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1.
J Pers Med ; 12(1)2022 Jan 02.
Article in English | MEDLINE | ID: mdl-35055343

ABSTRACT

Patients with Parkinson's disease that may benefit from device-assisted therapy can be identified with guidelines like Navigate PD. The decision to offer advanced treatment and the choice of treatment modality are, however, not straightforward, and some patients respond less favorably to a chosen therapy. Measurements with the Parkinson Kinetigraph (PKG) can detect motor fluctuations and could therefore predict patients that respond better or worse to intestinal levodopa/carbidopa gel infusion (LCIG). In a retrospective analysis of 45 patients that had been selected to start LCIG between 2014 and 2020, the effects of baseline PKG and clinical characteristic on the outcome were determined with ordinal regression. Although all patients had been found to have handicapping medication-related symptom fluctuations, patients without clear objective off fluctuations in the baseline PKG had low odds ratio for success. Lower odds for success were also found with increasing age, whereas gender, medication intensity and baseline PKG summary scores (median bradykinesia and dyskinesia scores, fluctuation dyskinesia score and percent time with tremor) had no significant effect. Absence of easily identified off-periods in the PKG has a negative prognostic value for the effect of LCIG and could prompt noninvasive infusion evaluation before surgery.

2.
Mov Disord Clin Pract ; 6(3): 254-258, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30949558

ABSTRACT

BACKGROUND: Mutations in the glucocerebrosidase gene (GBA) are a common genetic risk factor for Parkinson's disease (PD). Mutations in the N-terminus part of GBA are less commonly found in association with PD than those in the C-terminus. Phenotypic characterization of GBA-related PD has been challenging, in part attributed to differential impact of distinct GBA mutations. AIM: To provide a phenotypic description of two patients with PD heterozygous for the GBA mutation S107L. The S107L mutation is located in the catalytic domain of glucocerebrosidase and has not previously been reported in patients with PD. METHODS: Motor and nonmotor symptoms (NMS) of PD were evaluated using established rating scales and questionnaires. The genotype was determined by Sanger sequencing. RESULTS: Two half-brothers, both heterozygous carriers of S107L, exhibited an early PD onset with several NMS. CONCLUSIONS: In these patients, heterozygosity for S107L was associated with an early onset of PD with NMS.

3.
BMC Med Genet ; 19(1): 42, 2018 03 12.
Article in English | MEDLINE | ID: mdl-29529989

ABSTRACT

BACKGROUND: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. METHODS: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. RESULTS: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. CONCLUSIONS: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.


Subject(s)
Age of Onset , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , S100 Calcium Binding Protein beta Subunit/genetics , 3' Untranslated Regions/genetics , Aged , Alleles , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genotyping Techniques , Humans , Linear Models , Male , Parkinson Disease/diagnosis , Proportional Hazards Models , Sweden
4.
Clin Neurol Neurosurg ; 154: 43-48, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28113102

ABSTRACT

OBJECTIVE: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for motor fluctuations in Parkinson's disease (PD), but does not halt disease progression. The long-term deterioration of key functions such as cognition, speech, ability to swallow, gait, urinary bladder control, orientation and reality perception is decisive for patients' independency in daily life. In this paper we investigated patients with advanced PD operated at our center with STN-DBS for at least 15 years ago, in respect to key clinical milestones reflecting their overall function in daily living. PATIENTS AND METHODS: Retrospective analysis of clinical data concerning key clinical milestones including death in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska Hospital before January 1, 2001, were regularly assessed until death, drop-out, or January 11, 2016. RESULTS: Sixteen men and seven women with a median (range) disease duration of 18 (10-28) years were operated with STN-DBS. The median (range) follow-up time post-surgery was 12 (2-18) years and 692 person-years of disease duration were observed. In January 2016, nine PD-patients (39%) were still alive (eight with active STN-DBS). Initially, motor symptoms improved in all patients. Sustained benefit (implying active stimulation at the last follow up) was maintained in 19 of them (83%) but STN-DBS was inactivated in four (17%) due to inefficacy. Over time, all patients deteriorated slowly, and a majority developed severe non-motor and axial symptoms such as dementia, inability to talk, swallow and walk, urinary incontinence, psychosis, and need for nursing home care. At the last follow up, 16/23 (70%) patients were treated with antidepressants. CONCLUSION: A majority of PD-patients experience sustained motor benefit with continuous STN-DBS. However, over time, non-motor and axial symptoms slowly and severely restrict PD-patients' function in their daily living.


