Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

OBJECTIVE: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. METHODS: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. RESULTS: Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1-SD increase, 95% confidence interval [CI] = 1.21-1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1-SD increase, 95% CI = 1.34-2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32-16.32). INTERPRETATION: Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Translating Evidence to Advanced Parkinson's Disease Patients: A Systematic Review and Meta-Analysis.

In the advanced stages of Parkinson's disease (PD), patients frequently experience disabling motor complications. Treatment options include deep brain stimulation (DBS), levodopa-carbidopa intestinal gel (LCIG), and continuous subcutaneous apomorphine infusion (CSAI). Choosing among these treatments is influenced by scientific evidence, clinical expertise, and patient preferences. To foster patient engagement in decision-making among the options, scientific evidence should be adjusted to their information needs. We conducted a systematic review from the patient perspective. First, patients selected outcomes for a treatment choice: quality of life, activities of daily living, ON and OFF time, and adverse events. Second, we conducted a systematic review and meta-analysis for each treatment versus best medical treatment using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Finally, the evidence was transformed into comprehensible and comparable information. We converted the meta-analysis results into the number of patients (per 100) who benefit clinically from an advanced treatment per outcome, based on the minimal clinically important difference and the cumulative distribution function. Although this approach allows for a comparison of outcomes across the three device-aided therapies, they have never been compared directly. The interpretation is hindered by the relatively short follow-up time in the included studies, usually less than 12 months. These limitations should be clarified to patients during the decision-making process. This review can help patients integrate the evidence with their own preferences, and with their clinician's expertise, to reach an informed decision. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

α-Synuclein real-time quaking-induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism.

A reliable biomarker is needed for accurate and early differentiation between Parkinson disease and the various forms of atypical parkinsonism. We used a novel real-time quaking-induced conversion (RT-QuIC) assay to detect α-synuclein (α-syn) aggregates in cerebrospinal fluid (CSF) of 118 patients with parkinsonism of uncertain clinical etiology and 52 controls. Diagnostic accuracy to distinguish α-synucleinopathies from non-α-synucleinopathies and controls was 84% (sensitivity = 75%, specificity = 94%, area under the curve = 0.84, 95% confidence interval = 0.78-0.91, p < 0.0001, positive predictive value = 93%). CSF α-syn RT-QuIC could be a useful diagnostic tool to help clinicians differentiate α-synucleinopathies from other forms of parkinsonism when the clinical picture is uncertain. Ann Neurol 2019;85:777-781.

Inflammation biomarker discovery in Parkinson's disease and atypical parkinsonisms.

BACKGROUND: Parkinson's disease (PD) and atypical parkinsonisms (APD) have overlapping symptoms challenging an early diagnosis. Diagnostic accuracy is important because PD and APD have different prognosis and response to treatment. We aimed to identify diagnostic inflammatory biomarkers of PD and APD in cerebrospinal fluid (CSF) using the multiplex proximity extension assay (PEA) technology and to study possible correlations of biomarkers with disease progression. METHODS: CSF from a longitudinal cohort study consisting of PD and APD patients (PD, n = 44; multiple system atrophy (MSA), n = 14; vascular parkinsonism (VaP), n = 9; and PD with VaP, n = 7) and controls (n = 25) were analyzed. RESULTS: Concentrations of CCL28 were elevated in PD compared to controls (p = 0.0001). Five other biomarkers differentiated both MSA and PD from controls (p < 0.05) and 10 biomarkers differentiated MSA from controls, of which two proteins, i.e. beta nerve growth factor (ß-NGF) and Delta and Notch like epidermal growth factor-related receptor (DNER), were also present at lower levels in MSA compared to PD (both p = 0.032). Two biomarkers (MCP-1 and MMP-10) positively correlated with PD progression (rho > 0.650; p < 0.01). CONCLUSIONS: PEA technique identified potential new CSF biomarkers to help to predict the prognosis of PD. Also, we identified new candidate biomarkers to distinguish MSA from PD.

