Asymptomatic Parkin Mutation Carriers Research Articles

Differentiating symptomatic Parkin mutations carriers from patients with idiopathic Parkinson’s disease: Contribution of automated segmentation neuroimaging method

BackgroundParkin (PARK2) gene mutations are the predominant cause of autosomal recessive parkinsonism. Characteristic features include: early onset symptoms with slow clinical course, good response to low doses of levodopa, and frequently treatment-induced dyskinesia. Studies using a voxel-based morphometry approach showed a decrease in the gray matter volume of the basal ganglia in mutation carriers during the symptomatic stages. A bilateral, presumably compensatory increase of basal ganglia gray matter value was recently demonstrated in asymptomatic Parkin mutation carriers. Behavioral disorders including: anxiety, psychosis, panic attacks, depression, disturbed sexual, behavioral and obsessive–compulsive disorders have been reported in these patients. MethodA total of 28 Parkinson’s Disease (PD) patients consisting of 10 Young-Onset without Parkin mutations (YOPD), 9 Young-Onset with Parkin mutations (YOPD-p), 9 Late-Onset without Parkin mutations (LOPD) and 32 healthy control subjects were studied with an automated volumetric assessment method to quantify subcortical atrophy. Patients but not controls also underwent a neuropsychological and neuropsychiatric assessment. ResultsResults revealed a reduction of bilateral caudate nuclei volumes in YOPD-p patients compared to the YOPD patients while there were no statistically significant differences between other groups. YOPD-p patients showed similar results to other patient groups on neuropsychiatric and neuropsychological evaluation measures. ConclusionYOPD-p and YOPD patients showed a different pattern of volume changes in basal ganglia. Despite its relatively benign clinical course, carrying the Parkin mutation seems to be associated with greater atrophy in subcortical structures. Failure of compensatory mechanisms, different mutation types and pathophysiologic processes may underlie this diverse pattern of subcortical brain changes.

Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele

Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia–cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia–cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons (‘mirror neurons’) in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia–cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. Furthermore, Parkin mutation carriers showed a slightly reduced ability to recognize facial emotions that was least severe in individuals who showed the strongest increase of ventrolateral premotor activity. In addition, Parkin mutation carriers showed a significantly weaker than normal increase of activity in the left lateral orbitofrontal cortex (inferior frontal gyrus pars orbitalis, Brodmann area 47), which was unrelated to facial emotion recognition ability. These findings are consistent with the hypothesis that compensatory activity in the ventrolateral premotor cortex during processing of affective facial gestures can reduce impairments in facial emotion recognition in subclinical Parkin mutation carriers. A breakdown of this compensatory mechanism might lead to the impairment of facial expressivity and facial emotion recognition observed in manifest Parkinson's disease.

Eye movement disorders are different in Parkin -linked and idiopathic early-onset PD

Parkin gene mutations are the most common cause of early-onset parkinsonism. Patients with Parkin mutations may be clinically indistinguishable from patients with idiopathic early-onset Parkinson disease (EOPD) without Parkin mutations. Eye movement disorders have been shown to differentiate parkinsonian syndromes, but have never been systematically studied in Parkin mutation carriers. Eye movements were recorded in symptomatic (n = 9) and asymptomatic Parkin mutation carriers (n = 13), patients with idiopathic EOPD (n = 14), and age-matched control subjects (n = 27) during established oculomotor tasks. Both patients with EOPD and symptomatic Parkin mutation carriers showed hypometric prosaccades toward visual stimuli, as well as deficits in suppressing reflexive saccades toward unintended targets (antisaccade task). When directing gaze toward memorized target positions, patients with EOPD exhibited hypometric saccades, whereas symptomatic Parkin mutation carriers showed normal saccades. In contrast to patients with EOPD, the symptomatic Parkin mutation carriers showed impaired tracking of a moving target (reduced smooth pursuit gain). The asymptomatic Parkin mutation carriers did not differ from healthy control subjects in any of the tasks. Although clinically similarly affected, symptomatic Parkin mutation carriers and patients with idiopathic EOPD differed in several oculomotor tasks. This finding may point to distinct anatomic structures underlying either condition: dysfunctions of cortical areas involved in smooth pursuit (V5, frontal eye field) in Parkin-linked parkinsonism vs greater impairment of basal ganglia circuits in idiopathic Parkinson disease.

Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson's disease

A bilateral compensatory increase of basal ganglia (BG) gray matter value (GMV) was recently demonstrated in asymptomatic Parkin mutation carriers, who likely have an increased risk to develop Parkinson's disease (PD). We hypothesized BG morphological changes in symptomatic Parkin mutation carriers (sPARKIN-MC) and idiopathic PD patients (iPD) after the occurrence of PD symptoms, reflecting the breakdown of compensatory mechanisms. Nine sPARKIN-MC, 14 iPD, and 24 controls were studied clinically and with voxel-based morphometry. Analysis of variance revealed mainly BG decrease of GMV in sPARKIN-MC and to a lesser extent in iPD. However, a slight increase in GMV was also found in the right globus pallidus externus in sPARKIN-MC and in the right putamen in iPD. This may reflect a structural correlate of functional compensation that can only partially be maintained when nigrostriatal neurodegeneration becomes manifest. Simple regression analyses with the UPDRS-III and disease duration score revealed a distinct more bilateral linear decrease of BG GMV in sPARKIN-MC than in iPD that may correspond to previous findings showing a symmetric reduction in putaminal (18)F-DOPA-uptake and bilateral manifestation of symptoms in sPARKIN-MC. In symptomatic PD, BG are subject to a progressive atrophy, which gradually increases with disease severity and duration.

Brain parenchyma sonography detects preclinical parkinsonism.

Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult-onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound-heterozygous), compared to PMC with only one mutated allele (Mann-Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = -0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal (18)F-dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET-normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.

Striatal Hypertrophy: A Mechanism for Preclinical Compensation in Parkin-Associated Parkinsonism?

18F-Fluorodopa (F-DOPA) positron emission tomography (PET) demonstrated a reduction of striatal F-DOPA uptake in asymptomatic carriers of heterozygous Parkin mutations, indicating a latent dopaminergic dysfunction in the basal ganglia. We used voxel-based morphometry of high-resolution structural magnetic resonance images in a comparable group of asymptomatic Parkin mutation carriers to investigate whether this latent dopaminergic dysfunction is associated with structural abnormalities in the motor system. Structural MR data (T1-weighted FLASH 3D MR sequences; TE=5 ms; TR=15 ms; flip angle=30°; isotropic voxel size 1×1 x 1mm3) of 13 right handed asymptomatic carriers of heterozygous mutations in the Parkin gene (eight females, mean age: 38.6±5.8yrs, range: 28–47yrs) were compared with those of 13 age-matched healthy controls. MR images were preprocessed and analyzed using SPM2 software (FIL, London, UK). We used an optimized protocol for voxel-based morphometry, which involves non-linear spatial normalization to a customized grey matter template. Images were smoothed with a Gaussian kernel 12mm FWHM. Using a general linear model, voxel-by-voxel t-tests were computed to detect differences in grey matter volume between groups (significance threshold: p<0.01 and p<0.01 for cluster size; Gaussian Random Field theory). All asymptomatic carriers and controls had a normal neurological and neuropsychological examination. Voxel-based morphometry revealed a significant increase in grey matter volume in the left posterior putamen and globus pallidus internus (GPI) [Talairach coordinates: x=–25, y=0, z=3; SVC around the striatum p=0.03, corrected (FDR)]. There was also a subthreshold increase in grey matter volume in the right GPI. The increase in grey matter volume in the posterior striatum showed a close spatial correspondence to the location of dopamine hypometabolism found in the comparable group of asymptomatic carriers in the previous F-DOPA PET study (Hilker et al., 2001). This co-localization may suggest that the increase in grey matter volume might represent a long-term consequence of adaptive plasticity in the basal ganglia. Such an increase in structure might help the motor system to compensate for the preclinical dopaminergic deficit and prevent the manifestation of minor motor symptoms (Brezard et al., 2003). The higher increase in the grey mater density in the left striatum indicates a higher amount of compensation for the dominant right hand.