Subject(s)
Deep Brain Stimulation/methods , Outcome Assessment, Health Care , Parkinson Disease/physiopathology , Parkinson Disease/therapy , Subthalamic Nucleus , Aged , Aged, 80 and over , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parkinson Disease/surgery , Retrospective Studies , Subthalamic Nucleus/surgery
5.
Parkinsonism Relat Disord ; 29: 17-23, 2016 08.
Article in English | MEDLINE | ID: mdl-27318707

ABSTRACT

BACKGROUND: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG. METHODS: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naïve (N = 37), or had previous LCIG treatment for <2 (N = 22), or ≥2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored. RESULTS: Mean monthly costs per patient (€8226 ± 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naïve patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations. CONCLUSIONS: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naïve patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The long-term safety was consistent with the established LCIG profile.


Subject(s)
Carbidopa/therapeutic use , Gels/therapeutic use , Health Care Costs , Intestines/physiology , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Aged , Antiparkinson Agents/therapeutic use , Cohort Studies , Drug Combinations , Female , Humans , Male , Middle Aged , Severity of Illness Index , Statistics, Nonparametric , Visual Analog Scale
6.
J Hum Genet ; 60(7): 357-62, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25855069

ABSTRACT

The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.


Subject(s)
Parkinson Disease/genetics , Case-Control Studies , Chromosome Mapping , Epistasis, Genetic , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Sequence Analysis, DNA , rab GTP-Binding Proteins , rab1 GTP-Binding Proteins/genetics
7.
Mov Disord ; 29(10): 1319-22, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25044107

ABSTRACT

BACKGROUND: Differential diagnosis of parkinsonian disorders is challenging because of overlapping symptoms, especially during early stages of disease. No validated biomarkers are available for early and accurate diagnosis of multiple system atrophy and other parkinsonian disorders. It has been reported that flt3 ligand levels in cerebrospinal fluid could clearly differentiate patients with Parkinson's disease from patients with multiple system atrophy, with 99% sensitivity and 95% specificity. METHODS: We measured flt3 ligand levels in cerebrospinal fluid of subjects with Parkinson's disease (n = 37), multiple system atrophy (n = 30), and progressive supranuclear palsy (n = 19). RESULTS: In our cohort, no significant difference was found in flt3 ligand levels between Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. CONCLUSIONS: Our results suggest that cerebrospinal fluid flt3 ligand levels do not differentiate between parkinsonian disorders.


Subject(s)
Membrane Proteins/cerebrospinal fluid , Parkinsonian Disorders/cerebrospinal fluid , Aged , Analysis of Variance , Humans , Middle Aged , Multiple System Atrophy/cerebrospinal fluid , Severity of Illness Index , Supranuclear Palsy, Progressive/cerebrospinal fluid
8.
Parkinsonism Relat Disord ; 20(4): 382-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24507721

ABSTRACT

INTRODUCTION: There is an unmet need for biomarkers for Parkinson's disease (PD) and atypical parkinsonian disorders (APD). α-Synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation. The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system which seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder. METHODS: We investigated cerebrospinal fluid (CSF) α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with multiple system atrophy (MSA), 32 with progressive supranuclear palsy, and 12 with corticobasal degeneration. RESULTS: α-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies. UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001). Both markers discriminated PD well from controls (p < 0.0001; area under the curve [AUC] = 0.82 and 0.89, respectively). Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69). Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies. No correlation was found in controls. CONCLUSIONS: CSF levels of α-synuclein and UCH-L1 show distinct patterns in parkinsonian syndromes. Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provide key to understanding their pathoetiology and clinical course. Further large studies are needed to validate our findings.


