐Photon Emission Tomography Neuroimaging for Detection of Premotor Parkinson's Disease

Premotor Parkinson's disease (PD) refers to a prodromal stage of Parkinson's disease (PD) during which nonmotor clinical features may be present. Currently, it is difficult to make an early diagnosis for premotor PD. Molecular imaging with position emission tomography (PET) or single‐photon emission tomography (SPECT) offers a wide variety of tools for overcoming this difficulty. Indeed, molecular imaging techniques may play a crucial role in diagnosing, monitoring and evaluating the individuals with the risk for PD. For example, dopaminergic dysfunctions can be identified by detecting the expression of vesicular monoamine transporter (VMAT2) and aromatic amino acid decarboxylase (AADC) to evaluate the conditions of dopaminergic terminals functions in high‐risk individuals of PD. This detection provides a sensitive and specific measurement of nonmotor symptoms (NMS) such as olfactory dysfunction, sleep disorders, and psychiatric symptoms in the high‐risk patients, especially at the premotor phase. Molecular imaging technique is capable of detecting the dysfunction of serotonergic, noradrenergic, and cholinergic systems that are typically associated with premotor manifestations. This review discusses the importance of SPECT/PET applications in the detection of premotor markers preceding motor abnormalities with highlighting their great potential for early and accurate diagnosis of premotor symptoms of PD and its scientific significance.     

Dopaminergic basis for impairments in functional connectivity across subdivisions of the striatum in Parkinson's disease

The pathological hallmark of Parkinson's disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinson's disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting‐state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinson's disease, both “on” and “off” their regular dopaminergic medications, along with 40 age‐matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinson's disease in the “off” state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson's disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson's disease “off” state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinson's disease “on” state, these relationships were absent in Parkinson's disease when in the “off” state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine denervation in Parkinson's disease. Hum Brain Mapp 36:1278–1291, 2015. © 2014 Wiley Periodicals, Inc .     

Serotonergic markers in Parkinson's disease and levodopa‐induced dyskinesias

Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l ‐dopa)–induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l ‐dopa–induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age‐matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P < 0.0001) and the dopamine transporter (P < 0.0001) in the striatum, and dopaminergic neurons (P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l ‐dopa–induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD. © 2015 International Parkinson and Movement Disorder Society     

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.     

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease

Background

Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation.

Objective

The aim was to investigate SN free water values across prodromal and clinical stages of PD.

Methods

Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients.

Results

PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time.

Conclusions

The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.