Performance of a cost-effective olfactory test to evaluate hyposmia in Parkinson's disease patients.

BACKGROUND: Parkinson's disease (PD) causes motor and non-motor symptoms such as hyposmia, which is evaluated through olfactory tests in the clinical practice. OBJECTIVE: To assess the feasibility of using the modified Connecticut Chemosensory Clinical Research Center (mCCCRC) olfactory test and to compare its performance with the Sniffin' Sticks-12 (SS-12, Burghart Messtechnik GmbH, Wedel, Germany) test. METHODS: A transversal case-control study in which the patients were divided into the PD group (PDG) and the control group (CG). The cost and difficulty in handling substances to produce the mCCCRC test kits were evaluated. Sociodemographic characteristics, smoking habits, past coronavirus disease 2019 (COVID-19) infections, self-perception of odor sense, and cognition through the Montreal Cognitive Assessment (MoCA) were also evaluated. The PDG was scored by part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr Scale (H&Y) scale. Correlations were assessed through the Spearman rank correlation coefficient test (ρ, or rho). RESULTS: The mCCCRC test was easily manufactured and handled at a cost ten times lower compared with the SS-12. The groups (PDG: n = 34; CG: n = 38) were similar in terms of age, sex, level of schooling, smoking habits, and history of COVID-19. The tests results showed moderate correlation (rho = 0.65; p < 0.0001). The CG presented better cognitive performance and scored better in both tests (p < 0.0001). There was a tendency for a negative correlation with age, but good correlation with the MoCA (p = 0.0029). The results of the PDG group showed no correlation with olfactory results and motor performance or disease duration. The self-perception of hyposmia was low in both groups. CONCLUSION: The mCCCRC is an easy-to-apply and inexpensive method that demonstrated a similar performance to that of the SS-12 in evaluating olfaction in PD patients and healthy controls.

ANTECEDENTES: A doença de Parkinson (DP) cursa com sintomas motores e não motores como a hiposmia, que é avaliada por diferentes testes olfativos na prática clínica. OBJETIVO: Avaliar a viabilidade do teste olfatório Connecticut Chemosensory Clinical Research Center modificado (mCCCRC) e compará-la à do teste Sniffin' Sticks-12 (SS-12, Burghart Messtechnik GmbH, Wedel, Alemanha). MéTODOS: Estudo transversal de caso-controle em que os pacientes foram divididos no grupo DP (GDP) e no grupo controle (GC). O custo e as dificuldades no manuseio das substâncias necessárias para a produção dos kits do teste mCCCRC foram avaliados. Características sociodemográficas, tabagismo, histórico de infecção por doença do coronavírus 2019 (coronavírus disease 2019, COVID-19, em inglês), autopercepção do olfato e cognição pelo Montreal Cognitive Assessment (MoCA) também foram avaliados. O GDP foi avaliado pela parte III da Unified Parkinson's Disease Rating Scale (UPDRS-III) e pela escala de Hoehn and Yahr (H&Y). As correlações utilizaram o teste do coeficiente de correlação de postos de Spearman (ρ, ou rho). RESULTADOS: O mCCCRC foi facilmente poroduzido e manipulado com custo dez vezes inferior ao do SS-12. Os grupos (GDP: n = 34; GC: n = 38) eram similares em termos de idade, sexo, escolaridade, tabagismo e histórico de COVID-19. Os resultados obtidos em ambos os testes mostraram excelente correlação (rho = 0.65; p < 0.0001). O GC teve um desempenho cognitivo melhor e pontuou melhor nos dois testes (p < 0.0001). Houve uma tendência a uma correlação negativa com a idade, mas boa correlação com a pontuação no MoCA (p = 0.0029). Os resultados olfativos do GDP não mostraram correlação com desempenho motor ou duração da doença. A autopercepção de hiposmia foi baixa em ambos os grupos. CONCLUSãO: O mCCCRC é um teste de fácil aplicação, baixo custo, e apresentou um desempenho semelhante ao do SS-12 na avaliação olfativa de pacientes com DP e controles saudáveis.

Exploring Cardiovascular Autonomic Function before and after Chronic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment. OBJECTIVE: To evaluate the effect of chronic STN-DBS, levodopa, and their combination on cardiovascular autonomic functions in PD. METHODS: We performed cardiovascular reflex tests (CRTs) before and 6-months after STN-DBS surgery in 20 PD patients (pre-DBS vs. post-DBS). CRTs were executed without and with medication (med-OFF vs. med-ON). RESULTS: CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre- and post-DBS studies in med-OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med-OFF, both at pre-DBS and post-DBS evaluation. Levodopa-induced OH was documented in 25% and 5% of patients in pre-DBS/med-ON and post-DBS/med-ON study. CONCLUSION: Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa-induced OH decreases after STN-DBS surgery.

Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease.

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.

Probabilistic stimulation mapping from intra-operative thalamic deep brain stimulation data in essential tremor.

Deep brain stimulation (DBS) is a therapy for Parkinson's disease (PD) and essential tremor (ET). The mechanism of action of DBS is still incompletely understood. Retrospective group analysis of intra-operative data recorded from ET patients implanted in the ventral intermediate nucleus of the thalamus (Vim) is rare. Intra-operative stimulation tests generate rich data and their use in group analysis has not yet been explored.Objective.To implement, evaluate, and apply a group analysis workflow to generate probabilistic stimulation maps (PSMs) using intra-operative stimulation data from ET patients implanted in Vim.Approach.A group-specific anatomical template was constructed based on the magnetic resonance imaging scans of 6 ET patients and 13 PD patients. Intra-operative test data (total:n= 1821) from the 6 ET patients was analyzed: patient-specific electric field simulations together with tremor assessments obtained by a wrist-based acceleration sensor were transferred to this template. Occurrence and weighted mean maps were generated. Voxels associated with symptomatic response were identified through a linear mixed model approach to form a PSM. Improvements predicted by the PSM were compared to those clinically assessed. Finally, the PSM clusters were compared to those obtained in a multicenter study using data from chronic stimulation effects in ET.Main results.Regions responsible for improvement identified on the PSM were in the posterior sub-thalamic area (PSA) and at the border between the Vim and ventro-oral nucleus of the thalamus (VO). The comparison with literature revealed a center-to-center distance of less than 5 mm and an overlap score (Dice) of 0.4 between the significant clusters. Our workflow and intra-operative test data from 6 ET-Vim patients identified effective stimulation areas in PSA and around Vim and VO, affirming existing medical literature.Significance.This study supports the potential of probabilistic analysis of intra-operative stimulation test data to reveal DBS's action mechanisms and to assist surgical planning.

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata.

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Connectome-based predictive modelling estimates individual cognitive status in Parkinson's disease.

INTRODUCTION: The progressive nature of Parkinson's disease (PD) affords emphasis on accurate early-stage individual-level assessment of risk and intervention appropriateness. In PD, cognitive impairment (CI) may follow or precede motor symptoms but are generally underdetected. In addition to impeding daily functioning and quality of life, CIs increase the risk for later conversion to dementia, providing a pressing need to develop novel tools to detect and interpret them. Connectome-based predictive modelling (CPM) is an emerging machine-learning approach to individual prediction that holds translational promise due to its noninvasiveness and simple implementation. The aim of this study was to investigate CPM's potential to predict and understand CIs in PD. METHODS: Resting-state functional connectivity from 58 patients with PD of varying cognitive status was used to train a CPM-model to predict a global cognitive composite (GCC) score. The model was validated using cross-validation, permutation testing, and internal stability analyses. The combined predictive strength of two brain connectivity networks, positive and negative, directly and inversely correlated with GCC, respectively, was assessed. RESULTS: The model significantly predicted individual GCC scores, r = 0.63, pperm < .05. Separately, the positive and negative networks were similar in performance, rs ≥ .58, ps < .05, but varied in anatomical distribution. CONCLUSIONS: This study identified a connectome predictive of cognitive scores in PD, with features overlapping with established and emerging evidence on aberrant connectivity in PD-related CIs. Overall, CPM appears promising for clinical translation in this population, but longitudinal studies with out-of-sample validation are needed.

Prefrontal-subthalamic theta signaling mediates delayed responses during conflict processing.

While medial frontal cortex (MFC) and subthalamic nucleus (STN) have been implicated in conflict monitoring and action inhibition, respectively, an integrated understanding of the spatiotemporal and spectral interaction of these nodes and how they interact with motor cortex (M1) to definitively modify motor behavior during conflict is lacking. We recorded neural signals intracranially across presupplementary motor area (preSMA), M1, STN, and globus pallidus internus (GPi), during a flanker task in 20 patients undergoing deep brain stimulation implantation surgery for Parkinson disease or dystonia. Conflict is associated with sequential and causal increases in local theta power from preSMA to STN to M1 with movement delays directly correlated with increased STN theta power, indicating preSMA is the MFC locus that monitors conflict and signals STN to implement a 'break.' Transmission of theta from STN-to-M1 subsequently results in a transient increase in M1-to-GPi beta flow immediately prior to movement, modulating the motor network to actuate the conflict-related action inhibition (i.e., delayed response). Action regulation during conflict relies on two distinct circuits, the conflict-related theta and movement-related beta networks, that are separated spatially, spectrally, and temporally, but which interact dynamically to mediate motor performance, highlighting complex parallel yet interacting networks regulating movement.

Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. METHODS: We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. RESULTS: Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. INTERPRETATION: Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Persistence of Basal Ganglia Oscillatory Activity During Tremor Attenuation by Movement in Parkinson's Disease Patients.

BACKGROUND: One of the characteristics of parkinsonian tremor is that its amplitude decreases with movement. Current models suggest an interaction between basal ganglia (BG) and cerebello-thalamo-cortical circuits in parkinsonian tremor pathophysiology. OBJECTIVE: We aimed to correlate central oscillation in the BG with electromyographic activity during re-emergent tremor in order to detect changes in BG oscillatory activity when tremor is attenuated by movement. METHODS: We performed a prospective, observational study on consecutive parkinsonian patients who underwent deep brain stimulation surgery and presented re-emergent tremor. Coherence analysis between subthalamic nucleus/globus pallidus internus (STN/GPi) tremorous activity measured by microrecording (MER) and electromyogram (EMG) from flexor and extensor wrist muscles during rest, posture, and re-emergent tremor pause was performed during surgery. The statistical significance level of the MER-EMG coherence was determined using surrogate data analysis, and the directionality of information transfer between BG and muscle was performed using entropy transfer analysis. RESULTS: We analyzed 148 MERs with tremor-like activity from 6 patients which were evaluated against the simultaneous EMGs, resulting in 296 correlations. Of these, 26 presented a significant level of coherence at tremor frequency, throughout rest and posture, with a complete EMG stop in between. During the pause, all recordings showed sustained MER peaks at tremor frequency (±1.5 Hz). Information flows preferentially from BG to muscle during rest and posture, with a loss of directionality during the pause. CONCLUSIONS: Our results suggest that oscillatory activity in STN/GPi functionally linked to tremor sustains firing frequency during re-emergent tremor pause, thus suggesting no direct role of the BG circuit on tremor attenuation due to voluntary movements. © 2024 International Parkinson and Movement Disorder Society.

The impact of subthalamic deep-brain stimulation in restoring motor symmetry in Parkinson's disease patients: a prospective study.

BACKGROUND AND OBJECTIVES: The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). METHODS: Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. RESULTS: 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50% in pre-DBS MedOFF, 35% in MedOFF/StimON, 26% in MedON/StimOFF, and 12% in MedON/StimON state). Older patients at surgery and with higher baseline UPDRS II scores were significantly less likely to benefit from STN-DBS at the level of motor asymmetry. No significant correlation between motor asymmetry and ADLs (UPDRS II) or overall QoL (PDQ-39) score was observed. Asymmetric patients had significantly higher mobility, communication, and daily living PDQ-39 sub-scores. CONCLUSIONS: Both STN-DBS and levodopa lead to a reduction in motor asymmetry. Motor symmetry is associated with improvements in certain QoL sub-scores.

Pose-based tremor type and level analysis for Parkinson's disease from video.

PURPOSE: Current methods for diagnosis of PD rely on clinical examination. The accuracy of diagnosis ranges between 73 and 84%, and is influenced by the experience of the clinical assessor. Hence, an automatic, effective and interpretable supporting system for PD symptom identification would support clinicians in making more robust PD diagnostic decisions. METHODS: We propose to analyze Parkinson's tremor (PT) to support the analysis of PD, since PT is one of the most typical symptoms of PD with broad generalizability. To realize the idea, we present SPA-PTA, a deep learning-based PT classification and severity estimation system that takes consumer-grade videos of front-facing humans as input. The core of the system is a novel attention module with a lightweight pyramidal channel-squeezing-fusion architecture that effectively extracts relevant PT information and filters noise. It enhances modeling performance while improving system interpretability. RESULTS: We validate our system via individual-based leave-one-out cross-validation on two tasks: the PT classification task and the tremor severity rating estimation task. Our system presents a 91.3% accuracy and 80.0% F1-score in classifying PT with non-PT class, while providing a 76.4% accuracy and 76.7% F1-score in more complex multiclass tremor rating classification task. CONCLUSION: Our system offers a cost-effective PT classification and tremor severity estimation results as warning signs of PD for undiagnosed patients with PT symptoms. In addition, it provides a potential solution for supporting PD diagnosis in regions with limited clinical resources.

Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte-microglia C3-C3aR pathway.

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human α-synuclein overexpression (AAV-hα-Syn). This scenario was further validated in A53T α-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, α-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte-microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated α-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.

