Parkinsonian Signs Research Articles

Vowel articulation and intelligibility of speech in Spanish speakers with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus

Parkinson's disease (PD) can affect the intelligibility of speech. Although studies of vowel production are useful for measuring this impairment, they do not exist in Spanish speakers with the disease who have been treated with subthalamic nucleus deep brain stimulation (STN-DBS). STN-DBS is an effective treatment for the classic signs of PD, but with varied effects on speech. Data from two individuals with PD treated with STN-DBS were studied: one (P1) had impairment and the other (P2) had stable speech intelligibility after STN-DBS implantation. The triangular vowel space area (tVSA) and the vowel articulation index (VAI) were measured and compared before the implantation surgery, and at three, six and nine months after surgery. These measurements were compared with measurements of speech intelligibility (percentage of words correctly identified and degree of intelligibility). Both participants presented variations in measurements of vowel articulation after surgery. In P1, the reduction in the tVSA, but not the post-surgical change in the VAI, was consistent with reduced speech intelligibility. However, in P2, both measurements (tVSA and VAI) reflected stable speech intelligibility after surgery. Reduced speech intelligibility in Spanish speakers with PD after STN-DBS implantation may be reflected in a reduced tVSA.

Lipid Carrier Nanostructured Astilbin Ameliorates Rotenone-Induced Neurodegeneration in Mice Brain via Modulation of GSK3β-Nrf2 Signaling Pathways.

Astilbin is a flavanonol, found in St John's wort (Hypericum perforatum) and many other plants. It has been demonstrated that astilbin contains anti-inflammatory, antioxidant, and immune-suppressive properties. However, the bioavailability of astilbin remains a question for which drug delivery-based nanoparticles can be utilized. We formulated a nanostructured lipid carrier loaded with astilbin (NLC-AS) and tested its effects on the rotenone exposed PC12 cells and in a neurodegenerative mice model of Parkinson's disease (PD) induced by rotenone. Results show that rotenone caused dose-dependent inhibition of PC12 cell growth with about 50% cell death at 2 µM rotenone. Rotenone caused apoptosis in PC12 cells which was reduced to a notable level by NLC-AS through suppression of oxidative stress, especially via elevation of GSH and total antioxidant capacity, and inhibition of monoamine oxidase. Rotenone significantly augmented neurodegeneration in mouse brains by triggering apoptosis and oxidative damage, while NLC-AS treatment halted these processes. Rotenone-exposed mice showed neuronal deficits and impaired neurocognitive functions like loss of memory and learning restrictions which were restored to a remarkable level by NLC-AS administration. The protective effect of NLC-AS was mediated through the inhibition of GSK3β and induction of Nrf2 genes in the brain tissues. These findings suggest that NLC-AS administration may efficiently regulate the signs of PD in mice and prevent neurodegeneration and neurocognitive dysfunctions.

Brain Magnetic Resonance Imaging Findings in Chronic Kidney Disease Patients with and without Parkinsonism: A Case-Control Study

Introduction: Chronic kidney disease (CKD) poses a major public health concern on a global scale. Patients with CKD have a heightened risk of developing multiple movement disorders like parkinsonism. Timely diagnosis through imaging and effective management may hold the key to mitigating disease symptoms. Material and Methods: Twenty-eight individuals with CKD were categorized into two groups, nine patients showing signs of parkinsonism and a control group of nineteen patients without parkinsonism. All participants underwent non-contrast brain magnetic resonance imaging (MRI) scans, including T1, T2, DWI, and FLAIR sequences. The data were statistically analyzed using SPSS-24 and STATA software. Results: Nine patients exhibited parkinsonism symptoms, while nineteen did not. Brain MRI revealed hypointensities in structures like the putamen, globus pallidus, and cerebellar dentate nucleus in both groups. Comparative analysis showed no statistically significant differences in the percentages of these findings (P>0.05). Similarly, the presence of cerebral atrophy and cerebrovascular disease did not significantly differ between the groups. Factors such as diabetes, hypertension, and history of dialysis also failed to show significant distinctions (P>0.05 for all). Conclusion: The correlation between brain MRI alterations in CKD patients with parkinsonism symptoms and those without was not significant. Nevertheless, there was a strong association between the duration of CKD in patients and the presence of parkinsonism-related signs.