Subject(s)
Biomarkers/cerebrospinal fluid , Parkinsonian Disorders/cerebrospinal fluid , Ubiquitin Thiolesterase/cerebrospinal fluid , alpha-Synuclein/cerebrospinal fluid , Aged , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Multiple System Atrophy/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Supranuclear Palsy, Progressive/cerebrospinal fluid , Tauopathies/cerebrospinal fluid
9.
Article in English | MEDLINE | ID: mdl-24255800

ABSTRACT

BACKGROUND: Deep brain stimulation (DBS) of the thalamus is a safe and efficient method for treatment of disabling tremor in patient with essential tremor (ET). However, successful tremor suppression after surgery requires careful selection of stimulus parameters. Our aim was to examine the possible use of certain quantitative methods for evaluating the efficacy of thalamic DBS in ET patients in clinical practice, and to compare these methods with traditional clinical tests. METHODS: We examined 22 patients using the Essential Tremor Rating Scale (ETRS) and quantitative assessment of tremor with the stimulator both activated and deactivated. We used an accelerometer (CATSYS tremor Pen) for quantitative measurement of postural tremor, and a eurythmokinesimeter (EKM) to evaluate kinetic tremor in a rapid pointing task. RESULTS: The efficacy of DBS on tremor suppression was prominent irrespective of the method used. The agreement between clinical rating of postural tremor and tremor intensity as measured by the CATSYS tremor pen was relatively high (rs = 0.74). The agreement between kinetic tremor as assessed by the ETRS and the main outcome variable from the EKM test was low (rs = 0.34). The lack of agreement indicates that the EKM test is not comparable with the clinical test. DISCUSSION: Quantitative methods, such as the CATSYS tremor pen, could be a useful complement to clinical tremor assessment in evaluating the efficacy of DBS in clinical practice. Future studies should evaluate the precision of these methods and long-term impact on tremor suppression, activities of daily living (ADL) function and quality of life.

10.
J Mot Behav ; 45(5): 415-22, 2013.
Article in English | MEDLINE | ID: mdl-23972026

ABSTRACT

Several partly overlapping diseases have Parkinsonism as a symptom and tools that may differentiate between these disorders would be helpful. The authors evaluated the discriminating properties of the objective automated posturo-locomotor-manual (PLM) L-DOPA test in regard to health, and the movement disorders Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). A PLM test-retest procedure was performed in healthy controls (n = 37) and results were compared with PLM L-DOPA tests performed by 132 patients with Parkinsonism in intermediate to advanced stages (56 PD, 53 MSA, 23 PSP). The movement time (MT) for the standardized movement and its different components was measured. The discriminating abilities of individual, or combinations of, test variables were determined by forward stepwise multiple logistic regression and evaluated with receiver-operating characteristic (ROC) analysis. Each PLM variable separated healthy persons from patients with Parkinsonism before administration of L-DOPA (area under the curve (AUC) = 0.94-0.99, p < .001 for any separate variable). A combination of (MToff - MTon)/MToff and MTon had the highest ability to separate patients with PD from patients with atypical Parkinsonism (area under the curve = 0.91, p < .001). The PLM test discriminates between healthy controls and patients with Parkinsonism, and between patients with Parkinson's disease and patients with atypical Parkinsonism.


Subject(s)
Movement/physiology , Parkinsonian Disorders/physiopathology , Aged , Antiparkinson Agents/therapeutic use , Diagnosis, Differential , Female , Humans , Levodopa/therapeutic use , Linear Models , Logistic Models , Male , Middle Aged , Multiple System Atrophy/diagnosis , Multiple System Atrophy/physiopathology , Parkinsonian Disorders/diagnosis , Posture/physiology , ROC Curve , Reproducibility of Results , Supranuclear Palsy, Progressive/diagnosis , Supranuclear Palsy, Progressive/physiopathology
11.
Front Neurol ; 4: 95, 2013.
Article in English | MEDLINE | ID: mdl-23882256

ABSTRACT

Objective methods for quantifying patients' movement capacity would be useful in evaluating progression and interventions in neurodegenerative diseases. The Posturo-Locomotor-Manual (PLM) test is a standardized automated movement test developed to measure hypokinetic movements in patients with Parkinsonism. Our hypotheses were that the PLM movement time (MT) correlates with the Unified Parkinson's disease rating scale (UPDRS III) motor section, and that the components of the PLM test correlate with the corresponding constructed domains of UPDRS III. We also evaluated the coherence between the results of the two assessment methods after a test dose of levodopa (l-DOPA). We assessed motor function using the PLM method and UPDRS III in parallel, in the absence of medication and after administration of 200 mg l-DOPA, in 73 patients with moderate to advanced Parkinsonism: 47 with Parkinson's disease (PD), 17 with multiple system atrophy (MSA), and 9 with progressive supranuclear palsy (PSP). There was a fair correlation between the two assessment tools in the PD patients but not in the MSA or PSP patients. In the full dataset, there was a fair to good correlation between UPDRS III and the PLM MT. At group level, the UPDRS III l-DOPA test differentiated PD from MSA/PSP, whereas the PLM l-DOPA test differentiated between all three diagnoses.

