Clinical features and [11C]-CFT PET analysis of PARK2, PARK6, PARK7-linked autosomal recessive early onset Parkinsonism

Guo, Jifeng; Wang, Lei; He, Dan; Yang, Qiao-hong Ou; Duan, Zhongxiang; Zhang, Xue-wei; Nie, Li-luo; Yan, Xinxiang; Tang, Beisha

doi:10.1007/s10072-010-0360-z

Cited by 27 publications

(17 citation statements)

References 19 publications

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“…Mutations to the Pink1 (PTEN-induced putative kinase) gene in humans have been associated with both an autosomal recessive, early-onset form of PD as well sporadic cases [23–25]. Evidence indicates that associated deficits within the human Pink1 genetic form of PD may also include voice and swallow deficits similar to idiopathic PD, though this has not been well characterized in terms of onset, progression, and severity [26].…”

Section: Introductionmentioning

confidence: 99%

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

et al. 2018

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Parkinson disease (PD) compromises oropharyngeal swallowing, which negatively affects quality of life and contributes to aspiration pneumonia. Dysphagia often begins early in the disease process, and does not improve with standard therapies. As a result, swallowing deficits are undertreated in the PD population. The Pink1 −/− rat is used to model PD, and demonstrates widespread brainstem neuropathology in combination with early-onset sensorimotor dysfunction; however, to date, swallowing behaviors have not been evaluated. To test the hypothesis that Pink1 −/− rats demonstrate early-onset differences in swallowing, we analyzed within-subject oropharyngeal swallowing using videofluoroscopy. Pink1 −/− and wildtype (WT) controls at 4 (Pink1 −/− n = 16, WT = 16) and 8 (Pink1 −/− n = 12, WT = 12) months of age were tested. The average and maximum bolus size was significantly increased in Pink1 −/− rats at both 4 and 8 months. Bolus average velocity was increased at 8 months for all animals; yet, Pink1 −/− animals had significantly increased velocities compared to WT at 8 months. The data show a significant reduction in mastication rate for Pink1 −/− rats at 8 months suggesting the onset of oromotor dysfunction begins at this time point. Relationships among swallowing variables and neuropathological findings, such as increased alpha-synuclein protein in the nucleus ambiguus and reductions in noradrenergic cells in the locus coeruleus in the Pink1 −/− rats, were determined. The presence of early oropharyngeal swallowing deficits and relationships to brainstem pathology in Pink1−/− rat models of PD indicate that this may be a useful model of early swallowing deficits and their mechanisms. These findings suggest clinical implications for early detection and management of dysphagia in PD.

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Section: Introductionmentioning

confidence: 99%

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

et al. 2018

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“…Rats in this specific genetic model express a form of PD that is due to the complete knockout of the PINK1 gene, loss of function mutation, which is related to the PARK6 phenotype of human familial PD. In humans, PINK1 genetic variants contribute to early onset of PD with progressive deficits over time, extensive nigrostriatal dopamine depletion in the late stages of the disease, as well as other motor and non-motor deficits [24–26]. PINK1 −/− rats have comparable symptom profiles to sporadic PD patients; specifically, this model exhibits significant vocalization deficits beginning at 2 months (mo) of age (decreased vocal loudness) that persist and progress (decreased peak frequency and bandwidth) at 4, 6 and 8 mo of age [20].…”

Section: Introductionmentioning

confidence: 99%

Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson’s Disease

Kelm‐Nelson

Yang

Ciucci

2015

JPD

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Background Parkinson’s disease (PD) is a complex neurodegenerative disease with vocal communication deficits that manifest early, progress, and are largely resistant to medical interventions; however, they do respond to exercise-based speech and voice therapies. Objective and Methods To study how exercise-based vocal treatment can affect the progression of communication deficits related to PD, we studied ultrasonic vocalizations (USVs) in rats with homozygous knockout (−/−) of PINK1, a gene mutation known to cause PD, under the manipulation of a behavioral vocal exercise paradigm that allows us to precisely control dose and timing of exercise in the prodromal (prior to diagnosis) stages. Results We show that intensive vocal-training rescues frequency range and intensity deficits as well as leads to an increase in call complexity and duration of calls compared to sham-training; however, over time this training regime loses significant effect as the disease progresses. We also show effects of frequent handling and conspecific (male-female) interaction in the sham-training group as they demonstrated significantly higher call rate, intensity, frequency range, and call complexity compared to rats without any form of training and consequently less handling/interaction. Further, we confirm that this model exhibits progressive gross motor deficits that indicate neurodegeneration. Discussion This study suggests that the evolving nature of vocal communication deficits requires an adjustment of therapy targets and more intensive training over the course of this progressive disease and demonstrates the importance of frequent social experiences.

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“…Mutations in these genes are a common cause of early-onset Parkinson's disease (Klein et al ., 2007). While heterozygous carriers of a single Parkin or PINK1 mutation are usually free of clinical motor symptoms, it is now well established that these asymptomatic mutation carriers show a significant reduction of 18 F-fluoro- l -DOPA metabolism in the putamen (Hilker et al ., 2001, 2002; Khan et al ., 2002, 2005; Scherfler et al ., 2004; Pavese et al ., 2009; Guo et al ., 2011). Two recent functional MRI studies have indicated that asymptomatic Parkin and PINK1 mutation carriers show a stronger increase of cortical motor-related activity during execution of self-initiated movements than non-mutation carriers (Buhmann et al ., 2005; van Nuenen et al ., 2009 a ).…”

Section: Introductionmentioning

confidence: 99%

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

Anders

Sack

Pohl

et al. 2012

Brain

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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.

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Clinical features and [11C]-CFT PET analysis of PARK2, PARK6, PARK7-linked autosomal recessive early onset Parkinsonism

Cited by 27 publications

References 19 publications

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson’s Disease

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

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