Enhanced motivation of cognitive control in Parkinson's disease.

Motor and cognitive deficits in Parkinson's disease (PD) have been argued to reflect motivational deficits. In prior work, however, we have shown that motivation of cognitive control is paradoxically potentiated rather than impaired in Parkinson's disease. This is particularly surprising given the fact that Parkinson's disease is often accompanied by depression, a prototypical disorder of motivation. To replicate our previous finding and assess the effects of depression, we investigated performance of PD patients with (n = 22) and without depression (history) (n = 23) and age-matched healthy controls (n = 23) on a task specifically designed to measure the effect of reward motivation on task-switching. We replicated previous findings by showing contrasting effects of reward motivation on task-switching in PD patients and age-matched healthy controls. While the promise of high versus low reward improved task-switching in PD, it tended to impair task-switching in age-matched healthy controls. There were no effects of a depression (history) diagnosis in PD patients. These findings reinforce prior observations that Parkinson's disease is accompanied by enhanced incentive motivation of cognitive control and highlight the potential of incentive motivational strategies for overcoming cognitive deficits in Parkinson's disease.

Parkinson's Disease Diagnostic Observations (PADDO): study rationale and design of a prospective cohort study for early differentiation of parkinsonism.

BACKGROUND: Differentiation of Parkinson's disease (PD) from the various types of atypical parkinsonism (AP) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS) and vascular parkinsonism (VP), can be challenging, especially early in the disease course when symptoms overlap. A major unmet need in the diagnostic workup of these disorders is a diagnostic tool that differentiates the various disorders, preferably in the earliest disease stages when the clinical presentation is similar. Many diagnostic tests have been evaluated, but their added value was studied mostly in retrospective case-control studies that included patients with a straightforward clinical diagnosis. Here, we describe the design of a prospective cohort study in patients with parkinsonism in an early disease stage who have an uncertain clinical diagnosis. Our aim is to evaluate the diagnostic accuracy of (1) detailed clinical examination by a movement disorder specialist, (2) magnetic resonance imaging (MRI) techniques and (3) cerebrospinal fluid (CSF) biomarkers. METHODS/DESIGN: Patients with parkinsonism with an uncertain clinical diagnosis and a disease course less than three years will be recruited. Patients will undergo extensive neurological examination, brain MRI including conventional and advanced sequences, and a lumbar puncture. The diagnosis (including level of certainty) will be defined by a movement disorders expert, neuroradiologist and neurochemist based on clinical data, MRI results and CSF results, respectively. The clinical diagnosis after three years' follow-up will serve as the "gold standard" reference diagnosis, based on consensus criteria and as established by two movement disorder specialists (blinded to the test results). Diagnostic accuracy of individual instruments and added value of brain MRI and CSF analysis after evaluation by a movement disorder expert will be calculated, expressed as the change in percentage of individuals that are correctly diagnosed with PD or AP. DISCUSSION: This study will yield new insights into the diagnostic value of clinical evaluation by a movement disorder specialist, brain MRI and CSF analysis in discriminating PD from AP in early disease stages. The outcome has the potential to help clinicians in choosing the optimal diagnostic strategy for patients with an uncertain clinical diagnosis. TRIAL REGISTRATION: NCT01249768, registered November 26 2010.

What a neurologist should know about depression in Parkinson's disease.

Depression is a frequent non-motor symptom of Parkinson's disease. Its prevalence varies widely across studies (between 2.7% and 90%); around 35% have clinically significant depressive symptoms. Although depression can have an immense impact on the quality of life of affected patients and their caregivers, depressive symptoms in Parkinson's disease frequently remain unrecognised and, as a result, remain untreated. Here we overview the diagnostic challenges and pitfalls, including the factors contributing to the underdiagnosis of depression. We also discuss current ideas on the underlying pathophysiology. Finally, we offer a treatment approach based on currently available evidence.