12.
Mov Disord ; 28(13): 1882-5, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23847144

ABSTRACT

BACKGROUND: Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls. METHODS: We analyzed the glial activation markers YKL-40 and soluble CD14 in serum and cerebrospinal fluid from 37 controls, 50 patients with Parkinson's disease (PD), and 79 P+ patients (those with progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy). RESULTS: Cerebrospinal fluid levels of YKL-40 were decreased significantly in patients who had PD compared with controls (P < 0.05), patients who had multiple system atrophy (P < 0.01), and patients who had tauopathies (P < 0.0001). In addition, cerebrospinal fluid levels of YKL-40 were significantly lower in patients who had synucleinopathies than in those who had tauopathies (P < 0.0001). CONCLUSIONS: The decreased cerebrospinal fluid levels of YKL-40 suggest that glial activation is reduced in the brains of patients who have Parkinson's disease and synucleinopathies compared with patients who have tauopathies and controls.


Subject(s)
Adipokines/blood , Adipokines/cerebrospinal fluid , Basal Ganglia Diseases/blood , Basal Ganglia Diseases/cerebrospinal fluid , Lectins/blood , Lectins/cerebrospinal fluid , Neurodegenerative Diseases/blood , Neurodegenerative Diseases/chemically induced , Aged , Analysis of Variance , Chitinase-3-Like Protein 1 , Female , Humans , Lipopolysaccharide Receptors/blood , Lipopolysaccharide Receptors/cerebrospinal fluid , Male , Middle Aged , Multiple System Atrophy , Parkinson Disease , Supranuclear Palsy, Progressive , Tauopathies/blood , Tauopathies/cerebrospinal fluid , alpha-Synuclein/blood , alpha-Synuclein/cerebrospinal fluid
13.
Neurobiol Aging ; 34(6): 1708.e7-13, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23153929

ABSTRACT

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.


Subject(s)
Genetic Loci/genetics , Genome-Wide Association Study , Parkinson Disease/epidemiology , Parkinson Disease/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Genome-Wide Association Study/methods , Humans , Male , Middle Aged , Norway/epidemiology , Parkinson Disease/diagnosis , Polymorphism, Single Nucleotide/genetics , Sweden/epidemiology
14.
Arch Neurol ; 69(11): 1445-52, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22925882

ABSTRACT

OBJECTIVE: To assess the ability of 5 cerebrospinal fluid(CSF) biomarkers to differentiate between common dementia and parkinsonian disorders. DESIGN: A cross-sectional, clinic-based study. PARTICIPANTS: Cerebrospinal fluid samples (N=453) were obtained from healthy individuals serving as controls and from patients with Parkinson disease (PD), PD with dementia(PDD), dementia with Lewy bodies (DLB), Alzheimer disease (AD), progressive supranuclear palsy(PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). SETTING: Neurology and memory disorder clinics. MAIN OUTCOME MEASURES: Cerebrospinal fluid biomarker levels in relation to clinical diagnosis. RESULTS: Cerebrospinal fluid levels of -synuclein were decreased in patients with PD, PDD, DLB, and MSA but increased in patients with AD. Cerebrospinal fluid levels of α-amyloid 1-42 were decreased in DLB and even further decreased in AD. Cerebrospinal fluid levels of total tau and hyperphosphorylated tau were increased in AD. Multivariate analysis revealed that these biomarkers could differentiate AD from DLB and PDD with an area under the curve of 0.90, with -synuclein and total tau contributing most to the model. Cerebrospinal fluid levels of neurofilament light chain were substantially increased in atypical parkinsonian disorders (ie, PSP, MSA,and CBD), and multivariate analysis revealed that the level of neurofilament light chain alone could differentiate PD from atypical parkinsonian disorders, with an area under the curve of 0.93. CONCLUSIONS: Ascertainment of the -synuclein level in CSF somewhat improves the differential diagnosis of AD vs DLB and PDD when combined with established AD biomarkers.The level of neurofilament light chain alone may differentiate PD from atypical parkinsonian disorders.


Subject(s)
Biomarkers/cerebrospinal fluid , Dementia/cerebrospinal fluid , Dementia/diagnosis , Parkinson Disease/cerebrospinal fluid , Parkinson Disease/diagnosis , Aged , Aged, 80 and over , Amyloid beta-Peptides/cerebrospinal fluid , Cross-Sectional Studies , Dementia/complications , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Female , Hemoglobins/cerebrospinal fluid , Humans , Male , Middle Aged , Multiple System Atrophy/cerebrospinal fluid , Multiple System Atrophy/diagnosis , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/diagnosis , Neuropsychological Tests , Parkinson Disease/complications , Psychiatric Status Rating Scales , Severity of Illness Index , Statistics, Nonparametric , Supranuclear Palsy, Progressive/cerebrospinal fluid , Supranuclear Palsy, Progressive/diagnosis , alpha-Synuclein/cerebrospinal fluid , tau Proteins/cerebrospinal fluid
15.
Parkinsonism Relat Disord ; 16(8): 545-9, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20620095

ABSTRACT

Parkinson's disease (PD) and atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a group of neurodegenerative diseases sharing many similar signs and symptoms but distinguished by their particular clinical features, treatment response, prognosis and mortality. The differential diagnosis may be challenging, especially in early disease stages. Considering the importance of an accurate diagnosis both for clinical management and for research, new diagnostic tools are needed. In this study, we investigated 56 PD, 42 MSA, 39 PSP, 9 CBD patients, and 24 healthy controls. After screening the cerebrospinal fluid (CSF) proteome using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), we identified 4 proteins (ubiquitin [mass-to-charge ratio (m/z) 8590], beta2-microglobulin [m/z 11730], and 2 secretogranin 1 [chromogranin B] fragments [m/z 7260 and m/z 6250]) that differentiated healthy controls and PD patients from patients with APD. However, they could not differentiate PD patients from controls. As none of these changes were APD subgroup-specific, they most likely reflect the intensity and/or extent of the neurodegenerative process in general.


Subject(s)
Biomarkers/cerebrospinal fluid , Parkinsonian Disorders/cerebrospinal fluid , Parkinsonian Disorders/diagnosis , Aged , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Proteomics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
16.
Parkinsonism Relat Disord ; 16(2): 142-5, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19647470

ABSTRACT

Cerebrospinal fluid (CSF) levels of neurofilament light protein (NFL), a marker of neuronal damage, are normal in Parkinson's disease (PD) but elevated in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Therefore, CSF NFL can help differentiate between PD on one hand and MSA/PSP on the other. In the present study of 10 patients with PD, 21 with MSA, 14 with PSP, 11 with corticobasal degeneration (CBD), and 59 healthy controls, this previous observation is confirmed and also extended to include CBD by showing that similarly high CSF NFL levels are seen not only in MSA and PSP but also in CBD. CSF levels of glial fibrillary acidic protein (GFAP), a protein expressed mainly in fibrillary astrocytes, were similar in all investigated groups. In addition, consecutive analyses of CSF NFL and CSF GFAP levels showed relatively stable levels over time in all the investigated parkinsonian disorders, suggesting that the rate of neuronal degeneration is rather constant over time. Our results suggest that measurements of CSF NFL but not GFAP can be useful in the differential diagnosis of PD versus atypical parkinsonian disorders (APD). However they do not help differentiate between the different APD.


Subject(s)
Glial Fibrillary Acidic Protein/cerebrospinal fluid , Neurofilament Proteins/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Parkinsonian Disorders/cerebrospinal fluid , Case-Control Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Male , Middle Aged , Parkinson Disease/blood , Parkinsonian Disorders/blood , Retrospective Studies
17.
Neurobiol Aging ; 31(1): 114-7, 2010 Jan.
Article in English | MEDLINE | ID: mdl-18420308

ABSTRACT

PITX3 is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons, the gene of which is disrupted in a putative mouse model for Parkinson's disease (PD). The A-allele of a HapMap tagging SNP (rs4919621) that was genotyped in a population of 361 PD patients, 69 of which had early onset, and in 333 controls, was significantly more common in PD patients with an early age of onset when compared either to controls (p=0.002) or to PD patients with late onset (p=0.001). In contrast, a previous finding suggesting a SNP (rs3758549) in the putative promoter region of the PITX3 gene to be associated with PD could not be replicated.