Disfunción urinaria en la enfermedad de Parkinson: una revisión práctica / Urinary dysfunction in Parkinson's disease: a practical review

Resumen La enfermedad de Parkinson (EP) es una enfermedad multisistémica de naturaleza neurodegenerativa, que clínicamente se caracteriza por presencia de síntomas motores como bradicinesia, rigidez, temblor en reposo e inestabilidad postural. Sin embargo, también pueden estar presentes síntomas no motores que constituyen trastornos del ánimo, trastornos del sueño, disfunción cognitiva o disfunción autonómica. Dentro de las disfunciones autonómicas, los síntomas urinarios se han documentado en los pacientes con enfermedad de Parkinson. Los síntomas urinarios más comunes son la nicturia, urgencia urinaria, aumento de la frecuencia miccional e incontinencia de urgencia. El presente artículo hace una revisión narrativa de la literatura actual sobre los mecanismos fisiopatológicos, manifestaciones clínicas, diagnóstico y tratamiento de la disfunción urinaria en pacientes con enfermedad de Parkinson.

Parkinson's disease (PD) is a neurodegenerative multisystemic diseases, which is clinically characterized by the presence of motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability. However, non-motor symptoms constituting mood disorders, sleep disorders, cognitive dysfunction, or autonomic dysfunction may also be present. Within autonomic dysfunctions, urinary symptoms have been documented in patients with Parkinson's disease. The most common urinary symptoms are nocturia, urinary urgency, increased urinary frequency, and urge incontinence. This article makes a narrative review of the current literature on the pathophysiological mechanisms, clinical manifestations, diagnosis and treatment of urinary dysfunction in patients with Parkinson's disease.

Identification of an early-stage Parkinson's disease neuromarker using event-related potentials, brain network analytics and machine-learning.

OBJECTIVE: The purpose of this study is to explore the possibility of developing a biomarker that can discriminate early-stage Parkinson's disease from healthy brain function using electroencephalography (EEG) event-related potentials (ERPs) in combination with Brain Network Analytics (BNA) technology and machine learning (ML) algorithms. BACKGROUND: Currently, diagnosis of PD depends mainly on motor signs and symptoms. However, there is need for biomarkers that detect PD at an earlier stage to allow intervention and monitoring of potential disease-modifying therapies. Cognitive impairment may appear before motor symptoms, and it tends to worsen with disease progression. While ERPs obtained during cognitive tasks performance represent processing stages of cognitive brain functions, they have not yet been established as sensitive or specific markers for early-stage PD. METHODS: Nineteen PD patients (disease duration of ≤2 years) and 30 healthy controls (HC) underwent EEG recording while performing visual Go/No-Go and auditory Oddball cognitive tasks. ERPs were analyzed by the BNA technology, and a ML algorithm identified a combination of features that distinguish early PD from HC. We used a logistic regression classifier with a 10-fold cross-validation. RESULTS: The ML algorithm identified a neuromarker comprising 15 BNA features that discriminated early PD patients from HC. The area-under-the-curve of the receiver-operating characteristic curve was 0.79. Sensitivity and specificity were 0.74 and 0.73, respectively. The five most important features could be classified into three cognitive functions: early sensory processing (P50 amplitude, N100 latency), filtering of information (P200 amplitude and topographic similarity), and response-locked activity (P-200 topographic similarity preceding the motor response in the visual Go/No-Go task). CONCLUSIONS: This pilot study found that BNA can identify patients with early PD using an advanced analysis of ERPs. These results need to be validated in a larger PD patient sample and assessed for people with premotor phase of PD.

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Multimodal exercise program contributes to balance and motor functions in men and women with Parkinson's disease differently: an intervention study

Abstract Aim: To verify the effects of a multimodal exercise program on balance and motor functions, and the differences by sex, in people with Parkinson's disease (PD). Methods: The intervention study, was composed of 16 people with PD, that were assessed before and after 16 weeks of interventions with the multimodal exercise program. The effects were analyzed generally and by sex, using the Wilcoxon Test. The significance level was established at 5%. Results: Overall, there was an improvement in the strength of the lower limbs (LL) (p = 0.035) and upper limbs (UL) (p = 0.009), functional mobility (p = 0.003), gait (p = 0.050), balance (p = 0.001) and in motor scores of UPDRS III (p = 0.005), which categorize motor symptoms of the disease. In regards to sex, women affected muscle strength (p = 0.044) and flexibility of LL (p = 0.028), gait (p = 0.018), and motor aspects of the UPDRS III (p = 0.042). The men presented effects in muscle strength of the UL (p = 0.042). Women and men had a significant increase in functional mobility (p = 0.046 and p = 0.027, respectively) and in balance (p = 0.012 and p = 0.042, respectively). There was no significant difference for both sexes, in body mass and the reach behind the backtest. Conclusion: the multimodal exercise program contributed to the improvement in motor function and balance in men and women with PD. Nevertheless, the effects were more significant in women. The comprehension of the differences between men and women grants us a more directional and efficient approach to their treatment.

