Comparison of disease progression between brain-predominant Parkinson's disease versus Parkinson's disease with body-involvement phenotypes.

Recently, new disease phenotyping has been proposed based on the origin site of α-synuclein pathology in Parkinson's disease (PD). In addition, a great deal of evidences suggested of parallel degeneration in the central nervous system and peripheral nervous system in PD. The myocardial uptake pattern of 123I-meta-iodobenzylguanidine can be a surrogate imaging biomarker for the peripheral nervous system involvement in PD. This study aimed to compare the clinical progression between brain-predominant PD (br-PD) and PD with body-involvement (bo-PD) phenotypes according to the onset of cardiac sympathetic denervation (CSD); the bo-PD group was defined as having the early onset of CSD and the br-PD phenotype was defined as those without initial CSD but later developed CSD in subsequent scans (the delayed onset of CSD). Clinical chracteristics, dopamine transporter activity, and non-motor manifestations were compared between the groups. Motor symptoms and cognitive functions at the initial and follow-up tests [3.1 (±1.4) years interval] were compared between the groups. This study included 29 br-PD and 103 bo-PD patients. Symptoms of rapid-eye-movement sleep behavior disorder, excessive daytime sleepiness, constipation, and orthostatic hypotension were more frequent in the bo-PD than in the br-PD group. The Unified Parkinson's Disease Rating Scale part III score was higher at the initial and increased more steeply during the follow-up period in the bo-PD patients than in the br-PD patients. Although the general cognitive status was not much different between the groups at initial and follow-up, each group showed statistically different cognitive domain profiles and progression patterns. The results demonstrated that the bo-PD group had more severe initial symptoms and steeper motor deterioration than the br-PD group, which indicated that there may be the more pathological involvements of central and peripheral nervous systems in the bo-PD group.

A prospective multi-centre study of susceptibility map-weighted MRI for the diagnosis of neurodegenerative parkinsonism.

OBJECTIVES: This study aimed to compare susceptibility map-weighted imaging (SMwI) using various MRI machines (three vendors) with N-3-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophe nyl)nortropane (18F-FP-CIT) PET in the diagnosis of neurodegenerative parkinsonism in a multi-centre setting. METHODS: We prospectively recruited 257 subjects, including 157 patients with neurodegenerative parkinsonism, 54 patients with non-neurodegenerative parkinsonism, and 46 healthy subjects from 10 hospitals between November 2019 and October 2020. All participants underwent both SMwI and 18F-FP-CIT PET. SMwI was interpreted by two independent reviewers for the presence or absence of abnormalities in nigrosome 1, and discrepancies were resolved by consensus. 18F-FP-CIT PET was used as the reference standard. Inter-observer agreement was tested using Cohen's kappa coefficient. McNemar's test was used to test the agreement between the interpretations of SMwI and 18F-FP-CIT PET per participant and substantia nigra (SN). RESULTS: The inter-observer agreement was 0.924 and 0.942 per SN and participant, respectively. The diagnostic sensitivity of SMwI was 97.9% and 99.4% per SN and participant, respectively; its specificity was 95.9% and 95.2%, respectively, and its accuracy was 97.1% and 97.7%, respectively. There was no significant difference between the results of SMwI and 18F-FP-CIT PET (p > 0.05, for both SN and participant). CONCLUSIONS: This study demonstrated that the high diagnostic performance of SMwI was maintained in a multi-centre setting with various MRI scanners, suggesting the generalisability of SMwI for determining nigrostriatal degeneration in patients with parkinsonism. KEY POINTS: • Susceptibility map-weighted imaging helps clinicians to predict nigrostriatal degeneration. • The protocol for susceptibility map-weighted imaging can be standardised across MRI vendors. • Susceptibility map-weighted imaging showed diagnostic performance comparable to that of dopamine transporter PET in a multi-centre setting with various MRI scanners.

Plasticity in oligodendrocyte lineage progression: An OPC puzzle on our nerves.

