Late-stage Parkinson's Disease Research Articles

WED 128 Care and unmet needs in late-stage parkinsonism: a qualitative study

AimTo explore experiences and views about care needs and service use by people with late-stage Parkinsonism.MethodTen participants at Hoehn and Yahr stage 4 or 5 were interviewed using semi-structured open ended questions and qualitative content analysis.FindingsDespite severe disability, participants expressed their desire to maintain normality of activities and interests in their lives. Many perceived that even though health care was provided by professionals they could do nothing more for them. Participants experienced having to ‘fit-in’ to service structures that did not always accommodate their complex needs. The quality of relationships with health care professionals and formal carers shaped perception of service provision and mediated adaptation. Informal support and knowledge on disease management were key factors in their perceived ability to remain in control and to enable normal functioning. There was common reluctance to discuss, and uncertainty about, future plans. For example, moving to a residential nursing home was perceived an undesirable but potentially necessary only option for future care.ConclusionAddressing these findings including greater flexibility of healthcare structures and better future planning could increase ability of patients with late-stage parkinsonism to remain at home and improve quality of life of patients in this late disease stage.

Safinamide in the management of patients with Parkinson's disease not stabilized on levodopa: a review of the current clinical evidence.

Safinamide (Xadago®) is a novel medication with both dopaminergic and non-dopaminergic effects, approved first by the European Commission and more recently by the US Food and Drug Administration (FDA) as an adjunctive treatment to carbidopa/levodopa in patients with mid- to late-stage Parkinson’s disease (PD) and motor fluctuations. It works through multiple mechanisms, namely as a reversible selective monoamine oxidase-B inhibitor and through modulation of glutamate release. Safinamide is extensively metabolized via oxidation to several inactive metabolites that are excreted primarily through the urine. Several large Phase III clinical trials of patients with advanced PD with motor fluctuations have shown that safinamide, administered orally at doses of 50–100 mg daily, increased ON time with no or non-troublesome dyskinesia, decreased daily OFF time, improved overall motor function (as measured by Unified Parkinson’s Disease Rating Scale [UPDRS] part III total score), and quality of life (as measured by Clinical Global Impression-Change and 39-item Parkinson’s Disease Questionnaire). In large clinical trials of patients with early PD on a single dopamine agonist, safinamide administered orally at a dose of 100 mg daily improved overall motor function as measured by UPDRS part III total score; however, some of the results reported were exploratory. Safinamide is generally well-tolerated and safe, with few to no treatment-related adverse events. Safinamide does not cause new or worsening dyskinesia and may be able to reduce this symptom in patients reporting it at baseline. Evidence suggests that safinamide is a good option for add-on therapy to carbidopa/levodopa in patients with advanced PD with motor complications, but there is still insufficient evidence to recommend it as monotherapy or add-on therapy in patients with early PD.

Neuropalliative care aspects in patients with Parkinson's disease

Palliative Care in Parkinson's Disease (PD) is of growing interest. The burden of symptoms of late-stage PD patients is similar or even higher than those of patients suffering from oncological diseases. However, patients suffering from advanced phases of PD have tremendous unmet palliative care needs. The disease trajectories are often difficult to define, and initiation of palliative care approach has to be chosen carefully. Swallowing difficulties define the onset of the late and palliative phase and have to be seen as a landmark for palliative care involvement. Here we provide an approach to palliative care in PD in the final phase and also care for the relatives.

Dopaminergic Effect on Non-Motor Symptoms in Late Stage Parkinson's Disease.

Non-motor symptoms (NMS) are common in late stage Parkinson's disease (PD), as the frequency and severity of most of these symptoms increase with advancing disease. To assess effect of dopaminergic therapy on NMS in late stage PD and to investigate relationships between dopaminergic effect on NMS and on motor function. Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. Dopaminergic effect on non-motor symptomatology was assessed by the modified version of the Non-Motor Symptoms Scale (NMSS) in the "off" and the "on" state during a standardized L-dopa test, in parallel also assessing motor function. NMS were common and many of the symptoms occurred in >80% of the individuals. The highest NMSS scores were seen within the NMSS domains 3: mood/apathy and 7: urinary in both the "off" and the "on" state. There was a statistically significant (p < 0.001) improvement in the modified NMSS total score (median) from 79 in "off" to 64 in "on". There were statistically significant differences between the "off" and the "on" state for domains 2: sleep/fatigue, 3: mood/apathy, 5: attention/memory, 6: gastrointestinal and 7: urinary. The differences in the NMSS score between the "off" and the "on" state were in general larger for motor responders than for motor non-responders. In motor non-responders, differences of the NMSS score between the "off" and the "on" state were found for the total score, domain 3: mood/apathy and its item 11-flat moods. There is an effect of dopaminergic medication on NMS in late stage PD, to some extent also for those with a non-significant response on motor function during L-dopa test. It is therefore of importance to optimize dopaminergic therapy in order to give the most effective symptomatic treatment possible.

Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson's patients.

Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P ≤ 0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time × group, P = 0.002), whereas quantitative susceptibility mapping did not (P = 0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time × group, P ≥ 0.084), although both decreased longitudinally (time effect, P ≤ 0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P ≤ 0.006), but showed a significantly faster increase only in later-stage PD (time × group, P < 0.0001) that correlated with changes in nonmotor symptoms (r = 0.746, P = 0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P ≤ 0.002), but showed a longitudinal decrease (time × group, P = 0.004) only in later-stage PD that correlated with changes in motor signs (r = 0.837, P < 0.001). Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation

BackgroundHigh frequency (∼130 Hz) deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease (PD). Direct modulation of the hyperdirect pathway, defined as cortical layer V pyramidal neurons that send an axon collateral to the subthalamic nucleus (STN), has emerged as a possible component of the therapeutic mechanisms. However, numerous questions remain to be addressed on the basic biophysics of hyperdirect pathway stimulation. ObjectiveQuantify action potential (AP) initiation, propagation, and cortical invasion in hyperdirect neurons during subthalamic stimulation. MethodsWe developed an anatomically and electrically detailed computational model of hyperdirect neuron stimulation with explicit representation of the stimulating electric field, axonal response, AP propagation, and synaptic transmission. ResultsWe found robust AP propagation throughout the complex axonal arbor of the hyperdirect neuron. Even at therapeutic DBS frequencies, stimulation induced APs could reach all of the intracortical axon terminals with ∼100% fidelity. The functional result of this high frequency axonal driving of the thousands of synaptic connections made by each directly stimulated hyperdirect neuron is a profound synaptic suppression that would effectively disconnect the neuron from the cortical circuitry. ConclusionsThe synaptic suppression hypothesis integrates the fundamental biophysics of electrical stimulation, axonal transmission, and synaptic physiology to explain a generic mechanism of DBS.

Dopaminergic Effect on Non-Motor Symptoms in Late Stage Parkinson's Disease.

Background: Non-motor symptoms (NMS) are common in late stage Parkinson's disease (PD), as the frequency and severity of most of these symptoms increase with advancing disease. Objective: To assess effect of dopaminergic therapy on NMS in late stage PD and to investigate relationships between dopaminergic effect on NMS and on motor function. Method: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. Dopaminergic effect on non-motor symptomatology was assessed by the modified version of the Non-Motor Symptoms Scale (NMSS) in the "off" and the "on" state during a standardized L-dopa test, in parallel also assessing motor function. Results: NMS were common and many of the symptoms occurred in>80% of the individuals. The highest NMSS scores were seen within the NMSS domains 3: mood/apathy and 7: urinary in both the "off" and the "on" state. There was a statistically significant (p<0.001) improvement in the modified NMSS total score (median) from 79 in "off" to 64 in "on". There were statistically significant differences between the "off" and the "on" state for domains 2: sleep/fatigue, 3: mood/apathy, 5: attention/memory, 6: gastrointestinal and 7: urinary. The differences in the NMSS score between the "off" and the "on" state were in general larger for motor responders than for motor non-responders. In motor non-responders, differences of the NMSS score between the "off" and the "on" state were found for the total score, domain 3: mood/apathy and its item 11-flat moods. Conclusion: There is an effect of dopaminergic medication on NMS in late stage PD, to some extent also for those with a non-significant response on motor function during L-dopa test. It is therefore of importance to optimize dopaminergic therapy in order to give the most effective symptomatic treatment possible. (Less)

Levodopa Effect and Motor Function in Late Stage Parkinson's Disease.

