Autonomic dysfunction in parkinsonian LRRK2 mutation carriers

IntroductionThe aim of this study was to compare autonomic function in PD symptomatic carriers of the LRRK2 mutations and idiopathic Parkinson's disease (iPD) patients.Material and methodsWe studied 25 PD patients: 12 with the LRRK2 mutation (6 G2019S and 6 R1441G), and 13 with iPD. All patients underwent blood pressure and heart rate monitoring during head up tilt, Valsalva maneuver and deep breathing, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy.ResultsThree of the patients with iPD and one of the LRRK2 carriers had orthostatic hypotension. Arterial pressure “overshoot” during phase IV of Valsalva maneuver was less pronounced in patients with iPD. During passive tilt, LRRK2 carries had higher increase of blood pressure than iPD patients MIBG late myocardial/mediastinal uptake ratios were higher in LRRK2 mutation carriers (1.51 ± 0.28 vs 1.32 ± 0.25; p < 0.05).DiscussionCarriers of the LRRK2 mutation had less autonomic impairment than those with iPD as shown by higher cardiac MIBG uptake and a tendency to less impairment of autonomic non-invasive tests. It is important to carry out larger studies comparing the clinical, functional and pathological characteristics of these patients.     

Comprehensive LRRK2 and GBA screening in Portuguese patients with Parkinson's disease: Identification of a new family with the LRRK2 p.Arg1441His mutation and novel missense variants

Mutations in the LRRK2 and GBA genes are increasingly recognized as frequent determinants of familial and sporadic Parkinson's disease (PD). However, for several populations, accurate data on the prevalence and types of mutations are not available, because previous studies have not investigated the complete coding regions of these genes in large samples.We studied 312 PD patients ascertained at a single centre in Lisbon, Portugal. In 61 patients, with familial PD, we sequenced the entire open reading frames and exon-intron boundaries of LRRK2 and GBA. In LRRK2, we identified ten heterozygous p.Gly2019Ser (16.4%), and two heterozygous p.Arg1441His carriers (3.3%); furthermore, six patients each carried a novel LRRK2 heterozygous variant (five coding and one 3′-UTR variants) of undetermined pathogenic role. Segregation of the p.Arg1441His mutation with PD was observed in the families of both carriers. None of these variants were identified in 138 healthy controls. Screening of GBA revealed no mutations. In the remaining 251 PD patients (25 familial and 226 sporadic) we found ten additional carriers of the heterozygous p.Gly2019Ser and no carriers of the other mutations. Thus, the p.Gly2019Ser mutation was detected in a total number of 20 carriers out of 312 patients (6.4%), including twelve familial (14%) and eight sporadic patients (3.5%).This comprehensive study confirms that p.Gly2019Ser is the most important genetic cause of PD known so far in Portugal and supports the contention that p.Arg1441His is also a PD-causing mutation. These findings have relevance for the genetic testing and counseling of PD patients in this population.     

Dopamine turnover increases in asymptomatic LRRK2 mutations carriers

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinson's disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: ¹⁸F‐fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate K_occ, a marker of DA synthesis and storage; ¹¹C‐methylphenidate (MP, a DAT marker) and ¹¹C‐dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BP_{ND_MP} and BP_{ND_DTBZ}. On average, EDV showed the largest reduction from age‐matched control values (42%) followed by BP_{ND _ MP} (23%) and BP_{ND _ DTBZ} (17%), whereas K_occ remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT. © 2010 Movement Disorder Society     

Prevalence of GBA p.K198E mutation in Colombian and Hispanic populations

We aimed to replicate a recent study that found a high frequency of the GBA p.K198E mutant in Colombian patients with PD. We identified the p.K198E substitution at a lower frequency in our cohort of Colombians with PD (2.1%), and this was not significantly different than controls (1.7%, P = 0.86) emphasizing the need for larger genetic studies in Latin America.     

A novel LRRK2 mutation in an Austrian cohort of patients with Parkinson's disease.

To investigate the frequency of mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) in a sample of Austrian Parkinson's disease (PD) patients, we sequenced the complete coding region in 16 patients with autosomal dominant PD. Furthermore, we sequenced exons 31, 35, and 41 additionally in 146 patients with idiopathic PD and 30 patients with dementia with Lewy bodies. Furthermore, all 192 patients were screened for 21 putative LRRK2 mutations. While the most common mutation G2019S and the risk variant G2385R were not found in our samples, we detected a novel missense mutation (S973N) in a patient with familial, late-onset and dopa-responsive PD.     

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. © 2009 Movement Disorder Society     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

Parkinson's disease: SNCA-, PARK2-, and LRRK2- targeting microRNAs elevated in cingulate gyrus

IntroductionIn order to better understand the role of epigenetic influences in the etiology of Parkinson's disease (PD), we studied the expression of microRNAs in gyri cinguli of patients and controls.MethodsExpression profiling of 744 well-characterized microRNAs in gyri cinguli from patients and controls using TaqMan array microRNA cards. Verification of significantly dysregulated microRNAs by SYBR Green qRT-PCR.ResultsFirst screen by TaqMan array identified 43 microRNAs that were upregulated in gyri cinguli from patients. Of those microRNAs, 13 are predicted to regulate at least one of six genes mutated in monogenic forms of PD (DJ-1, PARK2, PINK1, LRRK2, SNCA, and HTRA2). Five of these 13 microRNAs (-144, -199b, -221, -488, -544) were also found upregulated by SYBR Green qRT-PCR and are predicted to regulate either SNCA, PARK2, LRRK2 or combinations thereof. Consistently, expression of SNCA, PARK2, and LRRK2 was reduced in patients. An additional 5 out of ten potential target genes tested were downregulated. These are DRAM (DNA damage regulated autophagy modulator 1), predicted to be regulated by miR-144, EVC (Ellis Van Creveld Protein) by miR-221, ZNF440 (Zinc Finger Protein 440) by miR-199b, MTFMT (Mitochondrial Methionyl-tRNA Formyltransferase) by miR-488 and XIRP2 (Xin Actin Binding Repeat Containing) possibly controlled by miR-544a.ConclusionThe study identified five microRNAs that play a role in the etiology of Parkinson's disease likely by modifying expression of SNCA, PARK2, LRRK2 and additional genes required for normal cellular function.     

Network abnormalities among non‐manifesting Parkinson disease related LRRK2 mutation carriers

Non‐manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an “at risk” group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting‐state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (D_EPNA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty‐four NMC and 41 non‐manifesting non‐carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non‐motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non‐motor cerebral changes among populations “at risk” for future development of PD.