Myelin deposition in the central nervous system has been shown to be responsive to experience, with sensory enrichment increasing myelination and sensory or social deprivation decreasing myelination. This process is referred to as "adaptive myelination" or "myelin plasticity" and signifies an essential component of new learning. However, whether these experience-driven adaptations are driven by (a) underlying changes in the generation of myelinating cells, (b) altered interactions between myelin sheath and axon, or (c) a combination of the above remains unclear. It has been suggested that myelination largely follows an "innate" and automatic programme, allowing for a predictable pattern of central nervous system myelin deposition over time. Adaptive myelination is thought to account for more nuanced alterations that do not dramatically shift this pattern, but ultimately drive functional responses. This makes the study of myelin plasticity particularly difficult, as it necessitates being able to clearly and specifically draw boundaries between the innate and adaptive programme. Thus, the field requires a holistic understanding of the remit of innate myelin development, prior to investigation of adaptive myelination. This review will collate literature regarding different aspects of oligodendrocyte and myelin development (namely, oligodendrocyte proliferation, differentiation, death and myelin sheath formation) in an innate context, before discussing how these parameters are proposed to change under adaptive conditions. It is the hope that this review will highlight the need for a comprehensive and integrated approach towards studying both innate and adaptive forms of myelination.

Cortical Thickness from MRI to Predict Conversion from Mild Cognitive Impairment to Dementia in Parkinson Disease: A Machine Learning-based Model.

Background Group comparison results associating cortical thinning and Parkinson disease (PD) dementia (PDD) are limited in their application to clinical settings. Purpose To investigate whether cortical thickness from MRI can help predict conversion from mild cognitive impairment (MCI) to dementia in PD at an individual level using a machine learning-based model. Materials and Methods In this retrospective study, patients with PD and MCI who underwent MRI from September 2008 to November 2016 were included. Features were selected from clinical and cortical thickness variables in 10 000 randomly generated training sets. Features selected 5000 times or more were used to train random forest and support vector machine models. Each model was trained and tested in 10 000 randomly resampled data sets, and a median of 10 000 areas under the receiver operating characteristic curve (AUCs) was calculated for each. Model performances were validated in an external test set. Results Forty-two patients progressed to PDD (converters) (mean age, 71 years ± 6 [standard deviation]; 22 women), and 75 patients did not progress to PDD (nonconverters) (mean age, 68 years ± 6; 40 women). Four PDD converters (mean age, 74 years ± 10; four men) and 20 nonconverters (mean age, 67 years ± 7; 11 women) were included in the external test set. Models trained with cortical thickness variables (AUC range, 0.75-0.83) showed fair to good performances similar to those trained with clinical variables (AUC range, 0.70-0.81). Model performances improved when models were trained with both variables (AUC range, 0.80-0.88). In pair-wise comparisons, models trained with both variables more frequently showed better performance than others in all model types. The models trained with both variables were successfully validated in the external test set (AUC range, 0.69-0.84). Conclusion Cortical thickness from MRI helped predict conversion from mild cognitive impairment to dementia in Parkinson disease at an individual level, with improved performance when integrated with clinical variables. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Port in this issue.

Neuropsychiatric symptoms and striatal monoamine availability in early Parkinson's disease without dementia.

BACKGROUND AND OBJECTIVE: Neuropsychiatric symptoms are relatively common in Parkinson's disease (PD). Many studies have revealed that striatal monoamine availability is associated with specific neuropsychiatric symptoms. This study was aimed to investigate the association between comprehensive neuropsychiatric symptoms and striatal monoamine availability in patients with early PD without dementia. METHODS: A total of 156 newly diagnosed patients with PD without dementia were included. All patients' mental and behavioral problems were assessed with the 12-item Neuropsychiatric Inventory (NPI). They underwent positron emission tomography (PET) with 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and brain magnetic resonance imaging (MRI). Patients were divided into no neuropsychiatric symptoms and neuropsychiatric symptoms groups according to total NPI score. After normalizing the PET images to spatially normalized MRI, regional standardized uptake value ratios (SUVRs) with a volume of interest template were analyzed for the two groups. RESULTS: Ninety-eight patients had more than one neuropsychiatric symptom. The SUVR of the thalamus in neuropsychiatric symptoms group was significantly lower than the SUVR in no neuropsychiatric symptoms group independent of age, sex, disease duration, or severity of motor symptoms. CONCLUSION: Patients with early PD who have neuropsychiatric symptoms had a lower monoamine availability in the thalamus than those with no neuropsychiatric symptoms. This finding suggests that decreased monoamine transporter availability in the thalamus may be an imaging biomarker of neuropsychiatric symptoms in patients with PD.

