Parkinson's disease is a progressive neurological disorder characterized by the preferential loss of dopaminergic neurons in the substantia nigra, which project to the striatum.
Parkinson's disease (PD) is a neurodegenerative disease involving the basal ganglia, resulting in motor and extra-motor deficits. These extra-motor deficits may be reflective of a self-regulatory deficit impacting patients' ability to regulate cognitive processes, thoughts, behaviors, and emotions.
With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD.
Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration 1).
Current subtype classifications may not be sufficiently robust to warrant formal delineation.
see also Tremor predominant Parkinson's disease.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease.
Typically, people with Parkinson's disease receive the diagnosis in the sixth or seventh decade of life. Age is the most important risk factor for the disease, and it has been estimated that 1 to 2% of people older than 60 years of age are affected.
Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury, and macroautophagy in Parkinson disease and related conditions remain enigmatic 2).
Although the exact etiology is unknown, sporadic PD is hypothesized to be a result of genetic susceptibility interacting with environmental insult. Epidemiological studies suggest that pesticide exposure is linked to higher PD risk, but there are no studies demonstrating SN changes with chronic pesticide exposure in human subjects.
The changes detected by MRI may mark “one of the hits” leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD 3).
Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD 4).
Diagnosis largely depends on clinical observation, but motor dysfunctions do not emerge until 70%-80% of the nigrostriatal nerve terminals have been destroyed. Therefore, a biomarker that indicates the degeneration dopaminergic neurons is urgently needed.
DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms 5).
Axial motor signs-including gait impairment, postural instability and postural abnormalities-are common and debilitating symptoms in patients with advanced Parkinson disease. Dopamine replacement therapy and physiotherapy provide, at best, partial relief from axial motor symptoms.
The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.
Thirty-eight of 45 patients enrolled at five sites completed a 5-year follow-up study. There were 26 patients with ET and 19 with PD undergoing 29 unilateral (18 ET/11 PD) and 16 bilateral (eight ET/eight PD) procedures. Patients with ET were evaluated using the Tremor Rating Scale, and patients with PD were evaluated using the Unified Parkinson's Disease Rating Scale. The mean age of patients with ET was 70.2 years and 66.3 years in patients with PD. Unilaterally implanted patients with ET had a 75% improvement of the targeted hand tremor; those with bilateral implants had a 65% improvement in the left hand and 86% in the right compared with baseline. Parkinsonian patients with unilateral implants had an 85% improvement in the targeted hand tremor and those with bilateral implants had a 100% improvement in the left hand and 90% improvement in the right. Common DBS-related adverse events in patients receiving unilateral implants were paresthesia (45%) and pain (41%), and in patients receiving implants bilaterally dysarthria (75%) and balance difficulties (56%) occurred. Device-related surgical revisions other than IPG replacements occurred in 12 (27%) of the 45 patients.
Thalamic stimulation is safe and effective for the long-term management of essential and Parkinsonian tremors. Bilateral stimulation can cause dysarthria and incoordination and should be used cautiously 6).
Jankovic et al. retrospectively analyzed the outcomes of 60 patients (62 patient sides) with medically intractable tremor who underwent stereotactic thalamotomy. Of these 60 patients, 42 had Parkinson's disease (of whom 2 patients underwent bilateral surgery for a total of 44 patient sides), 6 had essential tremor, 6 had cerebellar tremor, and 6 had post-traumatic tremor. The patients received follow-up for as long as 13 years (mean, 53.4 mo) after their operations. At the most recent follow-up visit, 86% of the patients with Parkinson's disease, 83% of the patients with essential tremor, 67% of the patients with cerebellar tremor, and 50% of the patients with post-traumatic tremor had cessation of or moderate-to-marked improvement in their contralateral tremor, with a concomitant improvement in function. The mean daily dose of levodopa for those patients preoperatively taking levodopa (n = 35) was reduced by approximately 156 mg at a mean of 53.4 months after thalamotomy. Immediate postoperative complications were common, occurring in 58% of patients. The most common complications were contralateral weakness (34%), dysarthria (29%), and confusion (23%). These complications generally resolved rapidly during the postoperative period 7).