Comparison of cognitive performance between patients with Parkinson's disease and dystonia using an intraoperative recognition memory test.

Neuroscientific studies on the function of the basal ganglia often examine the behavioral performance of patients with movement disorders, such as Parkinson's disease (PD) and dystonia (DT), while simultaneously examining the underlying electrophysiological activity during deep brain stimulation surgery. Nevertheless, to date, there have been no studies comparing the cognitive performance of PD and DT patients during surgery. In this study, we assessed the memory function of PD and DT patients with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). We also tested their cognitive performance during the surgery using a continuous recognition memory test. The results of the MoCA and MMSE failed to reveal significant differences between the PD and DT patients. Additionally, no significant difference was detected by the intraoperative memory test between the PD and DT patients. The intraoperative memory test scores were highly correlated with the MMSE scores and MoCA scores. Our data suggest that DT patients perform similarly to PD patients in cognitive tests during surgery, and intraoperative memory tests can be used as a quick memory assessment tool during surgery.

Common Factors of Alzheimer's Disease and Rheumatoid Arthritis-Pathomechanism and Treatment.

The accumulation of amyloid plaques, or misfolded fragments of proteins, leads to the development of a condition known as amyloidosis, which is clinically recognized as a systemic disease. Amyloidosis plays a special role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and rheumatoid arthritis (RA). The occurrence of amyloidosis correlates with the aging process of the organism, and since nowadays, old age is determined by the comfort of functioning and the elimination of unpleasant disease symptoms in the elderly, exposure to this subject is justified. In Alzheimer's disease, amyloid plaques negatively affect glutaminergic and cholinergic transmission and loss of sympathetic protein, while in RA, amyloids stimulated by the activity of the immune system affect the degradation of the osteoarticular bond. The following monograph draws attention to the over-reactivity of the immune system in AD and RA, describes the functionality of the blood-brain barrier as an intermediary medium between RA and AD, and indicates the direction of research to date, focusing on determining the relationship and the cause-effect link between these disorders. The paper presents possible directions for the treatment of amyloidosis, with particular emphasis on innovative therapies.

Subthalamic-Cortical Network Reorganization during Parkinson's Tremor.

Tremor, a common and often primary symptom of Parkinson's disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from 10 patients (9 male, 1 female) performing a naturalistic visual-motor task. From this task, we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.SIGNIFICANCE STATEMENT Tremor is a common symptom of Parkinson's disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this article, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinson's tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.

Determinants of quality of life in Parkinson's disease: a perspective of novel clinical subtypes.

OBJECTIVE: New subtyping classification systems of Parkinson's disease (PD) have been proposed for phenotyping patients into three different subtypes: mild motor-predominant (PD-MMP), intermediate (PD-IM) and diffuse malignant (PD-DM). The quality of life (QoL) underlying the novel PD clinical subtypes is unknown. This study aimed explore the feasibility of the classification in Chinese PD patients and to investigate the potential heterogeneous determinants of QoL among the three subtypes. METHODS: 298 PD patients were enrolled, including 129 PD-MMP patients, 121 PD-IM patients and 48 PD-DM patients. All patients completed the QoL assessment, clinical evaluations and neuropsychological tests. Univariate linear analysis and multiple stepwise regression analysis were performed to identify determinants of QoL. RESULTS: Compared to PD-MMP patients, PD-IM and PD-DM patients had more impaired QoL. The Geriatric Depression Rating Scale (GDS) score, Non-Motor Symptoms Questionnaire (NMSQ) score, Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score and Epworth Sleepiness Score (ESS) were independent contributors to QoL in PD-MMP patients. The GDS score, ESS and sniffin' sticks screening 12 test score were independent contributors to QoL in PD-IM patients. The GDS score and Mini Mental State Examination score were independent contributors to QoL in PD-DM patients. INTERPRETATION: The new novel subtyping classification is feasible for Chinese PD patients. Although depression was the most crucial determinant for QoL in PD-MMP, PD-IM and PD-DM patients, the other contributors of QoL in the three subtypes were heterogeneous. These findings may prompt clinicians to target specific factors for improving QoL depending on PD subtypes.