It is unclear to which degree Levodopa (L-dopa) remains effective also in the late stage of Parkinson's disease (PD) and to which degree motor fluctuations and dyskinesias remain a problem. To assess responsiveness of motor symptomatology to L-dopa in a group of patients with late stage PD. Moreover, to investigate the extent to which motor fluctuations and dyskinesias occur. Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. L-dopa responsiveness was assessed with a standardized L-dopa test in the defined "off" and defined "on" states. Motor function was assessed by the Unified PD Rating Scale (UPDRS) III and timed tests. Motor fluctuations and dyskinesias were assessed by the UPDRS IV. The participants were further monitored for 10 days with a mobile movement-analyses-system, the Parkinson's Kinetigraph (PKG). The median (q1-q3) L-dopa equivalent daily dose (LEDD) was 799 (536-973) mg. The UPDRS III score improved with ≥15% in 15 (50%) and with ≥30% in six (20%) participants during the L-dopa test. The median (q1-q3) UPDRS III score in "off" was 46 (37-53) and in "on" 36 (28-46). Twenty-one (70%) of the participants reported either predictable or unpredictable "off" fluctuations (items 36-37). The prevalence of dyskinesias (item 32, duration of dyskinesias ≥1) was 47%. The PKG indicated that dyskinesias primarily were mild and that a majority had a pronounced "off" symptomatology, spending a large proportion of the day either asleep or very inactive. Half of a group of patients with late stage PD had an L-dopa response of ≥15% on the UPDRS III. According to the UPDRS IV, a majority of the patients had motor fluctuations and about half had dyskinesias, although the PKG results suggested that these were not very severe.

The influence of smell and taste disturbances on the nutritional status in Parkinson disease

Objective: Malnutrition is an essential problem in the late stage of Parkinson disease (PD). The pathogen- esis of malnutrition in PD is multifactorial: motor dysfunctions, antiparkinsonian drugs’ side effects, dysau- tonomia, cognitive dysfunction, depression, dietary manipulation, and lack of family attention. Autonomic disturbance, and other coexisting diseases must be considered in the analysis of malnutrition risk factors.

Quantitative susceptibility mapping as an indicator of subcortical and limbic iron abnormality in Parkinson's disease with dementia.

Late stage Parkinson's disease (PD) patients were commonly observed with other non-motor comorbidities such as dementia and psychosis. While abnormal iron level in the substantia nigra was clinically accepted as a biomarker of PD, it was also suggested that the increased iron deposition could impair other brain regions and induce non-motor symptoms. A new Magnetic Resonance Imaging (MRI) called Quantitative Susceptibility Mapping (QSM) has been found to measure iron concentration in the grey matter reliably. In this study, we investigated iron level of different subcortical and limbic structures of Parkinson's disease (PD) patients with and without dementia by QSM.QSM and volumetric analysis by MRI were performed in 10 PD dementia (PDD) patients (73 ± 6 years), 31 PD patients (63 ± 8 years) and 27 healthy controls (62 ± 7 years). No significant differences were observed in the L-Dopa equivalent dosage for the two PD groups (p = 0.125).Putative iron content was evaluated in different subcortical and limbic structures of the three groups, as well as its relationship with cognitive performance. One-way ANCOVA with FDR adjustment at level of 0.05, adjusted for age and gender, showed significant group differences for left and right hippocampus (p = 0.015 & 0.032, respectively, BH-corrected for multiple ROIs) and right thalamus (p = 0.032, BH-corrected). Post-hoc test with Bonferroni's correction suggested higher magnetic susceptibility in PDD patients than healthy controls in the left and right hippocampus (p = 0.001 & 0.047, respectively, Bonferroni's corrected), while PD patients had higher magnetic susceptibility than the healthy controls in right hippocampus and right thalamus (p = 0.006 & 0.005, respectively, Bonferroni's corrected). PDD patients also had higher susceptibility than the non-demented PD patients in left hippocampus (p = 0.046, Bonferroni's corrected). The magnetic susceptibilities of the left and right hippocampus were negatively correlated with the Mini-Mental State Examination score (r = −0.329 & -0.386, respectively; p < 0.05).This study provides support for iron accumulation in limbic structures of PDD and PD patients and its correlation with cognitive performance, however, its putative involvement in development of non-motor cognitive dysfunction in PD pathogenesis remains to be elucidated.