31 patients underwent deep brain stimulation (DBS) surgery for motor symptom treatment. Patients completed measures indicative of SR and EF including neurocognitive tests, heart rate variability (HRV), and self-report questionnaires to examine these constructs in PD. The highest prevalence of impairments were observed for total impulse control disorder (ICD) symptoms (74%), depressive symptoms (48%), verbal fluency (phonemic: 39%; semantic: 36%), mental flexibility (32%), and self-reported SR impairments (Metacognition: 32%; Behavioral Regulation: 29%). Correlations among theoretically related constructs (i.e., SR, EF) were modest and variable; challenging the idea that SR is a unitary construct for which different domains depend on a common resource. In patients with PD post-DBS, higher resting HRV, thought to be indicative of better autonomic functioning, was linked to better EF in some instances but not others and not significantly associated with self-report SR. Overall, patients with PD exhibit various extra-motor deficits, ranging from subtle to severe. Health care professionals working with patients with PD should recognize the presence of extra-motor deficits, particularly ICDs, and obstacles that might arise from such impairments in patients' daily lives 8).
By applying a non-targeted and mass spectrometry-driven approach, Trezzi et al. investigated the CSF metabolome of 44 early-stage sporadic PD patients yet without treatment (DeNoPa cohort). They compared all detected metabolite levels with those measured in CSF of 43 age- and gender-matched healthy controls. After this analysis, they validated the results in an independent PD study cohort (Tübingen cohort).
They identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers-mannose, threonic acid, and fructose-and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800.
They identified PD-specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. The results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early-stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early-stage PD 9).
Sixty-nine participants with PD completed a Simon response conflict task and Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) scales based on Gray's (1987) reinforcement sensitivity theory. Analyses determined relationships between BIS, BAS, and the susceptibility to making impulsive action errors and the proficiency of inhibiting interference from action impulses.
BIS scores correlated positively with rates of impulsive action errors, indicating that participants endorsing low BIS tendencies were much more susceptible to acting on strong motor impulses. Analyses of subgroups with high versus low BIS scores confirmed this pattern and ruled out alternative explanations in terms of group differences in speed-accuracy tradeoffs. None of the scores on the BIS or BAS scales correlated with reactive inhibitory control.
PD participants who endorse diminished predilection toward monitoring and avoiding aversive experiences (low BIS) show much greater difficulty restraining fast, impulsive motor errors. Establishing relationships between motivational sensitivities and cognitive control processes may have important implications for treatment strategies and positive health outcomes in participants with PD, particularly those at risk for falling and driving difficulties related to impulsive reactions 10).
Listik et al. from the University of São Paulo describe a rare situation in which both essential tremor (ET) and PD coexist in a 72-year-old male referred for zona incerta ZI-DBS due to refractory tremor. The aim of this study was to evaluate whether there was a difference in the area stimulated to improve each type of tremor and whether tractography could improve and predict motor outcome.
Two months after the surgery, in order to define which of the cathodes was the most effective towards improving the tremor and parkinsonian symptoms, a double-blinded, monopolar evaluation was conducted on both hemispheres separately. Once the best contact and parameters were defined, the volume of tissue activation (VTA) was represented spatially for each type of tremor and, finally, the image model was fused with the tractography.
For both types of tremor, the hot spot stimulated region achieved the dentato-rubro-thalamic tract (DRTT) at the higher fiber density region. The DRTT fibers were asymmetrical between the right and left hemispheres.
Regardless of the type of tremor, DRTT can be the most effective region for stimulation. Tractography should be considered when planning the surgical target since the DRTT is not always symmetrical, and the reconstruction of the VTA together with the tractography can greatly improve the DBS programming, and, probably, the patient's outcome to the stimulation 11).
A 38-year-old male with Parkinson's disease developed intractable hemiballism in his left extremities due to a small lesion that was located adjacent to the right deep brain stimulation (DBS) lead, 10 months after bilateral subthalamic nucleus (STN)-DBS placement. He underwent a right globus pallidus internus (GPi)-DBS lead implantation. GPi-DBS satisfactorily addressed his hemiballism.
This case offered a unique look at basal ganglia physiology in human hemiballism. GPi-DBS is a reasonable therapeutic option for the treatment of medication refractory hemiballism in the setting of Parkinson's disease 12).