Mild cognitive impairment is common in nondemented Parkinson’s disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goaldirected action.The basal ganglia are a group of subcortical nuclei that have been linked to movement control since the end of the nineteenth century when David Ferrier concluded that the corpus striatum contained "the centres of automatic or sub-voluntary integration" (REF. 1 Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts view was expanded in the early twentieth century by observations that basal ganglia lesions were associated with movement disorders (BOX 1). The first functional model of basal ganglia architecture was developed in the late 1980s (FIG. 1a). In this model, cortical inputs enter the basal ganglia through the striatum (in primates this consists of the caudate nucleus and the putamen), and the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) serve as the principal output nuclei. The activity of striatal medium spiny projection neurons is conveyed to the output nuclei (GPi and SNr) through a monosynaptic GABA (γ-aminobutyric acid)-ergic projection (the 'direct' pathway) and a polysynaptic ('indirect') pathway that involves relays in the external globus pallidus (GPe) and the subthalamic nucleus (STN) 2 , 3 . Output from GABAergic GPi and SNr neurons keep targeted structures in the thalamus and brainstem under tonic inhibitory control: this tonic inhibition is blocked (that is, paused) by phasic inhibitory signals from the 'direct' striato-nigralpallidal projection 4 , which releases thalamocortical and brainstem structures from inhibition, thereby allowing movement to proceed. Dopaminergic input from the substantia nigra pars compacta (SNc) modulates corticostriatal transmission by exerting a dual effect on striatal projection neurons (FIG. 1). Neurons that co-express dopamine D1 receptors, substance P and dynorphin and give rise to the 'direct pathway' are excited by dopamine, whereas neurons that co-express D2 receptors and encephalin, and that give rise to the 'indirect pathway', are inhibited 5 (FIG. 1a). Consequently, according to this model, in the normal state, activation of the 'indirect circuits' at the level of the striatum would promote movement inhibition or...

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Background There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson’s disease. Objective The Movement Disorders Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson’s disease-mild cognitive impairment and its association with dementia. Methods Comprehensive PubMed literature review using systematic inclusion and exclusion criteria. Results A mean of 26.7% (range, 18.9–38.2%) of non-demented Parkinson’s disease patients have mild cognitive impairment. The frequency of Parkinson’s disease mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, non-amnestic is more common than amnestic impairment. A high proportion of patients with Parkinson’s disease-mild cognitive impairment progress to dementia in a relatively short period of time. Conclusions The primary conclusions of the Task Force are that: (1) Parkinson’s disease-mild cognitive impairment is common; (2) there is significant heterogeneity within Parkinson’s disease-mild cognitive impairment in the number and types of cognitive domain impairments; (3) Parkinson’s disease-mild cognitive impairment appears to place patients at risk of progressing to dementia; and (4) formal diagnostic criteria for Parkinson’s disease-mild cognitive impairment are needed.

Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.

A dopaminergic defi ciency in patients with Parkinson's disease (PD) causes abnormalities of movement, behaviour, learning, and emotions. The main motor features (ie, tremor, rigidity, and akinesia) are associated with a defi ciency of dopamine in the posterior putamen and the motor circuit. Hypokinesia and bradykinesia might have a dual anatomo-functional basis: hypokinesia mediated by brainstem mechanisms and bradykinesia by cortical mechanisms. The classic pathophysiological model for PD (ie, hyperactivity in the globus pallidus pars interna and substantia nigra pars reticulata) does not explain rigidity and tremor, which might be caused by changes in primary motor cortex activity. Executive functions (ie, planning and problem solving) are also impaired in early PD, but are usually not clinically noticed. These impairments are associated with dopamine defi ciency in the caudate nucleus and with dysfunction of the associative and other non-motor circuits. Apathy, anxiety, and depression are the main psychiatric manifestations in untreated PD, which might be caused by ventral striatum dopaminergic defi cit and depletion of serotonin and norepinephrine. In this Review we discuss the motor, cognitive, and psychiatric manifestations associated with the dopaminergic defi ciency in the early phase of the parkinsonian state and the diff erent circuits implicated, and we propose distinct mechanisms to explain the wide clinical range of PD symptoms at the time of diagnosis.

No abstract

To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD).