An MRI time course of 512 echo-planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodology (FMRI). Time courses of low frequency (< 0.1 Hz) fluctuations in resting brain were observed to have a high degree of temporal correlation (P < 10(-3)) within these regions and also with time courses in several other regions that can be associated with motor function. It is concluded that correlation of low frequency fluctuations, which may arise from fluctuations in blood oxygenation or flow, is a manifestation of functional connectivity of the brain.

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI.

Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders. Methods: A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included “Parkinson’s disease”, “diagnosis” and “signs and symptoms”. Results: Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD. Conclusions: A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.

https://jnnp.bmj.com/content/jnnp/79/4/368.full.pdf

Parkinson’s disease: clinical features and diagnosis

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

/pdf/mds-clinical-diagnostic-criteria-for-parkinson-s-disease-74dzuucoq6.pdf

MDS clinical diagnostic criteria for Parkinson's disease

Measuring Health: A Guide to Rating Scales and Questionnaires

BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

/pdf/a-randomized-trial-of-deep-brain-stimulation-for-parkinson-s-40jf18b006.pdf

A Randomized Trial of Deep-Brain Stimulation for Parkinson's Disease

A 62-year-old woman with 12-year history of Parkinson’s disease (PD) developed intermittent severe neck flexion, associated with pain. Anterocollis was one of the initial symptoms noted by the patient at the age of 50. Examination while off levodopa showed severe anterocollis, generalized bradykinesia, and gait difficulty. There was no associated neck muscle weakness, dysautonomic symptoms, or pseudohypertrophy of her muscles. Her head stayed up even when she was lying down. She was on carbidopa/levodopa 25/100 (2 tabs q2 hours) and carbidopa/levodopa 50/200 controlled-release (1 tab at bedtime); her anterocollis and neck pain improved dramatically with levodopa (Video S1). The anterocollis resolved after bilateral subthalamic deep brain stimulation (STN DBS). STN was chosen as off symptoms respond better with this target. Anterocollis has been defined as marked (minimum 45°) neck flexion (maybe partially overcome by voluntary or passive movement), unable to fully extend the neck against gravity but able to exert force against the resistance of the examiner’s hand. Dropped head syndrome is associated with neurodegenerative diseases (PD, multiple system atrophy [MSA], dementia with Lewy bodies, progressive supranuclear palsy [PSP], dystonias [dopa-responsive dystonia or segmental dystonia], motor neuron disease, inherited or acquired myopathies, myasthenia gravis, and drugs [dopamine-agonists, amantadine, donepezil]). Anterocollis is common in MSA with a prevalence rate of 42%, whereas the prevalence in PD is 5.8% and it is difficult to manage. In these cases, anterocollis was constantly present and did not respond to levodopa. Anterocollis tends to occur in MSA slightly earlier than PD. The cause of anterocollis in Parkinsonism can be dystonia of cervical flexors, myopathy of cervical extensors, or both. Some patients with head drop in PD may improve with an increase in the dose of antiparkinsonian drugs, but anterocollis only in the “off” state has not been reported. Anterocollis is not exclusive to Parkinsonism and our case demonstrates anterocollis as an “off” phenomenon in PD. The possible pathophysiology of anterocollis in our case is presumed to be “off” dystonia, as there was no associated muscle weakness.

Anterocollis as an "Off" Phenomenon in Parkinson Disease.

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common pathogenic mutation, accounting for 1% of sporadic and 4% of hereditary Parkinson’s disease (PD). However, despite reports that suggest that LRRK2-positive patients are more prone to have a tremor and that their disease may run a more benign course, patients with the LRRK2 mutation remain clinically indistinguishable from sporadic PD. Two studies that are highlighted here aimed to elucidate the importance of the LRRK2 gene mutation and its relevance to PD. They did so by comparing different characteristics in PD patients with and without the mutation, in family members without PD with the LRRK2 mutation (carriers) and without the mutation, and normal controls (outside the family). In the study by Marras et al, tremor was more often a presenting symptom in LRRK2-positive PD patients compared with PD patients without the mutation. The LRRK2-positive PD patient group also had better olfaction but poorer visual discrimination and lower mood scores compared with their mutation-negative counterparts. They also found that LRRK2 carriers without parkinsonism had higher UPDRS scores, more constipation, and worse color discrimination than normal controls. But a more intriguing finding was a similar worsening of UPDRS scores, visual discrimination, and constipation in LRRK2-negative family members (ie, noncarrier normal relatives of patients) compared with unrelated normal controls. This suggests that either the LRRK2 mutation cannot explain the development of PD and that there may be other factors at play or that the data have limitations because of study-related methods (such as blinding, recruitment, design, etc.). The second study, by Saunders-Pullman et al, focused on olfaction in the following groups: LRRK2-positive PD patients, LRRK2-negative PD patients, mutation carriers without parkinsonism, and normal controls. As reported before, PD patients showed deficits in olfaction regardless of their mutation status; however, PD patients with the mutation had less olfactory impairment than their counterparts without the LRRK2 mutation. LRRK2 mutation carriers without parkinsonism also had mild deficits in olfaction that were more severe than in normal controls but milder than patients with PD, suggesting that olfactory dysfunction may be marker for developing PD in this population as well. Thus, both these studies attempted to probe the association between a known genetic mutation with specific phenotypic characteristics by studying a homogeneous population of PD patients with LRRK2 mutation and LRRK2 carriers who had not yet manifested symptoms of PD. The surprising finding of deficits in LRRK2 mutation–negative family members needs to be explored further.

Learning PD from the lark.

The Non Motor Staging of Parkinson's Disease: Results from an International Study

Ropinirole versus placebo in primary restless legs syndrome.

I.P2 Prevalence of non motor symptoms in Parkinson's Disease: An international survey using NMSQuest in 525 patients

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