Partial deletion of p75NTR in large-diameter DRG neurons exerts no influence upon the survival of peripheral sensory neurons in vivo.

The p75 neurotrophin receptor (p75NTR ) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2-month-old mice is not affected following the deletion of p75NTR in large-diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75NTR -mediated neuronal survival in the PNS.

Low thalamic monoamine transporter availability is related to excessive daytime sleepiness in early Parkinson's disease.

Although excessive daytime sleepiness (EDS) is a frequent non-motor dysfunction in Parkinson's disease (PD), the exact pathophysiology remains elusive. This study investigates the relationship between daytime sleepiness and presynaptic monoamine transporter densities of the basal ganglia in patients with early PD. Sixty-four patients with early PD who were evaluated with positron emission tomography (PET) using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane were enrolled. EDS was evaluated with the Epworth Sleepiness Scale (ESS); nocturnal disabilities and nighttime sleep problems were assessed with Parkinson's Disease Sleep Scale 2nd version. PET images were normalized, and the standardized uptake value ratios (SUVRs) for caudate, putamen, globus pallidus, thalamus, and ventral striatum were obtained. The associations between regional SUVRs and ESS scores were analyzed. Among the patients studied, 12 had EDS defined as ESS > 10. The SUVR of the thalamus demonstrated a significant inverse relationship with ESS score, and thalamic monoamine availability appeared to predict EDS when controlling for covariates. The findings suggest that disrupted dopaminergic and serotonergic modulation of the thalamus may be implicated in EDS in PD. This in vivo study might contribute to elucidation of the neurobiological mechanism of hypersomnolence in PD.

"Depressed" caudate and ventral striatum dopamine transporter availability in de novo Depressed Parkinson's disease.

Depression can occur before the onset of motor symptoms in Parkinson's disease (PD) patients. The pathophysiology of depression in PD involves various brain regions and relevant functional circuits. This study investigated whether there exist distinctive patterns of presynaptic monoamine transporter densities in the basal ganglia depending on the degree of depression in patients with PD. A total of 123 early and drug-naïve PD patients were enrolled. Their affective status was evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS), and subjects were subgrouped into one of the following three groups according to their MADRS scores: no depression, mild depression, and moderate-to-severe depression. All patients underwent positron emission tomography (PET) using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane. The PET images were normalized, and differences in the regional standardized uptake value ratios (SUVRs) for each side of the caudate, putamen, globus pallidus, thalamus, and ventral striatum were analyzed and compared between the three groups. A trend analysis was performed across the groups to discern any associations between SUVR values of the basal ganglia and depression severity. The SUVR values of the caudate, anterior caudate nuclei, and ventral striatum declined as MADRS increased. The SUVR values of the striatum showed an inverse dose-dependent trend of antero- and ventroposterior gradient across the groups. This result indirectly revealed the involvement of the associative and limbic circuitry of the brain that are modulated by monoamines in early PD with depression. This might suggest an in vivo causal relationship between the ventral striatum, caudate and depression.

Excessive daytime sleepiness and its impact on quality of life in de novo Parkinson's disease.

