Objective: To describe the phenotype of levodopa-induced "on" freezing of gait (FOG) in Parkinson disease (PD). Methods:We present a diagnostic approach to separate "on" FOG (deterioration during the "on state") from other FOG forms. Four patients with PD with suspected "on" FOG were examined in the "off state" (Ͼ12 hours after last medication intake), "on state" (peak effect of usual medication), and "supra-on" state (after intake of at least twice the usual dose).Results: Patients showed clear "on" FOG, which worsened in a dose-dependent fashion from the "on" to the "supra-on" state. Two patients also demonstrated FOG during the "off state," of lesser magnitude than during "on." In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating "off " FOG. Conclusions:True "on" FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating "off " FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states. Neurology Freezing of gait (FOG) is common in Parkinson disease (PD). FOG refers to sudden, relatively brief episodes of gait arrest, experienced subjectively by patients as their feet being "glued to the floor."1 The relationship between FOG and dopaminergic medication is complex. Most common is "off " FOG, which is relieved by dopaminergic medication.1 Less well recognized types include "unresponsive FOG," which is indifferent to changes in dopaminergic medication 2,3 ; "pseudo-on" FOG, seen during a seemingly optimal "on" state, but which nevertheless improves with stronger dopaminergic stimulation; and "on" FOG, induced by dopaminergic medication. 4 Here, we describe the phenotype of "on" FOG, illustrated by 4 patients with PD. We also present a diagnostic approach to separate the various FOG subtypes, as a basis for understanding pathophysiology and for tailored therapeutic intervention.METHODS Four patients (ages 59 -82, disease duration 6 -20 years) with a history of deteriorating FOG during "on" are described in appendix e-1 on the Neurology ® Web site at www.neurology.org. Subjects were tested in 3 states: 1) "practically defined off " state, after 12 hours without medication; 2) "on" state, 45-60 minutes after intake of regular levodopa doses; and 3) "supra-on" state, after at least twice the regular dose. The Institutional Review Board approved the study protocol and written informed consent was obtained. These tests were done on 1 day, in a fixed order, without blinding. Subject 3 was also tested 1 month later in the "supra-off " state, after 72 hours without any medication. Motor evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS)-III subscale (table e-1) and timed gait tasks (gait initiation, straight walking with 2 180-degree turns, and 1 360-degree turn in each direction). Determination of FOG appearance was based on patient and investigator judgment.Standard proto...

Objective Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. Methods We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. Results Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10−6 for ALS and p = 4.3 × 10−5 for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. Interpretation The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

Compensatory mechanisms are a crucial component of the cerebral changes triggered by neurodegenerative disorders. Identifying such compensatory mechanisms requires at least two complementary approaches: localizing candidate areas using functional imaging, and showing that interference with these areas has behavioral consequences. Building on recent imaging evidence, we use this approach to test whether a visual region in the human occipito-temporal cortex-the extrastriate body area-compensates for altered dorsal premotor activity in Parkinson's disease (PD) during motor-related processes. We separately inhibited the extrastriate body area and dorsal premotor cortex in 11 PD patients and 12 healthy subjects, using continuous theta burst stimulation. Our goal was to test whether these areas are involved in motor compensatory processes. We used motor imagery to isolate a fundamental element of motor planning, namely subjects' ability to incorporate the current state of their body into a motor plan (mental hand rotation). We quantified this ability through a posture congruency effect (i.e., the improvement in subjects' performance when their current body posture is congruent to the imagined movement). Following inhibition of the right extrastriate body area, the posture congruency effect was lost in PD patients, but not in healthy subjects. In contrast, inhibition of the left dorsal premotor cortex reduced the posture congruency effect in healthy subjects, but not in PD patients. These findings suggest that the right extrastriate body area plays a compensatory role in PD by supporting a function that is no longer performed by the dorsal premotor cortex.

Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. Results:The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by nigrostriatal dopamine depletion. The motor symptoms of PD appear only when dopaminergic cell death reaches a critical threshold of 50% to 80%.1 This suggests that the nervous system has a marked potential to compensate for these changes.2 However, human studies of cerebral compensation in premotor PD are lacking, given the difficulty of predicting who will develop PD in the future.Previous work has shown that compensatory mechanisms in idiopathic PD depend on brain regions relatively unaffected by dopamine depletion, such as the anterior striatum.3,4 Using fMRI in early-stage PD, we recently showed a shift in corticostriatal connectivity from severely affected striatal regions (posterior putamen) to less affected striatal regions (anterior putamen). 5If these changes reflect compensation, they should also occur in the premotor phase of PD, when functional reorganization of cerebral circuits prevents overt clinical symptoms. 2 *These authors contributed equally to this work.