Could istradefylline be a treatment option for postural abnormalities in mid-stage Parkinson's disease?

BasegroundPostural abnormalities are refractory complications observed in mid- to late-stage Parkinson's disease (PD). MethodsWe analyzed the effects of istradefylline, a selective adenosine A2A receptor antagonist, on posture in 21 levodopa-treated PD patients from the subanalysis of a three-month open-label study. ResultsThe subitem score of posture (3.13) on the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III significantly improved following istradefylline treatment (baseline, 1.3±1.0 points vs 3months, 0.9±0.9 points; p<0.05). Among 18 patients who had postural abnormalities at baseline, defined as 1 point or greater on MDS-UPDRS part III subitem 3.13, posture improved in 9 (50%) and was unchanged in 9 (50%) patients after istradefylline treatment. Improved and unchanged groups did not show differences in baseline characteristics, except for tendency for a higher rate of Hoehn and Yahr stage IV and V (Off state) observed in the improved group. Changes in scores of posture (3.13) did not correlate with those of other MDS-UPDRS part III items, PD Questionnaire-8, PD Sleep Scale-2 and Epworth Sleepiness Scale. ConclusionBased on our preliminary findings, istradefylline could be an effective treatment option for postural abnormalities in mid-stage PD patients.

The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein

The aberrant accumulation of alpha-synuclein (α-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of α-syn. We previously identified the pathological accumulation of α-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (α-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified α-Gal A activity and levels of its glycosphingolipid metabolites in postmortem temporal cortex specimens from control individuals and in PD individuals staged with respect to α-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in α-Gal A activity and the 46kDa “active” species of α-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in α-Gal A activity/levels correlated significantly with increased α-syn phosphorylated at serine 129 (p129S-α-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb3), a substrate of α-Gal A indicated no significant differences with respect to different stages of PD temporal cortex. However, significant correlations were observed between increased levels of several Gb3 isoforms and with decreased α-Gal A activity and/or increased p129S-α-syn. Deacylated Gb3 (globotriaosylsphingosine or lyso-Gb3) was also analyzed in PD brain tissue but was below the limit of detection of 20pmol/g. Analysis of other lysosomal enzymes revealed a significant decrease in activity for the lysosomal aspartic acid protease cathepsin D but not for glucocerebrosidase (GCase) or cathepsin B in late-stage PD temporal cortex. However, a significant correlation was observed between decreasing GCase activity and increasing p129S-α-syn. Together our findings indicate α-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of α-syn, and further suggest the potential for α-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.

Asymmetric Total Syntheses of Communesin F and a Putative Member of the Communesin Family.

Here we report asymmetric total syntheses of communesin F and a putative member of the communesin family of bis-aminal alkaloid natural products. The successful strategy featured the invention of an asymmetric organocatalytic reaction to unify two oxindole subunits, a Ti(Oi Pr)4 -mediated dehydrative skeletal rearrangement, and a late-stage Pd(OAc)2 -catalyzed directed CH-alkenylation reaction. Collectively, the synthetic technologies disclosed herein enabled the preparation of a late-stage polycyclic intermediate catered for the synthesis of both naturally occurring and designed communesins. More importantly, speculated and yet to be discovered member(s) of the communesin family can now be accessed to facilitate a better understanding of the communesin biosynthetic network.

Urethral dynamics of different Hoehn-Yahr stage in patients with parkinson's disease

Objective To detect the differences of urodynamics in different Hoehn-Yahr staging in patients with parkinson's disease (PD)in shiyan area. Methods Forty - five patients with primary PD who were treated in our hospital were grouped according to Hoehn-Yahr (H-Y) staging criteria. The urodynamic difference of each group was detected by urodynamic analyzer. Results There were significant differences in urodynamics between PD with different H-Y staging, and the early stage PD manifested as detrusor instability, and the late stage PD mainly showed that the initial bladder volume and the maximum bladder volume increased, the incidence of low compliance bladder increased. With the increase of PD staging, detrusor muscle damage, the maximum urinary flow rate, detrusor pressure gradually reduced, residual urine increased significantly. Conclusions Patients with sporadic PD with different H-Y grades may have characteristic urethral changes in bladder and urethral dysfunction, which may be helpful for treatment and prognosis. Key words: Parkinson Disease; Urodynamics

