Somatosensory processing in a German family with PINK1 mutations: its potential role in Parkinson disease.

BACKGROUND: It is unclear whether sensory symptoms in Parkinson disease (PD) are of primary or of secondary origin attributable to motor symptoms such as rigidity and bradykinesia. OBJECTIVE: The aim of this study was to elucidate whether sensory abnormalities are present and may precede motor symptoms in familial parkinsonism by characterizing sensory function in symptomatic and asymptomatic PINK1 mutation carriers. METHODS: Fourteen family members with PINK1 mutation and 14 healthy controls were examined clinically, with nerve conduction studies and quantitative sensory testing (QST). RESULTS: Thresholds for mechanical detection, mechanical pain and pressure pain were higher in PINK1 mutation carriers compared to controls. Higher thresholds for mechanical detection, mechanical pain and pressure pain were even found in asymptomatic, clinically not or only mildly affected PINK1 mutation carriers. CONCLUSIONS: Data suggest that PINK1-associated PD is associated with a primary hypofunction of nociceptive and non-nociceptive afferent systems that can already be found at the time when motor signs of PD are only subtle. As nerve conduction studies did not reveal differences between PINK1 mutation carriers and controls, we propose that the somatosensory impairment is related to abnormal central somatosensory processing.

Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations.

OBJECTIVE: To investigate substantia nigra (SN) echogenicity in members of a family with homozygous and heterozygous PTEN induced kinase (PINK1) mutations with or without signs of Parkinson's disease (PD). METHODS: Transcranial sonography (TCS) was used to investigate 20 members of a family with PINK1 mutations, including four homozygous and 11 heterozygous mutation carriers and five individuals with no mutation. For comparison, a healthy control group of 18 subjects without a positive family history of PD (control group) and a healthy control group of 15 subjects with a positive family history of sporadic PD (relative group) were investigated. For statistical analysis, the larger area of the two SNs echogenicity (aSNmax) of each individual was selected. RESULTS: A significantly increased aSNmax was found for all subgroups compared with the control group. The group of homozygous carriers of a PINK1 mutation had a significantly increased aSNmax compared with all of the other subgroups, except the group of heterozygous mutation carriers. CONCLUSIONS: These findings in carriers of a PINK1 mutation are comparable with those in carriers of Parkin mutations and non-genetic PD. The increased aSNmax in family members without a mutation suggests an additional contributing factor independent of the PINK1 mutation that may also play a role in relatives of patients with sporadic PD.

Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles.

To further evaluate (1) transcranial sonography (TCS) for (pre)clinical diagnosis of Parkinson's disease (PD) and (2) to examine asymptomatic carriers of Parkin mutations we investigated substantia nigra (SN) hyperechogenicity in PD patients and unaffected subjects with and without Parkin mutations. The area (aSN) of the hyperechogenic SN were calculated bilaterally and study subjects were assigned to high versus low value groups. Eleven of the (affected and unaffected) mutation carriers had previously undergone 18-fluoro-dopa-(FDOPA)-PET scans. Fifty-eight individuals were investigated, including 24 with clinically definite and 34 without symptoms or signs of PD. Of the patients, three had one mutated and six had two mutated Parkin alleles. Of the unaffected subjects, 13 carried a single Parkin mutated allele. After dichotomization, 21 subjects had high and 37 subjects low values of mean aSN. Regarding the clinical status, 13 (62%) of the individuals with a high mean aSN had PD,while 26 (70%) of the study subjects with low values did not show signs of PD (p = 0.0393). Similarly, probands with high mean aSN values more frequently carried Parkin mutations (58%) than probands with low values (27%, p = 0.0234). A negative correlation between FDOPA uptake in the posterior putamen and maximum aSN was found in the group of mutation carriers (r = -0.809, p = 0.0234). In conclusion, hyperechogenicity of the SN is found in both idiopathic and Parkin-associated PD. Further strengthening the notion of a potential relationship between SN hyperechogenicity and Parkin mutational status, a larger aSN was associated with an increasing number of mutated alleles in our study.

Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study.

BACKGROUND: An inverse association between cigarette smoking and the risk of idiopathic PD has been found in many epidemiologic studies. The therapeutic and possible neuroprotective effects of nicotine formulations on parkinsonian symptoms are controversial. METHODS: In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and tolerability of transdermal nicotine patches as an add-on treatment for cardinal symptoms were evaluated in 32 nonsmoking patients with PD. After a 1-week run-in phase, patients were randomized to receive nicotine patches (containing 17.5 mg nicotine in the first and 35.0 mg nicotine in the second and third weeks) or identically appearing placebo patches. After this treatment, 3 weeks without patch application followed. The same blinded examiner assessed the patients with the Columbia University Rating Scale, the Webster scale, the Schwab-England scale, a timed walking test, with an instrumental test for fine motor skills and hand tremor, and with the Hamilton Depression Scale. RESULTS: No significant drug effects between both groups were observed in any of the scores and quantitative tests. Side effects were mild and comparable in frequency between both groups. CONCLUSIONS: With the dosage and the period of treatment chosen, transdermal nicotine patches are not effective as an add-on treatment for symptoms of PD.

Radiculopathy and myelopathy in patients with primary cervical dystonia.

In a prospective series of 34 incident patients with primary cervical dystonia (CD), 6 showed clinical or radiological signs of cervical radiculopathy (RP) or myelopathy (MP) during the course of their movement disorder. Age at onset in these patients was in the range reported for pure spondylotic cervical RP without an accompanying movement disorder. Radiologically, spondylosis was mild in 1 case and absent in 2 cases. The intervals between onset of CD and RP were shorter than in literature reports of RP/MP in dystonic-athetotic patients of cerebral paresis. Clinically, RP/MP in patients with CD mostly appears at mid-cervical levels, whereas cases with cerebral paresis are more frequently affected at higher cervical segments. We propose that RP/MP does not occur more frequently in CD than in pure spondylotic cervical RP.

Parkinson disease: analysis of mitochondrial DNA in monozygotic twins.

We have sequenced all mitochondrial complex I and tRNA genes in five pairs of monozygotic twins with a longitudinal diagnosis of idiopathic Parkinson disease (PD). At the time of molecular genetic analysis, four of the pairs were discordant for PD. Five novel homoplasmic sequence variants, including two missense mutations (ND2 4924 G/A, ND3 10192 C/T), were detected in mitochondrial genes of complex I in four of the pairs. In addition, a total of 20 known polymorphisms affecting both complex I and tRNA genes was found. Importantly, mitochondrial DNA sequences were identical in diseased and non-affected siblings of each pair. Our results demonstrate that missense mutations of mitochondrial complex I may occur in clinically discordant parkinsonian twins, questioning the direct pathogenic relevance of at least some of these mutations.

Effects of amantadine treatment on in vitro production of interleukin-2 in de-novo patients with idiopathic Parkinson's disease.

An involvement of immunological events in the process of neurodegeneration has frequently been reported. We investigated the cytokine producing capacity for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in whole blood cultures of de-novo patients with idiopathic Parkinson's disease (PD) at the time of first diagnosis and after oral amantadine treatment. Before treatment, productions of IL-2 and IFN-gamma were markedly decreased in PD patients compared to patients with major depressive disorder and healthy controls. After amantadine treatment, the in vitro IL-2 secretion defect was corrected to normal levels in half of the patients, and the increase in IL-2 production was correlated with an increase in IFN-gamma secretion. Our findings suggest that immunological abnormalities occur in the course of PD and that a formerly unappreciated therapeutic potential of amantadine may arise from its immunomodulatory effects on altered T cell function in patients with PD.