Phenotypic effect of GBA1 variants in individuals with and without Parkinson's disease: The RAPSODI study

BackgroundVariants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype.The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. ObjectivesTo compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. MethodsWe present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. ResultsA total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. ConclusionsOur results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.

Naringenin, a Functional Food Component, Improves Motor and Non-Motor Symptoms in Animal Model of Parkinsonism Induced by Rotenone.

Parkinson's disease (PD) and other age-related neurodegenerative ailments have a strong link to oxidative stress. Bioflavonoid naringenin has antioxidant properties. The effects of pre- and post-naringenin supplementation on a rotenone-induced PD model were examined in this work. Naringenin (50mg/kg, p.o.) was administered to rats for two weeks before the administration of rotenone in the pre-treatment phase. In contrast, rotenone (1.5mg/kg, s.c.) was administered for eight days before naringenin (50mg/kg, p.o.) was supplemented for two weeks in the post-treatment phase. During behavioral investigation, the motor and non-motor signs of PD were observed. Additionally, estimation of neurochemical and biochemical parameters was also carried out. Compared to controls, rotenone treatment substantially increased oxidative stress, altered neurotransmitters, and caused motor and non-motor impairments. Rotenone-induced motor and non-motor impairments were considerably reduced by naringenin supplementation. The supplementation also increased antioxidant enzyme activities and restored the changes in neurotransmitter levels. The findings of this work strongly imply that daily consumption of flavonoids such as naringenin may have a therapeutic potential to combat PD.

Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder.

To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years. A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

Clinical characteristics of pathological confirmed prodromal dementia with Lewy bodies

IntroductionMisdiagnosis rate of Dementia with Lewy Bodies (DLB) remains high despite being second most common cause of neurodegenerative dementia. To date, understanding of clinical profile of pathologically confirmed prodromal DLB remains limited. The main objective of this study was to describe and compare it with pathologically confirmed Alzheimer's disease (AD). MethodsWe accessed the National Alzheimer's Coordinating Center database from 2005 to December 2022 data freeze and included 111 and 501 prodromal DLB and AD patients respectively. First visit data was analyzed. ResultsClinician-determined memory impairment is common in prodromal DLB (>70%) but associated with higher risk for AD diagnosis (OR 0.355, p = 0.0003). DLB had a higher proportion of non-amnestic mild cognitive impairment (MCI) diagnoses but statistically insignificance in differentiating the two. Inattention (OR 2.273, p = 0.0015), and neuropsychiatric features, such as visual hallucinations (OR 11.98, p < 0.0001), depressed mood (OR1.709, p = 0.0292), apathy (1.824, p = 0.0345), and night/REM sleep behaviors, are associated with DLB diagnosis. Hallucinations are infrequent (7–11%). Motor symptoms, particularly gait disorders (OR 4.570, p < 0.001), falls (OR3.939, p = 0.0003), tremors (OR2.237, p = 0.0154), slowness (OR3.573, p < 0.0001), and parkinsonism signs (OR2.443, p < 0.0001), are common. 32% showed no parkinsonism during initial presentation. Neuropsychological examination revealed less impaired memory and language but impaired executive function in DLB. ConclusionIn clinical practice, it is important to note that memory symptoms although being higher risk associated with AD diagnosis, are prominent in prodromal DLB. Psychosis is infrequent, and non-amnestic MCI is not necessarily associated with higher risk of DLB diagnosis. A careful clinical approach is key to improve the diagnosis of prodromal DLB.