Nigrosome-1 on Susceptibility Weighted Imaging to Differentiate Parkinson's Disease From Atypical Parkinsonism: An In Vivo and Ex Vivo Pilot Study.

BACKGROUND: Previous case-control studies have suggested that the absence of a swallow-tail appearance in the substantia nigra on high-resolution SWI, representing nigrosome-1, has high accuracy to identify Parkinson's disease (PD). The first goal of our study was to evaluate nigrosome-1 ex vivo using optimized high-resolution susceptibility sensitive MRI. Our second goal was to evaluate its diagnostic value in vivo using a clinical 3T SWI sequence to differentiate between PD and atypical parkinsonism (AP) in a cohort of patients with early-stage parkinsonism. MATERIAL/METHODS: Case-control pilot study to evaluate nigrosome-1 ex vivo (2 PD, 2 controls), using high-resolution susceptibility sensitive sequences at 11.7 T MRI. Next, evaluation of nigrosome-1 in vivo using a clinical 3 T SWI sequence in a prospective cohort of 60 patients with early-stage parkinsonism (39 PD, 21 AP). Moreover, 12 control subjects were scanned. The bilateral substantia nigra was evaluated by two neuroradiologists for the presence, absence or indecisive presence of nigrosome-1. The discriminative power was evaluated by Receiver-Operating Characteristic. RESULTS: We identified nigrosome-1 in ex vivo control subjects. Nigrosome-1 was not identified in the ex vivo PD cases. In our prospective clinical cohort study, the AUC for the swallow-tail sign to discriminate between PD and AP was 0.56 (0.41-0.71) for reader 1 and 0.68 (0.55-0.82) for reader 2. CONCLUSIONS: The diagnostic accuracy of the swallow-tail sign was marginal to discriminate between PD and AP using our clinical 3 T SWI sequence.

Freezing of gait in Parkinson's disease is related to impaired motor switching during stepping.

BACKGROUND: Parkinson's disease (PD) has been associated with set switching difficulty in both the motor and the cognitive domain. However, the contribution of these set switching deficits to the primary motor symptoms of the disease is unclear. We investigated whether set switching deficits contribute to gait and stepping problems in PD. By contrasting motor and cognitive set switching within the same paradigm, we investigated the nature of set switching deficits associated with freezing of gait (FOG). METHODS: We integrated step initiation with set switching within one task and compared patients with and without FOG with healthy subjects. Motor set switching was defined as a change in stepping direction from one trial to the next. Cognitive set switching was defined as a change in task rule (ie, respond according to the shape or color of the presented stimulus). RESULTS: We found delayed motor switching in PD patients with FOG. We did not observe impaired cognitive switching. CONCLUSIONS: These findings suggest that motor set switching deficits, commonly reported in tasks using verbal or tapping responses, extend to stepping and can contribute to the occurrence of freezing episodes during gait initiation.

Conventional 3T brain MRI and diffusion tensor imaging in the diagnostic workup of early stage parkinsonism.