Promising non-pharmacological therapies in PD: Targeting late stage disease and the role of computer based cognitive training

Non-pharmacological interventions are increasingly being acknowledged as valuable treatment options to overcome or reduce functional problems in patients with Parkinson's disease (PD). There is a wide range of such non-pharmacological treatments for which the supportive evidence is emerging. Physiotherapy is one good example in this domain. However, there are also several promising non-pharmacological treatment strategies that have thus far received less research attention. Here, we describe two relatively new, but encouraging approaches. First, we focus on a hitherto largely overseen subgroup of PD, namely those with late-stage disease, a population that is often excluded from clinical studies. Importantly, the aims and therapeutic strategies in late-stage PD differ considerably from those in early-stage PD, and an emphasis on non-pharmacological management is particularly important for this vulnerable subgroup. Second, we focus on computer-based cognitive training, as an example of a relatively new intervention that includes innovative elements such as personalized training, artificial intelligence, and virtual reality. We review the latest evidence, practical considerations and future research perspectives, both for non-pharmacological approaches in late-stage PD and for computer-based cognitive training.

Chemical Exchange Saturation Transfer MRI Signal Loss of the Substantia Nigra as an Imaging Biomarker to Evaluate the Diagnosis and Severity of Parkinson's Disease.

The early diagnosis of Parkinson's disease (PD) and the accurate evaluation of disease severity are crucial for intervention and treatment in PD patients. In this study, we applied chemical exchange saturation transfer (CEST) imaging to patients at different stages of PD and explored the clinical value of the CEST signal loss of the substantia nigra as an imaging biomarker of PD. The measured CEST signal intensities (including amide proton transfer-weighted or APTw, and total CEST or CESTtotal) of the substantia nigra in PD patients showed a significantly decreased tendency with PD progression. Compared to normal controls, the APTw and CESTtotal intensities of PD patients significantly decreased at both the early and advanced or late stages. These APTw and CESTtotal values of the substantia nigra were also significantly lower in advanced or late stage PD patients than in early stage PD patients. For PD patients with unilateral symptoms, the APTw and CESTtotal values in the substantia nigra on the affected side were significantly lower than those in normal controls. Both the APTw and CESTtotal values of PD were significantly correlated with the severity of disease and disease duration. Our findings suggest that the CEST MRI signal of the substantia nigra is a potential imaging biomarker for the diagnosis and monitoring of the severity of PD.

Speech and Voice Response to a Levodopa Challenge in Late-Stage Parkinson's Disease.

Parkinson's disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa's (l-dopa) effect on quality of speech is inconclusive; no data are currently available for late-stage PD (LSPD). To assess the modifications of speech and voice in LSPD following an acute l-dopa challenge. LSPD patients [Schwab and England score <50/Hoehn and Yahr stage >3 (MED ON)] performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients' therapeutic condition using Praat 5.1 software. 24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 [IQR: 71.5-81.7] and 14.5 [IQR: 11-15.7] years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality (R = 0.51; p = 0.013) and speech rate (R = -0.55; p = 0.008). l-Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis. Speech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD.

Substantia Nigra Neuromelanin as an Imaging Biomarker of Disease Progression in Parkinson’s Disease

A specific T1-weighted magnetic resonance imaging (MRI) sequence has been shown to detect substantia nigra (SN) neuromelanin (NM) signal changes that accurately discriminate Parkinson's disease (PD) patients from controls, even in early disease stages. However, it is unclear what happens to these SN changes in later disease stages and if they can be a marker of disease progression. to investigate the pattern of SN-NM area loss and contrast ratio (CR) intensity changes in late-stage PD (LSPD) compared to earlier disease stages. A comparative cross-sectional study was performed, analyzing SN-NM MRI signal in LSPD (Schwab and England Activities of Daily Living Scale score <50 or Hoehn Yahr Stage [HY] >3), comparing this group with de novo, 2-5 year PD and controls. SN-NM signal area and CR values for the internal and lateral SN regions were obtained with semi-automated methods. 13 LSPD, 12 de novo patients with PD, 10 PD patients with a 2-5 year disease duration, and 10 controls were included. NM signal area was significantly decreased in LSPD compared to de novo PD (P-value = 0.005; sensitivity: 75%; specificity 92% and AUC: 0.86). In the lateral SN region, a decrease in the CR was detected in all PD groups compared to controls; despite not reaching statistical significance, a slight increment was observed comparing LSPD to 2-5 year PD. NM signal area significantly correlated with HY (R = -0.37; P < 0.05) and Movement disorder Society Unified Parkinson's Disease Rating Scale part II (MDS-UPDRS) (R = -0.4; P < 0.05) while a weak correlation was found with MDS-UPDRS part III (R = -0.26; P: 0.1). SN area evaluated by NM-sensitive MRI may be a promising biomarker of nigral degeneration and disease progression in PD patients.