Nigrostriatal dysfunction in RFC1-related disorder/CANVAS

IntroductionParkinsonism is now recognized as an additional feature in RFC1/CANVAS syndrome; however, no systematic evaluation of nigrostriatal dopaminergic function has been published so far. MethodsThis is an observational, single-center study, which analyzed 13 patients with molecular confirmation of RFC1/CANVAS. Disease severity was assessed with the SARA scale. Each subject was carefully evaluated for the presence of parkinsonian features. Dopamine transporter (DAT) imaging was acquired and reconstructed in the transverse, coronal and sagittal planes 4 h after venous injection of 99mTc-TRODAT-1. An experienced nuclear physician performed the visual analysis of all images. ResultsPatients had a mean age of 62.3 ± 8.8 years, and there were 9 women. The mean SARA score was 15.5 ± 5.8. Nine patients had abnormal DAT imaging results. The putamen was more frequently affected than the caudate nucleus on both sides. Considering all regions, uptake of 99mTc-TRODAT-1 did not correlate with disease duration or SARA scores. Parkinsonism was noticed in 3/13 patients, all of which had abnormal DAT scans. Interestingly, six subjects had reduced DAT imaging uptake, but no clinical signs of parkinsonism. ConclusionNigrostriatal dysfunction is frequent in RFC1/CANVAS even in the absence of clinical parkinsonism and may occur early in the disease course.

Analysis of Behavior and Brain Neuronal Density in B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Mice Modeling Parkinson’s Disease

Parkinson’s disease (PD) is a progressive age-related neurodegenerative pathology of the central nervous system, characterized by a selective loss of dopaminergic neurons of the nigrostriatal pathway and by the presence of specific inclusions (Lewy bodies) in dopamine neurons. To study the mechanisms of this pathology and to search for possible ways to correct it, genetic models of PD in mice have been created. Transgenic mice of the B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J strain (referred as B6.Cg-Tg further in the text) represent a model of PD, have the A53T mutation in the human alpha-synuclein gene. The aim of this work was to study the locomotor activity and the level of anxiety, as well as the density of neurons in the brain of male B6.Cg-Tg mice at the age of six months. Wild type C57BL/6J mice of the same sex and age were used as controls. The results of the current study demonstrate that B6.Cg-Tg mice are characterized by the high locomotor activity and the low anxiety. Besides, a selective decrease in the density of neurons in the subventricular zone, the substantia nigra, as well as the CA1, CA3, CA4 zones and the granular layer of the dentate gyrus of the hippocampus was observed in these mice. Thus, mice of the B6.Cg-Tg strain at the age of six months only partially correspond to the main pathophysiological signs of PD. Decrease in the density of neurons in the substantia nigra, as well as in the CA1 and CA3 zones of the hippocampus of B6.Cg-Tg mice resemble similar changes in PD. However, these mice demonstrated neither bradykinesia nor high level of anxiety.

Nigral-specific increase in ser31 phosphorylation compensates for tyrosine hydroxylase protein and nigrostriatal neuron loss: Implications for delaying parkinsonian signs

Compensatory mechanisms that augment dopamine (DA) signaling are thought to mitigate onset of hypokinesia prior to major loss of tyrosine hydroxylase (TH) in striatum that occurs in Parkinson's disease. However, the identity of such mechanisms remains elusive. In the present study, the rat nigrostriatal pathway was unilaterally-lesioned with 6-hydroxydopamine (6-OHDA) to determine whether differences in DA content, TH protein, TH phosphorylation, or D1 receptor expression in striatum or substantia nigra (SN) aligned with hypokinesia onset and severity at two time points. In striatum, DA and TH loss reached its maximum (>90%) 7 days after lesion induction. However, in SN, no DA loss occurred, despite ∼60% TH loss. Hypokinesia was established at 21 days post-lesion and maintained at 28 days. At this time, DA loss was ∼60% in the SN, but still of lesser magnitude than TH loss. At day 7 and 28, ser31 TH phosphorylation increased only in SN, corresponding to less DA versus TH protein loss. In contrast, ser40 TH phosphorylation was unaffected in either region. Despite DA loss in both regions at day 28, D1 receptor expression increased only in lesioned SN. These results support the concept that augmented components of DA signaling in the SN, through increased ser31 TH phosphorylation and D1 receptor expression, contribute as compensatory mechanisms against progressive nigrostriatal neuron and TH protein loss, and may mitigate hypokinesia severity.