Subject(s)
Brain Chemistry/genetics , Genetic Predisposition to Disease/genetics , Homeodomain Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Genetic/genetics , Transcription Factors/genetics , Age of Onset , Cell Survival/genetics , DNA Mutational Analysis , Dopamine/metabolism , Female , Gene Frequency , Genetic Markers/genetics , Genetic Testing , Genotype , Humans , Male , Middle Aged , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Neurons/metabolism , Parkinson Disease/metabolism , Promoter Regions, Genetic/genetics , Substantia Nigra/metabolism
18.
J Neurol Sci ; 279(1-2): 76-9, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19195665

ABSTRACT

BACKGROUND: Two cerebrospinal fluid (CSF) biomarkers specific for neurodegeneration have recently emerged - the neurofilament light (NfL, 68 kDa) and heavy (NfH, 190-210 kDa) chains. This study investigated whether the CSF NfH and NfL levels or their stoichiometric relationship changed over time in a neuroprotective treatment trial. METHODS: Serial CSF samples (n=95) from 42 patients with multiple system atrophy (MSA), half randomized to treatment with recombinant human growth hormone (r-hGH) and the other half to placebo, were collected at baseline, 6 and 12 months. The concentration of CSF NfL and NfH was determined using standard ELISAs. RESULTS: There was no consistent change in the levels of either protein over the 12 month period, or between treatment with active r-hGH versus placebo. The molar stoichiometry of CSF NfL:NfH was 4:1 (R=0.37, p=0.0002) and increased following treatment with r-hGH (p=0.03). CONCLUSION: These results indicate that CSF levels of both NfL and NfH on their own are not useful markers of disease progression in MSA, at least over a 12-month period. Future work is needed to elucidate whether the CSF stoichiometry and dynamics of Nf subunits in individual patients are a feature of the underlying pathology and of diagnostic or prognostic value.


Subject(s)
Human Growth Hormone/therapeutic use , Multiple System Atrophy/cerebrospinal fluid , Multiple System Atrophy/drug therapy , Neurofilament Proteins/cerebrospinal fluid , Neuroprotective Agents/therapeutic use , Adult , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Human Growth Hormone/biosynthesis , Humans , Linear Models , Longitudinal Studies , Male , Middle Aged , Recombinant Proteins/therapeutic use
19.
J Neural Transm (Vienna) ; 116(3): 333-8, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19189040

ABSTRACT

The key symptoms of Parkinson's disease (PD) are caused by degeneration of dopamine neurons originating in substantia nigra. Whereas, transcription factor LMX1A is crucial for the differentiation of mesencephalic dopamine neurons, LMX1B appears to be important for both the development and the survival of these cells. The aim of this study was to investigate if genetic variation in LMX1A and LMX1B differs between patients with PD (n = 357) and control subjects (n = 1428) by genotyping 33 single nucleotide polymorphisms (SNPs) in LMX1A and 11 SNPs in LMX1B. Three SNPs in LMX1A and one in LMX1B were associated with PD. After splitting for gender, six SNPs were associated with PD in women and four in men. The significances obtained did not survive correction for multiple testing, and our results should hence be interpreted with caution, but are partly in line with a previous report, and should thus be of sufficient interest to encourage further studies of these genes in PD.


Subject(s)
Homeodomain Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Aged , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , LIM-Homeodomain Proteins , Male , Polymerase Chain Reaction , Sex Factors
20.
Parkinsonism Relat Disord ; 15(3): 205-12, 2009 Mar.
Article in English | MEDLINE | ID: mdl-18562238

ABSTRACT

Parkinsonian disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a large group of common neurodegenerative diseases. The initial differential diagnosis can be extremely challenging with major implications for prognosis. The 42 amino acid fragment of amyloid-beta (Abeta42), neurofilament light chain (NFL), neurofilament heavy chain (pNFH), tau protein, glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), S-100B protein, and myelin basic protein (MBP) are brain related proteins (BRP) present in neurons and glia cells. They are released in the cerebrospinal fluid (CSF) after brain tissue damage caused by a variety of neurological diseases, including the parkinsonian disorders. A review of the literature shows that, carefully interpreted, the CSF levels of BRP can be of value in the differential diagnosis of parkinsonian disorders.


Subject(s)
Nerve Tissue Proteins/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Parkinson Disease/diagnosis , Brain/metabolism , Brain/pathology , Diagnosis, Differential , Humans , PubMed/statistics & numerical data
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