Excessive daytime sleepiness (EDS) is one of the most common sleep problems in patients with Parkinson's disease (PD); however, its clinical implications are not clear, especially in early stage, non-medicated PD patients. This study investigated EDS in Korean patients with de novo PD and its impact on quality of life. This cross-sectional study was carried out with 198 PD patients who underwent a structured clinical interview and examination based on common and conventional scales. Motor and nonmotor symptoms were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and Non-Motor Symptoms Scale (NMSS). EDS was evaluated with the Epworth Sleepiness Scale (ESS), the nocturnal disabilities and nighttime sleep problems were assessed with Parkinson's Disease Sleep Scale 2nd version, and quality of life was measured with the Parkinson's Disease Quality of Life 39 (PDQ-39). The relationships between ESS score and each scale were investigated. Among the patients studied, 42 patients had EDS defined as ESS > 10. Patients with EDS had a higher motor burden, greater nocturnal disabilities, more severe non-motor symptoms, and lower quality of life than did patients without EDS. Partial correlations revealed that ESS score was related to PDQ-39 summary index, irrespective of age, body mass index, or disease duration. These results show that EDS can have an immense negative impact on quality of life. The causes of EDS are multifactorial, which complicates its treatment. Further investigations are required to determine the safety and efficacy of potential EDS therapies and to develop novel EDS treatments in PD.

Reliability and validity of the Korean version of the community balance and mobility scale in patients with hemiplegia after stroke.

[Purpose] The aim of this study was to translate and adapt the Community Balance and Mobility Scale (CB&M) into Korean (K-CB&M) and to verify the reliability and validity of scores obtained with Korean patients. [Subjects and Methods] A total of 16 subjects were recruited from St. Vincent's Hospital in South Korea. At each testing session, subjects completed the K-CB&M, Berg balance scale (BBS), timed up and go test (TUG), and functional reaching test. All tests were administered by a physical therapist, and subjects completed the tests in an identical standardized order during all testing sessions. [Results] The inter- and intra-rater reliability coefficients were high for most subscores, while moderate inter-rater reliability was observed for the items "walking and looking" and "walk, look, and carry", and moderate intra-rater reliability was observed for "forward to backward walking". There was a positive correlation between the K-CB&M and BBS and a negative correlation between the K-CB&M and TUG in the convergent validity assessments. [Conclusion] The reliability and validity of the K-CB&M was high, suggesting that clinical practitioners treating Korean patients with hemiplegia can use this material for assessing static and dynamic balance.

Correlation of olfactory function factors with cardiac sympathetic denervation in Parkinson's disease.

BACKGROUND: Hyposmia is a common nonmotor symptom of Parkinson's disease (PD) and reportedly associated with dysautonomia in PD. The smell identification test for measuring olfactory function consists of multiple items to discriminate specific scents. In the present study, factor analysis of the smell identification test was performed, and the correlation of extracted factors with cardiac sympathetic denervation (CSD) in patients with PD was investigated. METHODS: The present study included 183 early PD patients who underwent the Cross-Cultural Smell Identification Test (CC-SIT) and 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy. Factor analysis of 12 items on the CC-SIT was performed using the computed correlation matrix for the binary items, and five smell factors were extracted. Multiple linear regression was performed to determine the correlation of olfactory function with late heart-to-mediastinum (H/M) ratio of 123I-MIBG uptake. RESULTS: The mean CC-SIT score was 6.1 ± 2.6, and 133 patients (72.7%) had CSD. The CC-SIT score and five smell factors were not associated with dopamine transporter uptake or cognitive functions. However, the CC-SIT score significantly correlated with age (P < 0.001) and late H/M ratio (P < 0.001). Factors 1 and 5 showed an increasing trend with larger H/M ratio, although it was not statistically significant (ß = 0.203, P = 0.085 and ß = 0.230, P = 0.085, respectively). Factor 5 significantly correlated with the H/M ratio in PD patients with CSD (ß = 0.676, P = 0.036). DISCUSSION: The results showed olfactory dysfunction to be selectively associated with cardiac sympathetic burden in PD. The correlation of certain factors with CSD indicates the possibility of selective hyposmia in PD patients.