Mild Motor Signs in Healthy Aging Are Associated with Lower Synaptic Density in the Brain.

To investigate whether mild motor signs (MMS) in old age correlate with synaptic density in the brain. Normal aging is associated with a decline in movement quality and quantity, commonly termed "mild parkinsonian signs" or more recently MMS. Whether MMS stem from global brain aging or pathology within motor circuits remains unresolved. The synaptic vesicle glycoprotein 2A positron emission tomography (PET) ligand 11 C-UCB-J allows the investigation of brain-motor associations at the synaptic level in vivo. Fifty-eight healthy older adults (≥50 years) were included from two monocentric control cohorts. Brain magnetic resonance imaging and 11 C-UCB-J PET data were available in 54 participants. 11 C-UCB-J PET binding was quantified by standardized uptake value ratio (SUVR) values in grey matter (GM) volumes of interest (VOIs): caudate, putamen, globus pallidus, substantia nigra, thalamus, cerebellum, and the frontal, parietal, temporal, and occipital cortex. Multiple linear regression analyses were performed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score measuring MMS as the dependent variable and mean SUVR values in each VOI as the independent variable with age, Fazekas score (white matter lesion [WML] load), VOI and cohort as covariates. Participants (68 ± 7.5 years; 52% female) had an average MDS-UPDRS part III score of 3.3 ± 2.8. The MDS-UPDRS part III score was inversely associated with synaptic density, independently of WML load or GM volume, in the caudate, substantia nigra, thalamus, cerebellum, and parietal, occipital, temporal cortex. Cohen's f2 showed moderate effect sizes for subcortical (range, 0.30-0.35), cortical (0.28-0.35) and cerebellar VOIs (0.31). MMS in healthy aging are associated with lower synaptic density throughout the brain. © 2023 International Parkinson and Movement Disorder Society.

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

To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. 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. 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 (β = -0.047, p < .001) and 2015 (β = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (β = -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. 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.

Clinical and functional correlates of parkinsonism in a population-based sample of individuals aged 75 + : the Pietà study

BackgroundParkinsonism is strongly associated with ageing, and many studies have suggested that parkinsonian signs may affect up to half of older adults and is associated with a wide range of adverse health outcomes. We compared clinical and functional characteristics of oldest-old community-dwelling individuals with parkinsonism (parkinsonian group [PG]) to individuals without parkinsonism (non-parkinsonian group [NPG].MethodsThe Pietà study is a population-based study conducted in Caeté, southeast Brazil, involving 607 individuals aged 75 + years submitted to an extensive clinical evaluation. A subset of 65 PG individuals (61.5% women, median age of 82 years) was compared to 542 NPG individuals (64.8% women, median age of 80 years).ResultsPG individuals had significantly more functional impairment, clinical comorbidities (including number of falls, loss of bladder control and dysphagia) and major depression. Multivariate analysis revealed that older age, higher UPDRSm scores, lower category fluency test (animals/minute) and delayed recall memory scores were associated with PG. This group was also more cognitively impaired, with lower performance than NPG individuals in the Mini-Mental State Examination, category fluency test (animals/minute), clock drawing and in delayed recall (p < 0.001 for all tests). UPDRSm scores were the most contributing factor to cognition that independently explained variability in functionality of the entire sample.ConclusionIndividuals aged 75 + years with parkinsonism were significantly more clinically and functionally impaired in this population-based sample. Cognitive dysfunction explained most of the loss of functionality in these patients. UPDRS-m scores contributed independently to explain variability in functionality in the whole sample.

Effects of Cerebrovascular and Lewy Body Pathology on Parkinsonian Signs in Community-Dwelling Older Adults.

