Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity ...or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials.
Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical ...fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy.
High angular resolution diffusion imaging in twenty patients with advanced Parkinson's disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy.
All patients responded well to treatment (46% mean improvement off medication UPDRS-III p < 0.0001) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = −10(−9.5), Y = −13(-1) and Z = −7(−3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity.
These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia.
•Optimal DBS tissue activation areas are identified in the subthalamic nucleus.•Stimulation in the supero-lateral subthalamic nucleus is most effective.•Connectivity pattern predicts improvement in cardinal symptoms in Parkinson's.
The ultimate goal in Parkinson's disease (PD) research remains the identification of treatments that are capable of slowing or even halting the progression of the disease. The failure of numerous ...past disease-modification trials in PD has been attributed to a variety of factors related not only to choosing wrong interventions, but also to using inadequate trial designs and target populations. In patients with clinically established PD, neuronal pathology may already have advanced too far to be modified by any intervention. Based on such reasoning, individuals in yet prediagnostic or prodromal disease stages, may provide a window of opportunity to test disease-modifying strategies. There is now sufficient evidence from prospective studies to define diagnostic criteria for prodromal PD and several approaches have been studied in observational cohorts. These include the use of PD-risk algorithms derived from multiple established risk factors for disease as well as follow-up of cohorts with single defined prodromal markers like hyposmia, rapid eye movement sleep behavior disorders, or PD gene carriers. In this review, we discuss recruitment strategies for disease-modification trials in various prodromal PD cohorts, as well as potential trial designs, required trial durations, and estimated sample sizes. We offer a concluding outlook on how the goal of implementing disease-modification trials in prodromal cohorts might be achieved in the future.
The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM ...sleep behavior disorder (iRBD) over an observational period of 5 years.
Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin' Sticks test assessing odor identification, odor discrimination, and olfactory threshold. Patients with iRBD were prospectively followed up over a period of 4.9 ± 0.3 years (mean ± SD). The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria.
After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) with iRBD developed a Lewy body disease (6 Parkinson disease and 3 dementia with Lewy bodies). The entire Sniffin' Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4% (95% confidence interval: 66.1%-92.0%) in predicting conversion. The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 (95% confidence interval: 1.8-29.6) compared with the top 2 tertiles.
Assessment of olfactory function, particularly odor identification, may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials.
The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease ...(PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.
•The thalamic target for surgery for tremor is not readily visible on conventional MRI.•Probabilistic tractography is used to segment the thalamus based on connectivity.•The best target area is connected to the contralateral dentate cerebellar nucleus.•GPU processing is used to segment the thalamus in a clinically feasible timescale.•This technique can map out the DRT tract with clear mesencephalic crossing.
Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined.
In a cross-sectional investigation of the ...population-based Bruneck Study cohort, 488 community-residing elderly aged 60-97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored.
Overall, 32.2% (95% confidence interval CI 28.2%-36.4%) of participants presented with impaired gait. Prevalence increased with age (p<0.001), but 38.3% (95%CI 30.1%-47.3%) of the subjects aged 80 years or older still had a normally preserved gait. A total of 24.0% (95%CI 20.4%-28.0%) manifested neurological gait disorders, 17.4% (14.3%-21.0%) non-neurological gait problems, and 9.2% (6.9%-12.1%) a combination of both. While there was no association of neurological gait disorders with gender, non-neurological gait disorders were more frequent in women (p = 0.012). Within the group of neurological gait disorders 69.2% (95%CI 60.3%-76.9%) had a single distinct entity and 30.8% (23.1%-39.7%) had multiple neurological causes for gait impairment. Gait disorders had a significant negative impact on quantitative gait measures, but only neurological gait disorders were associated with recurrent falls (odds ratio 3.3; 95%CI 1.4-7.5; p = 0.005 for single and 7.1; 2.7-18.7; p<0.001 for multiple neurological gait disorders). Finally, we detected a significant association of gait disorders, in particular neurological gait disorders, with depressed mood, cognitive dysfunction, and compromised quality of life.
Gait disorders are common in the general elderly population and are associated with reduced mobility. Neurological gait disorders in particular are associated with recurrent falls, lower cognitive function, depressed mood, and diminished quality of life.
Purpose
To assess patient characteristics associated with health-related quality of life (HR-QoL) and its mental and physical subcategories 3 months after diagnosis with COVID-19.
Methods
In this ...prospective multicentre cohort study, HR-QoL was assessed in 90 patients using the SF-36 questionnaire (36-item Short Form Health Survey), which consists of 8 health domains that can be divided into a mental and physical health component. Mental health symptoms including anxiety, depression, and post-traumatic stress disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and Post-traumatic Stress Disorder Checklist-5 (PCL-5) 3 months after COVID-19. Using descriptive statistics and multivariable regression analysis, we identified factors associated with impaired HR-QoL 3 months after COVID-19 diagnosis.
Results
Patients were 55 years of age (IQR, 49–63; 39% women) and were classified as severe (23%), moderate (57%), or mild (20%) according to acute disease severity. HR-QoL was impaired in 28/90 patients (31%). Younger age per year, adjOR (95%CI) 0.94 (0.88–1.00),
p
= 0.049, longer hospitalization per day, adjOR (95%CI) 1.07 (1.01–1.13),
p
= 0.015, impaired sleep adjOR (95%CI) 5.54 (1.2–25.61),
p
= 0.028, and anxiety adjOR (95%CI) 15.67 (3.03–80.99),
p
= 0.001) were independently associated with impaired HR-QoL. Twenty-nine percent (
n
= 26) scored below the normal range on the mental health component of the SF-36 and independent associations emerged for anxiety, depression, and self-reported numbness. Impairments in the physical health component of the SF-36 were reported by 12 (13%) patients and linked to hypogeusia and fatigue.
Conclusion
Every third patient reported a reduction in HR-QoL 3 months after COVID-19 diagnosis and impairments were more prominent in mental than physical well-being.
Abstract Parkinson's disease (PD) is known as a chronic neurodegenerative disorder with a relentlessly progressive course of illness. Although in recent decades there have been many advances in ...symptomatic therapy, there is still no established therapy that will halt or slow progression in a clinically meaningful way. So far, disease-modification trials have focused on indices of progression of cardinal motor features such as bradykinesia, rigidity and tremor as captured by the Unified Parkinson's Disease Rating Scale, and the emerging need for effective symptomatic dopaminergic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation, leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites inevitably leads to poorly l -dopa-responsive motor symptoms such as postural instability, freezing and falls, or non-motor symptoms. Furthermore, treatment-induced motor complications also contribute to PD disability. Progression of PD is multidimensional with superimposed age-related co-morbidities. Hence there is no consensus on how to best implement more clinically meaningful end-points for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers identifying preclinical stages of illness and describing disease progression – thus faithfully reflecting early and advancing neurodegeneration – that could be used in short-term clinical trials testing putative disease-modifying agents.
Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia ...have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.
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