INTRODUCTION: The aim of this study is to evaluate whether the diagnostic accuracy of 3 T brain MRI is improved by region of interest (ROI) measures of diffusion tensor imaging (DTI), to differentiate between neurodegenerative atypical parkinsonism (AP) and Parkinson's disease (PD) in early stage parkinsonism. METHODS: We performed a prospective observational cohort study of 60 patients presenting with early stage parkinsonism and initial uncertain diagnosis. At baseline, patients underwent a 3 T brain MRI including DTI. After clinical follow-up (mean 28.3 months), diagnoses could be made in 49 patients (30 PD and 19 AP). Conventional brain MRI was evaluated for regions of atrophy and signal intensity changes. Tract-based spatial statistics and ROI analyses of DTI were performed to analyze group differences in mean diffusivity (MD) and fractional anisotropy (FA), and diagnostic thresholds were determined. Diagnostic accuracy of conventional brain MRI and DTI was assessed with the receiver operating characteristic (ROC). RESULTS: Significantly higher MD of the centrum semiovale, body corpus callosum, putamen, external capsule, midbrain, superior cerebellum, and superior cerebellar peduncles was found in AP. Significantly increased MD of the putamen was found in multiple system atrophy-parkinsonian form (MSA-P) and increased MD in the midbrain and superior cerebellar peduncles in progressive supranuclear palsy (PSP). The diagnostic accuracy of brain MRI to identify AP as a group was not improved by ROI measures of MD, though the diagnostic accuracy to identify MSA-P was slightly increased (AUC 0.82 to 0.85). CONCLUSION: The diagnostic accuracy of brain MRI to identify AP as a group was not improved by the current analysis approach to DTI, though DTI measures could be of added value to identify AP subgroups.

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias.

BACKGROUND: Overlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-ß42 (Aß42), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD. METHODS: We retrospectively analyzed concentrations of MHPG, Aß42, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters. RESULTS: The currently used combination of Aß42, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aß42, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia. CONCLUSIONS: Our results confirm in a separate patient cohort that addition of MHPG to Aß42, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.

The impact of deep brain stimulation of the subthalamic nucleus on facial emotion recognition in patients with Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is successful in patients with advanced Parkinson's disease (PD) but may worsen cognitive outcome, including facial emotion recognition (FER). Data-analyses on 59 consecutive PD patients with complete pre- and postoperative assessments, using a sensitive FER test, showed no changes in FER 1 year after STN-DBS surgery, both after group and individual analyses. These findings do however not exclude the impact of FER in and on itself on the outcome after STN-DBS.

Structural Network Efficiency Predicts Conversion to Incident Parkinsonism in Patients With Cerebral Small Vessel Disease.

BACKGROUND: To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. METHODS: In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed. RESULTS: We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (ß = -0.047, p < .001) and 2015 (ß = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (ß = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers. CONCLUSIONS: Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.

Long-Term Longitudinal Course of Cognitive and Motor Symptoms in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Patients with cerebral small vessel disease (SVD) show a heterogenous clinical course. The aim of the current study was to investigate the longitudinal course of cognitive and motor function in patients who developed parkinsonism, dementia, both, or none. METHODS: Participants were from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study, a prospective cohort of patients with SVD. Parkinsonism and dementia were, respectively, diagnosed according to the UK Parkinson's Disease Society brain bank criteria and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major neurocognitive disorder. Linear and generalized linear mixed-effect analyses were used to study the longitudinal course of motor and cognitive tasks. RESULTS: After a median follow-up of 12.8 years (interquartile range 10.2-15.3), 132 of 501 (26.3%) participants developed parkinsonism, dementia, or both. Years before diagnosis of these disorders, participants showed distinct clinical trajectories from those who developed none: Participant who developed parkinsonism had an annual percentage of 22% (95% CI 18%-27%) increase in motor part of the Unified Parkinson's Disease Rating Scale score. This was significantly higher than the 16% (95% CI 14%-18%) of controls, mainly because of a steep increase in bradykinesia and posture and gait disturbances. When they developed dementia as well, the increase in Timed Up and Go Test time of 0.73 seconds per year (95% CI 0.58-0.87) was significantly higher than the 0.20 seconds per year increase (95% CI 0.16-0.23) of controls. All groups, including the participants who developed parkinsonism without dementia, showed a faster decline in executive function compared with controls: Annual decline in Z-score was -0.07 (95% CI -0.10 to -0.05), -0.09 (95% CI -0.11 to -0.08), and -0.11 (95% CI -0.14 to -0.08) for participants who developed, respectively, parkinsonism, dementia, and both parkinsonism and dementia. These declines were all significantly faster than the annual decline in Z-score of 0.07 (95% CI -0.10 to -0.05) of controls. DISCUSSION: A distinct pattern in deterioration of clinical markers is visible in patients with SVD, years before the diagnosis of parkinsonism and dementia. This knowledge aids early identification of patients with a high risk of developing these disorders.

