Heart-brain synchronization breakdown in Parkinson's disease.

Heart rate variability (HRV) abnormalities are potential early biomarkers in Parkinson's disease (PD) but their relationship with central autonomic network (CAN) activity is not fully understood. We analyzed the synchronization between HRV and brain activity in 31 PD patients and 21 age-matched healthy controls using blood-oxygen-level-dependent (BOLD) signals from resting-state functional brain MRI and HRV metrics from finger plethysmography recorded for 7.40 min. We additionally quantified autonomic symptoms (SCOPA-AUT) and objective autonomic cardiovascular parameters (blood pressure and heart rate) during deep breathing, Valsalva, and head-up tilt, which were used to classify the clinical severity of dysautonomia. We evaluated HRV and BOLD signals synchronization (HRV-BOLD-sync) with Pearson lagged cross-correlations and Fisher's statistics for combining window-length-dependent HRV-BOLD-Sync Maps and assessed their association with clinical dysautonomia. HRV-BOLD-sync was lower significantly in PD than in controls in various brain regions within CAN or in networks involved in autonomic modulation. Moreover, heart-brain synchronization index (HBSI), which quantifies heart-brain synchronization at a single-subject level, showed an inverse exposure-response relationship with dysautonomia severity, finding the lowest HBSI in patients with severe dysautonomia, followed by moderate, mild, and, lastly, controls. Importantly, HBSI was associated in PD, but not in controls, with Valsalva pressure recovery time (sympathetic), deep breathing E/I ratio (cardiovagal), and SCOPA-AUT. Our findings support the existence of heart-brain de-synchronization in PD with an impact on clinically relevant autonomic outcomes.

Characterization of molecular biomarkers in cerebrospinal fluid and serum of E46K-SNCA mutation carriers.

INTRODUCTION: Blood and cerebrospinal fluid represent emerging candidate fluids for biomarker identification in Parkinson's disease (PD). METHODS: We studied 8 individuals carrying the E46K-SNCA mutation (3 PD dementia (PDD), 1 tremor-dominant PD, 2 young rigid-akinetic PD and 2 asymptomatic) and 8 age- and sex-matched healthy controls. We quantified the levels of total alpha-synuclein (a-syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with SiMoA (Quanterix) in cerebrospinal fluid (CSF) of mutation carriers and in serum of all participants. The correlation between the concentration of biofluid markers and clinical outcomes was evaluated. RESULTS: Although based on a small number of cases, CSF a-syn was decreased in symptomatic E46K-SNCA carriers compared to the asymptomatic ones. Asymptomatic carriers exhibited similar serum biomarker levels as compared to matched controls, except for serum a-syn, which was higher in asymptomatic individuals. Carriers with PDD diagnosis displayed increased levels of serum NfL and GFAP compared to matched controls. These findings highly correlated with cognitive and motor status of E46K-SNCA carriers, but not with disease duration. CONCLUSIONS: Patients with familial forms of neurodegenerative disease exhibit variable penetrance of the phenotype and are exceptionally valuable for delineating biomarkers. Serum and CSF molecular biomarkers in E46K-SNCA mutation carriers show that a-syn might be suitable to track the conversion from asymptomatic to PD, whereas NfL and GFAP might serve to foresee the progression to PD dementia. These findings should be interpreted with caution and need to be replicated in other genetic synucleinopathy cohorts.

Blood Pressure and Risk of Cognitive Impairment: The Role of Vascular Disease in Neurodegeneration.

(1) Background: Both cerebral vascular disorders and cognitive decline increase in incidence with age. The role of cerebral vascular disease and hemodynamic changes in the development of cognitive deficits is controversial. The objective of this study was to assess the cardiovascular response during cardiac stress testing in neurologically asymptomatic individuals who developed cognitive impairment several years after previous cardiac stress testing. (2) Methods: This was a retrospective cohort study of patients who underwent cardiac stress testing between January 2001 and December 2010. Patients were followed up until May 2015, and we selected those who developed cognitive dysfunction including dementia, mild cognitive impairment, and subjective cognitive decline, after the stress test. Heart rate and blood pressure both at rest and at peak exercise, and the mean R-R interval at rest were recorded. For each patient who developed cognitive impairment, we selected one matched control who did not show cognitive decline by the end of the follow-up period. (3) Results: From the cohort of 7224 patients, 371 developed cognitive impairment; of these, 186 (124 men) met the inclusion criteria, and 186 of the other patients were selected as matched controls. During follow-up, cognitive impairment appeared 6.2 ± 4.7 years after the cardiac stress test. These patients who had subsequently developed cognitive impairment had significantly lower at-rest systolic, diastolic, and mean blood pressure than controls (p < 0.05). Further, compared with controls, their maximum heart rate was significantly higher at peak exercise. (4) Conclusion: The results from this study suggest that differences in cardiovascular response to stress might be present in individuals who develop cognitive decline. These findings challenge the possibility of assessing blood pressure and heart rate variability at rest and during cardiac stress as potential risk factors associated with cognitive impairment.

Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease.

OBJECTIVE: This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD). METHODS: Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs. RESULTS: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63µm in iPD patients and 0.23µm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration. INTERPRETATION: Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165-176.