The roles of Lewy body (LB) and separately of cerebrovascular disease (CVD) pathologies in the severity of parkinsonian signs are well recognized in old age. We investigated whether the 2 pathologies act synergistically to further potentiate the severity of parkinsonism beyond their separate effects. We used postmortem data of decedents from 3 longitudinal community-based studies of aging who underwent annual clinical evaluation to assess parkinsonian signs using 26 items of the motor portion of a modified Unified Parkinson Disease Rating Scale. A summary score was developed from each item score to construct a global parkinsonian score, with a higher score indicating more severe parkinsonism. A detailed neuropathologic evaluation was performed to identify LB, Alzheimer disease pathology, nigral neuronal loss, atherosclerosis, macroscopic infarcts, and other CVD pathologies (arteriolosclerosis, cerebral amyloid angiopathy, and microscopic infarcts). A series of regression models with terms for LB, CVD pathology, and the interaction of LB with CVD pathologies was fit for global parkinsonism proximate to death and for individual parkinsonian signs scores including, parkinsonian gait, rigidity, tremor, and bradykinesia. In 1,753 participants (mean age at death = 89 years; 68% women), LB was observed in 26% of participants, and CVD pathologies were present in more than two-thirds of participants. LB and 3 CVD pathologies (atherosclerosis, arteriolosclerosis, and macroscopic infarcts) were each independently associated with the severity of global parkinsonism proximate to death (LB: β = 0.318, SE = 0.08, p < 0.001; atherosclerosis: β = 0.373, SE = 0.079, p < 0.001; arteriolosclerosis: β = 0.253, SE = 0.078, p = 0.001; macroscopic infarcts: β = 0.333, SE = 0.077, p < 0.001). A linear regression model adjusted for demographics, CVD, and neurodegenerative pathologies showed interaction between LB and macroscopic infarcts (β = 0.463, SE = 0.168, p = 0.006), with LBs being associated with worse global parkinsonism when macroinfarcts are present. Similar interactions were found for atherosclerosis and LBs (β = 0.371, SE = 0.173, p = 0.032) and for parkinsonian gait as the outcome (macroscopic infarcts: β = 0.662, SE = 0.239, p = 0.005; atherosclerosis: β = 0.509, SE = 0.246, p = 0.038). Findings were not affected when the 66 participants with a clinical diagnosis of Parkinson disease were excluded. By contrast, there were no interactions between LB and other CVD pathologies or between atherosclerosis and macroscopic infarcts for global parkinsonism proximate to death. These findings suggest that atherosclerosis and macroscopic infarcts interact with LB pathology to increase the severity of parkinsonism beyond their additive effects in older persons.

Task Specific Tremor in Parkinson's Disease Responds to Apomorphine.

Task specific tremor (TST) is a poorly understood entity without any standard treatments, that may subsequently develop tremor during additional tasks, later develop postural/kinetic tremor (essential tremor criteria), and later develop Parkinson's disease. The pathophysiology is not understood as it has features of tremor, dystonia, and parkinsonism. To assess response of TST to apomorphine and thus infer pathophysiology. We administered sublingual apomorphine to 8 patients diagnosed with Parkinson's disease based on clinical criteria and dopamine imaging, who all initially presented with TST and later presented other parkinsonian signs and dopamine imaging deficits. Apomorphine improved TST, which was refractory to oral levodopa and other tremor therapies, in 6/8 subjects. These results offer a treatment option for TST, which is usually refractory to other pharmacologic treatments, in patients with other parkinsonian features, and infers a dopaminergic pathophysiology of TST.

Identifying prognostic factors of dementia in individuals with mild cognitive impairment (MCI): Are statistical models adequate?