Does spinal cord stimulation improve gait in Parkinson's disease: A comprehensive review.

INTRODUCTION: Axial disability, including gait disturbances, is common in Parkinson's disease (PD), especially in advanced stages. Epidural spinal cord stimulation (SCS) has been investigated as a treatment option for gait disorders in PD. Here, we review the literature on SCS in PD and evaluate its efficacy, optimal stimulation parameters, optimal electrode locations, possible effects of concurrent deep brain stimulation, and possible working mechanisms on gait. METHODS: Databases were searched for human studies involving PD patients who received an epidural SCS intervention and who had at least one gait-related outcome measure. The included reports were reviewed with respect to design and outcomes. Additionally, the possible mechanisms of action underlying SCS were reviewed. RESULTS: Out of 433 records identified, 25 unique studies with in total 103 participants were included. Most studies included only a few participants. The gait disorders of most PD patients with concurrent pain complaints, mostly low back pain, improved with SCS in almost all cases, regardless of stimulation parameters or electrode location. Higher-frequency stimulation (>200 Hz) seemed to be more effective in pain-free PD patients, but the results were inconsistent. Heterogeneity in outcome measures and follow-up times hindered comparability. CONCLUSIONS: SCS may improve gait in PD patients with neuropathic pain, but its efficacy in pain-free patients remains uncertain due to a lack of thorough double-blind studies. Apart from a well-powered, controlled, double-blind study design, future studies could further explore the initial hints that higher-frequency stimulation (>200 Hz) might be the best approach to improve gait outcomes in pain-free patients.

Improving the diagnostic accuracy in parkinsonism: a three-pronged approach.

Separating Parkinson's disease from the various causes of atypical parkinsonism (AP) is a common and clinically relevant challenge in clinical practice. Distinguishing between the different causes of AP is even more difficult. Here the authors discuss a systematic, clinically based and three-pronged approach that can assist clinicians in establishing the correct diagnosis in the consulting room. The three consecutive steps include: (1) to verify that the clinical syndrome truly represents parkinsonism (hypokinetic-rigid syndrome); (2) to search systematically for 'red flags' (alarm signs that may signal the presence of AP); and (3) to integrate these two steps, as a basis for a narrow differential diagnosis and a guide for further ancillary tests.

Factors associated with mortality in early stages of parkinsonism.

Prognosis of patients with parkinsonism varies greatly between the various parkinsonian syndromes. However, it is often difficult to distinguish the different forms, particularly in early stages. We examined predictors of mortality and functional outcome in patients with recent-onset parkinsonism with an initially uncertain diagnosis (n = 156). Patients were recruited between 2003 and 2006, comprehensively investigated, and followed prospectively (up to 15 years, mean 7 years). A final clinical diagnosis was established after follow-up. Independent predictors of mortality were investigated with multivariable Cox regression and combined into a simple prediction model. Model performance to predict 5- and 10-year mortality and functional outcome after 3 years was evaluated and externally validated in a second cohort of 62 patients with parkinsonism with an initially uncertain diagnosis. Ninety-one patients died (58%). Orthostatic hypotension, impaired cognition, abnormal tandem gait, and elevated neurofilament light chain concentration in serum or CSF were associated with mortality. A simple model that combined these factors showed excellent performance for prediction of functional outcome after 3 years and mortality after 5 and 10 years (c-statistic ~0.90 for all models). Model performance was confirmed after external validation: prediction of functional outcome after 3 years (c-statistic 0.89, 95% CI 0.80-0.98) and mortality after 5 years (c-statistic 0.91, 95% CI 0.84-0.99) were comparable to the results in the discovery cohort. These findings help clinicians to estimate a patient's prognosis, irrespective of the specific diagnosis.