Microglia is associated with p-Tau aggregates in the olfactory bulb of patients with neurodegenerative diseases.

The olfactory bulb (OB) seems to be the first affected structure in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Deposits of protein aggregates, increased dopaminergic neurons, and decreased cholinergic inputs have all been described in the OB of these diseases. We investigated here the contribution of the activated microglial cells to the increased deposits of protein aggregates. We quantified the number of activated microglial cells and astrocytes in the OB of patients with histological diagnosis of PD (n = 5), AD (n = 13), and LBD (n = 7) and aged-matched controls (n = 8). Specific consensus diagnostic criteria were applied for AD, LBD, and PD. Protein aggregates were scored in the OB as grade 0, none; grade 1, mild; grade 2, moderate; and grade 3, severe. OB sections from the 33 subjects were stained with specific antibodies markers for reactive astrocytes (GFAP) and microglial cells (Iba1 and HLA-DR). The total number of Iba1-ir (Iba-immunoreactive) and HLAD-DR cells was estimated by stereological analysis, while quantification of astrocytes was performed by GFAP optical density. Statistical analysis was done using the Stata 12.0 software. The number of microglia and activated microglia cells (HLA-RD-ir) was increased in patients with neurodegenerative diseases (p < 0.05). Moreover, the density of GFAP-ir cells was higher in the OB of patients. Neither the number of microglia cells nor the density of astrocytes correlated with the number of b-amyloid and alpha-synuclein deposits, but the density of Iba1-ir cells correlated with the number of p-Tau aggregates. Activated microglial cells and reactive astrocytes are present in the OB of patients with neurodegenerative diseases. The lack of correlation between the number of activated microglia cells and protein deposits indicate that they might independently contribute to the degenerative process. The presence of microglia is related to phosphorylated Tau deposits in neurodegenerative diseases.

Neurological reasons for consultation and hospitalization during the COVID-19 pandemic.

BACKGROUND: COVID-19 disease affects the nervous system and led to an increase in neurological consults for patients at admission and through the period of hospitalization during the peak of the pandemic. METHODS: Patients with clinical and laboratory diagnosis of COVID-19 that required a neurologic consultation or those who presented with neurological problems on admission that led to a diagnosis of SARS-CoV-2 infection during a 2-month period at the peak of the pandemic were included in this study. Demographic and clinical variables were analyzed. RESULTS: Thirty-five patients were included. The presenting neurologic manifestations on admission led to the diagnosis of COVID-19 in 14 patients (40%). The most common reasons for consultation during the hospitalization period were stroke (11), encephalopathy (7), seizures (6), and neuropathies (5) followed by a miscellaneous of syncope (2), migraine (1), anosmia (1), critical illness myopathy (1), and exacerbation of residual dysarthria (1). The most common neurological disturbances were associated with severe disease except for neuropathies. Patients with encephalopathies and seizures had markedly increased D-dimer and ferritin values, even higher than stroke patients. RT-PCR was performed in 8 CSF samples and was negative in all of them. CONCLUSION: Neurological disturbances represent a significant and severe burden in COVID-19 patients, and they can be the presenting condition that leads to the diagnosis of the viral infection in a high percentage of patients. Evidence of direct viral mechanisms was scarce, but the pathogenesis of the diverse manifestations remains enigmatic.

CAV-2-Mediated GFP and LRRK2G2019S Expression in the Macaca fascicularis Brain.

Parkinson's disease is characterized by motor and nonmotor symptoms that gradually appear as a consequence of the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Currently, no treatment can slow Parkinson's disease progression. Inasmuch, there is a need to develop animal models that can be used to understand the pathophysiological mechanisms underlying dopaminergic neuron death. The initial goal of this study was to determine if canine adenovirus type 2 (CAV-2) vectors are effective gene transfer tools in the monkey brain. A second objective was to explore the possibility of developing a large nonhuman primate that expresses one of the most common genetic mutations causing Parkinson's disease. Our studies demonstrate the neuronal tropism, retrograde transport, biodistribution, and efficacy of CAV-2 vectors expressing GFP and leucine-rich repeat kinase 2 (LRRK2G2019S) in the Macaca fascicularis brain. Our data also suggest that following optimization CAV-2-mediated LRRK2G2019S expression could help us model the neurodegenerative processes of this genetic subtype of Parkinson's disease in monkeys.

Autonomic dysfunction is associated with neuropsychological impairment in Lewy body disease.

OBJECTIVE: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD). METHODS: We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue. RESULTS: Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory). CONCLUSION: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.

Cardiac sympathetic innervation in the MPTP non-human primate model of Parkinson disease.