AbstractBackgroundIdentifying prognostic factors of MCI to dementia conversion is crucial. Most risk scores are developed based on selected variables using data‐driven methods from available variables in patient data. However, there is mixed evidence about the reliability of predictors selected based on data alone. Structured expert elicitation (SEE) is one approach to elicit clinician expert knowledge about relevant predictors for dementia risk. This study aims to identify critical predictors of dementia risk in persons with MCI from both SEE and random survival forests (RSF) and compare the differences between the two approaches.MethodClinical expert knowledge was quantified using SEE methodology: 11 experts (6 neurologists, 3 geriatricians, and 2 geriatric psychiatrists) were recruited to complete two rounds of surveys to rank predictors of dementia risk. RSF variable importance was used to assess the rank order of the potential predictors, according to the corresponding reduction of predictive accuracy when the predictor is replaced with its random permutation value risk using data from the Prospective Registry for Persons with Memory Symptoms of the Cognitive Neurosciences Clinic at the University of Calgary (N = 273; 26 potential predictors).ResultAccording to experts, the SEE revealed age and cerebrospinal fluid profile patterns consistent with Alzheimer’s disease (AD) as the two most important predictors of dementia risk in persons with MCI. In contrast, data‐driven RSF approach, using information from routine clinical practice without AD biomarkers, identified the Consortium to Establish a Registry for AD total score and the Montreal cognitive assessment (MoCA) total score as the most important predictors. Both approaches identified four common variables (among the top 10 predictors) included age, signs of parkinsonism, MoCA total score, and behaviour impairment.ConclusionOur findings revealed discrepancies between a data‐driven approach and SEE in identifying significant predictors of dementia in people with MCI. The SEE identified some crucial predictors, such as AD biomarker status, that are not routinely collected in registries and observational studies or available in widespread practice. Most published risk scores are not used in practice. This study offers a possible explanation: what is important to clinicians may be not included in the risk scores.

Concurrent decoding of distinct neurophysiological fingerprints of tremor and bradykinesia in Parkinson's disease.

Parkinson's disease (PD) is characterized by distinct motor phenomena that are expressed asynchronously. Understanding the neurophysiological correlates of these motor states could facilitate monitoring of disease progression and allow improved assessments of therapeutic efficacy, as well as enable optimal closed-loop neuromodulation. We examined neural activity in the basal ganglia and cortex of 31 subjects with PD during a quantitative motor task to decode tremor and bradykinesia - two cardinal motor signs of PD - and relatively asymptomatic periods of behavior. Support vector regression analysis of microelectrode and electrocorticography recordings revealed that tremor and bradykinesia had nearly opposite neural signatures, while effective motor control displayed unique, differentiating features. The neurophysiological signatures of these motor states depended on the signal type and location. Cortical decoding generally outperformed subcortical decoding. Within the subthalamic nucleus (STN), tremor and bradykinesia were better decoded from distinct subregions. These results demonstrate how to leverage neurophysiology to more precisely treat PD.

Oculomotor abnormalities indicate early executive dysfunction in prodromal X-linked dystonia-parkinsonism (XDP)

BackgroundX-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease.MethodsTwenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs.ResultsThe error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients.ConclusionsDespite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson’s disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.

Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: A case for diminished GDNF-signaling

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance statementAlthough preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson's disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.

The Anatomy and Clinical Significance of Sensory Disturbance in Parkinson's Disease.

The clinical features of Parkinson's disease (PD) include tremors and rigidity. However, paresthesia has not drawn clinical attention. PD involves the whole body and begins with gastrointestinal lesions, which do not start in the midbrain substantia nigra, but from the beginning of the medulla oblongata of the glossopharyngeal nerve nuclei, to the motor nerve dorsal nucleus of the vagus nerve, to the pons and midbrain, and finally to the neocortex. The human eye, ear, nose, tongue, and body perceive the external world. (1) Visual impairment in patients with PD can be easily confused with senile eye disease. This change in retinal pigment cells has many similarities to the degeneration of dopaminergic neurons in the substantia nigra in PD. (2) Selective high-frequency hearing impairment can cause a certain degree of communication barriers, only understanding the son's bass but not the daughter's soprano, and there is a certain relationship between hearing and body postural balance. (3) Olfactory loss is one of the earliest signs of PD and an important indicator for the early screening of PD. (4) Taste disorders, including loss of taste and taste memory, can cause cognitive impairment. (5) The body's sense of touch, pressure, pain, temperature, and position abnormalities interfere with the motor symptoms of PD and seriously affect the quality of life of patients. This article discusses vision, hearing, smell, taste, touch, and analyses of neuroanatomy and pathology, revealing its clinical significance.