Subthalamic Nucleus Deep Brain Stimulation Employs trkB Signaling for Neuroprotection and Functional Restoration.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common neurosurgical treatment for Parkinson's disease motor symptoms. In preclinical models, STN DBS provides neuroprotection for substantia nigra (SN) dopamine neurons and increases BDNF in the nigrostriatal system and primary motor cortex. However, whether BDNF signaling in the SN participates in the neuroprotective effects of DBS remains unknown. We demonstrate that STN DBS in male rats activates signaling downstream of tropomyosin receptor kinase type B (trkB), namely, phosphorylation of Akt and ribosomal protein S6, in SN neurons. Long-term trkB blockade abolished STN DBS-mediated neuroprotection of SN neurons following progressive 6-hydroxydopamine lesion and was associated with decreased phosphorylated ribosomal protein S6 immunoreactivity. Acute trkB blockade in rats with stable nigrostriatal denervation attenuated the forelimb akinesia improvement normally induced by STN DBS. These results suggest that STN DBS increases BDNF-trkB signaling to contribute to the neuroprotective and symptomatic efficacy of STN DBS.SIGNIFICANCE STATEMENT Subthalamic nucleus deep brain stimulation (STN DBS) is increasingly used in mid- to late-stage Parkinson's disease (PD) but with an incomplete knowledge of its molecular mechanisms. STN DBS is neuroprotective against neurotoxicants in animal models and increases BDNF. This study is the first to show that BDNF signaling through the cognate tropomyosin receptor kinase type B (trkB) receptor occurs in substantia nigra pars compacta neurons and is required for neuroprotection. In addition, blockade of trkB unexpectedly reduced the functional benefit of STN DBS on a short timescale that is inconsistent with canonical trkB signaling pathways, suggesting a noncanonical role for trkB in STN DBS-mediated behavioral effects. Together, these data implicate trkB signaling in the symptomatic efficacy and disease-modifying potential of STN DBS.

Altered neural responses to heat pain in drug-naive patients with Parkinson disease.

Pain is a frequent but still neglected nonmotor symptom of Parkinson disease (PD). However, neural mechanisms underlying pain in PD are poorly understood. Here, we explored whether the high prevalence of pain in PD might be related to dysfunctional descending pain control. Using functional magnetic resonance imaging we explored neural responses during the anticipation and processing of heat pain in 21 PD patients (Hoehn and Yahr I-III) and 23 healthy controls (HC). Parkinson disease patients were naive to dopaminergic medication to avoid confounding drug effects. Fifteen heat pain stimuli were applied to the participants' forearm. Intensity and unpleasantness ratings were provided for each stimulus. Subjective pain perception was comparable for PD patients and HC. Neural processing, however, differed between groups: PD patients showed lower activity in several descending pain modulation regions (dorsal anterior cingulate cortex [dACC], subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex [DLPFC]) and lower functional connectivity between dACC and DLPFC during pain anticipation. Parkinson disease symptom severity was negatively correlated with dACC-DLPFC connectivity indicating impaired functional coupling of pain modulatory regions with disease progression. During pain perception PD patients showed higher midcingulate cortex activity compared with HC, which also scaled with PD severity. Interestingly, dACC-DLPFC connectivity during pain anticipation was negatively associated with midcingulate cortex activity during the receipt of pain in PD patients. This study indicates altered neural processing during the anticipation and receipt of experimental pain in drug-naive PD patients. It provides first evidence for a progressive decline in descending pain modulation in PD, which might be related to the high prevalence of pain in later stages of PD.