PURPOSE: Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces degeneration of dopaminergic neurons and reproduces the motor features of Parkinson disease (PD); however, the effect of MPTP on extranigral structures has been poorly studied. The aim of this research was to study the cardiac sympathetic innervation of control and MPTP-treated monkeys in order to describe the influence of MPTP toxicity on cardiac tissue. METHODS: Eight monkeys were included in the study and divided into two groups, four monkeys serving as controls and four forming the MPTP group. Sections from the anterior left ventricle were immunohistochemically examined to characterize the sympathetic fibers of cardiac tissue. The intensity of immunoreactivity in the nerve fibers was quantitatively analyzed using ImageJ software. RESULTS: As occurs in PD, the sympathetic peripheral nervous system is affected in MPTP-treated monkeys. The percentage of tyrosine hydroxylase immunoreactive fibers in the entire fascicle area was markedly lower in the MPTP group (24.23%) than the control group (35.27%) (p < 0.05), with preservation of neurofilament immunoreactive fibers in the epicardium of MPTP-treated monkeys. Alpha-synuclein deposits were observed in sections of the anterior left ventricle of MPTP-treated monkeys but not in control animals, whereas phosphorylated synuclein aggregates were not observed in either controls or MPTP-treated monkeys. CONCLUSION: The peripheral autonomic system can also be affected by neurotoxins that specifically inhibit mitochondrial complex I.

The relationship between inflammatory bowel disease and Parkinson's disease: true or fiction?

Gastrointestinal (GI) symptoms can precede by many years the motor symptoms of Parkinson's disease (PD) and these patients can show some degree of inflammation associated with abnormal aggregates of alpha-synuclein in the GI tract. The abnormal accumulation of alpha-synuclein and the spreading of the aggregates from the gut to the brain might be promoted by inflammation, rising the hypothesis of a possible relationship between inflammatory bowel disease and PD. Many population-based studies have explored this association, but they have found conflicting results. It is essential to clarify this hypothesis and to try to elucidate the milestones of this relationship. There is no clear concordance between the results and the interpretation of different previous findings, probably due to many confounding factors such as drugs with anti-inflammatory activity, surgery, genetic predisposition and also selection bias. If there is a real association between both diseases, gastroenterologists and neurologists should be able to detect possible triggers of the disease or on the other hand, protective factors, that may be considered in clinical practice.

Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers.

BACKGROUND AND OBJECTIVE: In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls. PATIENTS AND METHODS: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan). RESULTS: All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035). INTERPRETATION: These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.

History and future challenges of the subthalamic nucleus as surgical target: Review article.

For many years the subthalamic nucleus had a poor reputation among neurosurgeons as a result of the acute movement disorders that develop after its lesion or manipulation through different surgical procedures. However, this nucleus is now considered a key structure in relation to parkinsonism, and it is currently one of the preferred therapeutic targets for Parkinson's disease. The implication of the subthalamic nucleus in the pathophysiology of chorea and in the parkinsonian state is thought to be related to its role in modulating the basal ganglia, a fundamental circuit in movement control. Indeed, recent findings have renewed interest in this anatomical structure. Accordingly, this review aims to present a history of the subthalamic nucleus, evolving from the classic surgical concepts associated with the avoidance of this structure, to our current understanding of its importance based on findings from more recent models. Future developments regarding the relationship of the subthalamic nucleus to neuroprotection are also discussed in this review. © 2018 International Parkinson and Movement Disorder Society.

Effect of Dexmedetomidine and Propofol on Basal Ganglia Activity in Parkinson Disease: A Controlled Clinical Trial.

BACKGROUND: Deep brain stimulation electrodes can record oscillatory activity from deep brain structures, known as local field potentials. The authors' objective was to evaluate and quantify the effects of dexmedetomidine (0.2 µg·kg·h) on local field potentials in patients with Parkinson disease undergoing deep brain stimulation surgery compared with control recording (primary outcome), as well as the effect of propofol at different estimated peak effect site concentrations (0.5, 1.0, 1.5, 2.0, and 2.5 µg/ml) from control recording. METHODS: A nonrandomized, nonblinded controlled clinical trial was carried out to assess the change in local field potentials activity over time in 10 patients with Parkinson disease who underwent deep brain stimulation placement surgery (18 subthalamic nuclei). The relationship was assessed between the activity in nuclei in the same patient at a given time and repeated measures from the same nucleus over time. RESULTS: No significant difference was observed between the relative beta power of local field potentials in dexmedetomidine and control recordings (-7.7; 95% CI, -18.9 to 7.6). By contrast, there was a significant decline of 12.7% (95% CI, -21.3 to -4.7) in the relative beta power of the local field potentials for each increment in the estimated peak propofol concentrations at the effect site relative to the control recordings. CONCLUSIONS: Dexmedetomidine (0.2 µg·kg·h) did not show effect on local field potentials compared with control recording. A significant deep brain activity decline from control recording was observed with incremental doses of propofol.

Chronic migraine: a therapeutic challenge for clinicians.

Chronic migraine is a common disabling condition. Severe migraine attacks should be treated with triptans, but these agents are contraindicated in patients with vascular problems and may not be effective or tolerated in around one third of the patients. New acute migraine therapies without vasoconstrictive activity and triptan-specific side effects are emerging. For the prophylaxis of chronic migraine, only topiramate and OnabotulinumtoxinA have been shown to be effective in placebo-controlled randomized trials, so novel therapeutic strategies are needed. The growing understanding of the pathophysiology of chronic migraine will contribute to the identification of new treatment targets.