Gender Distribution in Deep Brain Stimulation for Parkinson's Disease: The Effect of Awake versus Asleep Surgery.

There is evidence that men are more likely to undergo deep brain stimulation (DBS) for Parkinson's disease (PD), suggesting that women are relatively undertreated. 121 consecutive PD patients undergoing awake DBS with microelectrode recording and intraoperative clinical testing (30 patients, 5 women) or asleep MRI-guided and CT-verified (91 patients, 38 women) bilateral subthalamic nucleus DBS were included in this study. The results showed an increase in the proportion of female patients from 16.7% to 41.8% after changing our operative technique (OR = 5.61; 95% CI: 1.52-20.78; p = 0.010) from awake to asleep, suggesting that women are more likely to undergo DBS when operated asleep.

Role of dopamine and clinical heterogeneity in cognitive dysfunction in Parkinson's disease.

Parkinson's disease (PD) is commonly treated with dopaminergic medication, which enhances some, while impairing other cognitive functions. It can even contribute to impulse control disorder and addiction. We describe the history of research supporting the dopamine overdose hypothesis, which accounts for the large within-patient variability in dopaminergic medication effects across different tasks by referring to the spatially non-uniform pattern of dopamine depletion in dorsal versus ventral striatum. However, there is tremendous variability in dopaminergic medication effects not just within patients across distinct tasks, but also across different patients. In the second part of this chapter we review recent studies addressing the large individual variability in the negative side effects of dopaminergic medication on functions that implicate dopamine, such as value-based learning and choice. These studies begin to unravel the mechanisms of dopamine overdosing, thus revising the strict version of the overdose hypothesis. For example, the work shows that the canonical boosting of reward-versus punishment-based choice by medication is greater in patients with depression and a non-tremor phenotype, which both implicate, among other pathology, more rather than less severe dysregulation of the mesolimbic dopamine system. Future longitudinal cohort studies are needed to identify how to optimally combine different clinical, personality, cognitive, neural, genetic and molecular predictors of detrimental medication effects in order to account for as much of the relevant variability as possible. This will provide a useful tool for precision neurology, allowing individual and contextual tailoring of (the dose of) dopaminergic medication in order to maximize its cognitive benefits, yet minimize its side effects.

The Role of Microelectrode Recording in Deep Brain Stimulation Surgery for Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: STN-DBS is a cornerstone in the treatment of advanced Parkinson's disease (PD). The traditional approach is to use an awake operative technique with microelectrode recording (MER). However, more centers start using an asleep MRI-guided technique without MER. OBJECTIVE: We systematically reviewed the literature to compare STN-DBS surgery with and without MER for differences in clinical outcome. METHODS: We systematically searched PubMed, Embase, MEDLINE, and Web of Science databases for randomized clinical trials and consecutive cohort studies published between 01-01-2000 and 26-08-2021, that included at least 10 PD patients who had received bilateral STN-DBS. RESULTS: 2,129 articles were identified. After abstract screening and full-text review, 26 studies were included in the final analysis, comprising a total of 34 study groups (29 MER and 5 non-MER). The standardized mean difference (SMD) in change in motor symptoms between baseline (OFF medication) and 6-24 months follow-up (OFF medication and ON stimulation) was 1.64 for the MER group and 1.87 for non-MER group (p = 0.59). SMD in change in levodopa equivalent daily dose (LEDD) was 1.14 for the MER group and 0.65 for non-MER group (p < 0.01). Insufficient data were available for comparative analysis of PDQ-39 and complications. CONCLUSION: The change in motor symptoms from baseline to follow-up did not differ between studies that used MER and those that did not. The postoperative reduction in LEDD from baseline to follow-up was greater in the MER-group. In the absence of high-quality studies comparing both methods, there is a clear need for a well-designed comparative trial.