In non-human primates, invasive tracing and electrostimulation studies have identified strong ipsilateral cortico-cortical connections between dorsal premotor- (PMd) and the primary motor cortex (M1(HAND) ). Here, we applied dual-site transcranial magnetic stimulation (dsTMS) to left PMd and M1(HAND) through specifically designed minicoils to selectively probe ipsilateral PMd-to-M1(HAND) connectivity in humans. A suprathreshold test stimulus (TS) was applied to M1(HAND) producing a motor evoked potential (MEP) of about 0.5 mV in the relaxed right first dorsal interosseus muscle (FDI). A subthreshold conditioning stimulus (CS) was given to PMd 2.0-5.2 ms after the TS at intensities of 50-, 70-, or 90% of TS. The CS to PMd facilitated the MEP evoked by TS over M1(HAND) at interstimulus intervals (ISI) of 2.4 or 2.8 ms. There was a second facilitatory peak at ISI of 4.4 ms. PMd-to-M1(HAND) facilitation did not change as a function of CS intensity. Even at higher intensities, the CS alone failed to elicit a MEP or a cortical silent period in the pre-activated FDI, excluding a direct spread of excitation from PMd to M1(HAND). No MEP facilitation was present while CS was applied rostrally over lateral prefrontal cortex. Together our results indicate that our dsTMS paradigm probes a short-latency facilitatory PMd-to-M1(HAND) pathway. The temporal pattern of MEP facilitation suggests a PMd-to-M1(HAND) route that targets intracortical M1(HAND) circuits involved in the generation of indirect corticospinal volleys. This paradigm opens up new possibilities to study context-dependent intrahemispheric PMd-to-M1(HAND) interactions in the intact human brain.

Deep brain stimulation of the subthalamic nuclei (STN) is a good therapeutic option to reduce dyskinesias and improve appendicular motor signs in well-selected patients with advanced Parkinson's disease (PD). Concerns about long-term adverse effects play an increasingly role in the decision whether or not to refer patients for this treatment. Worsening of gait as a consequence of STN stimulation for PD has been described, but may be under-recognized in clinical practice. The aim of this study was to evaluate the effects of STN stimulation on gait relative to global outcome in a group of consecutively operated patients. For this purpose, we used a standardized patient questionnaire that asked about global outcome and specific effects on gait, as experienced both 6 months postoperatively and currently (at the time of completing the questionnaire; mean: 2.7 +/- 1.1 years). A delayed worsening of gait after bilateral STN stimulation was experienced by a considerable proportion of patients (42% of subjects, for gait in the OFF phase), and this was apparently relatively "selective" because their global outcome scores continued to be improved. These findings highlight the presence of a hitherto poorly recognized long-term complication of bilateral STN stimulation. Further systematic studies are required to pinpoint the clinical and surgical determinants of this late gait deterioration.

Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. Methods:Nonmanifesting individuals carrying a single heterozygous Parkin (n ϭ 13) or PINK1 (n ϭ 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease areassociated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit. Neurology ® 2009;72:1041-1047 GLOSSARY BOLD ϭ blood oxygen level-dependent; CMA ϭ cingulate motor area; FDR ϭ false discovery rate; fMRI ϭ functional MRI; HRF ϭ hemodynamic response function; IPS ϭ intraparietal sulcus; M1 HAND ϭ primary motor hand area; PD ϭ Parkinson disease; PMd ϭ dorsal premotor cortex; SMA ϭ supplementary motor area; SPM ϭ statistical parametric mapping; SVC ϭ small volume correction; TE ϭ echo time; TMS ϭ transcranial magnetic stimulation; TR ϭ repetition time; VOI ϭ volumes of interest.Several genes have been identified that can lead to Parkinson disease (PD), including four recessively inherited forms caused by mutations in the Parkin (PARK2), DJ-1 (PARK7), PINK1 (PARK6), and ATP13A2 (PARK9) genes.1-3 These familial forms of PD show a substantial clinical overlap with sporadic PD. Nonmanifesting individuals who carry a single heterozygous mutation in the Parkin and PINK1 gene associated with recessively inherited PD

Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non-manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates for a preclinical dopaminergic dysfunction.