Björn Holmberg

Cerebrospinal fluid Aβ42 is reduced in multiple system atrophy but normal in Parkinson's disease and progressive supranuclear palsy

The 42‐amino–acid isoform of β‐amyloid Aβ42 in the cerebrospinal fluid (CSF) has recently been proposed as a biochemical marker for Alzheimers disease (AD) and subcortical white‐matter dementia (SWD). In both of these conditions, concentration of CSF‐Aβ42 is reduced. We quantified CSF‐Aβ42 from patients fulfilling strict clinical criteria for multiple system atrophy (MSA; n = 36), Parkinsons disease (PD; n = 48) and progressive supranuclear palsy (PSP; n = 15). The study groups were consecutively recruited among patients referred to a movement disorder unit, and 32 healthy, age‐matched volunteers were used as controls. The CSF concentration of Aβ42 was significantly reduced in the MSA group (P < 0.001), whereas the PD and PSP groups did not differ from controls. On an individual basis, low content of Aβ42 was seen in 9 MSA patients regardless of age and disease duration. Three PD patients with long disease duration also had low concentrations but all PSP patients were normal. We conclude that the reduced CSF‐Aβ42 concentration may be a clue to the pathogenesis of MSA. There is a decreased production, or more possible, an increased consumption of CSF‐Aβ42. The analysis of this protein may also become a supplement to the clinical differentiation of parkinsonian syndromes in a movement disorder unit.

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinsons 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.

Consecutive analyses of cerebrospinal fluid axonal and glial markers in Parkinson's disease and atypical parkinsonian disorders

Cerebrospinal fluid (CSF) levels of neurofilament light protein (NFL), a marker of neuronal damage, are normal in Parkinsons 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.

Safety and tolerability of growth hormone therapy in multiple system atrophy: A double-blind, placebo-controlled study

The objective of this study was to investigate tolerability and possible neurotrophic effects of growth hormone (GH) in treatment of multiple system atrophy (MSA). In this double‐blind pilot study, MSA patients were randomized to recombinant human growth hormone (r‐hGH, n = 22), 1 mg every second day (6 months) followed by alternating daily injections of 1 mg and 0.5 mg (6 months), or matched placebo (n = 21). Safety analysis demonstrated no obvious between‐group differences. In both groups, there was progressive worsening of Unified Parkinsons Disease Rating Scale total score, which tended to be less in r‐hGH‐treated patients (12.9% at 6 months, 25.3% at 12 months) than in placebo (17.0% and 35.7%). Similarly, there was a trend to less worsening in Unified MSA Rating Scale total score with r‐hGH (13.2% and 21.2%) than with placebo (21.1% and 36.5%). Cardiovascular reflex autonomic testing also tended to show less deterioration with r‐hGH than with placebo at 12 months. However, 95% CI did not indicate treatment differences for any efficacy measures. In conclusion, r‐hGH administration in MSA patients for up to 1 year appears safe and might influence disease symptoms, signs and, possibly, progression. The results support further studies utilizing higher doses in more patients.

Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease

This interim 12‐month analysis is a part of an open‐label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health‐related quality of life (HRQoL) effects in routine care.

Levels of brain related proteins in cerebrospinal fluid: An aid in the differential diagnosis of parkinsonian disorders

Parkinsonian disorders such as Parkinsons 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.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson’s disease with symptom fluctuations

Backgroundu2002–u2002 Motor fluctuations in patients with advanced Parkinson’s disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed.

CSF-neurofilament and levodopa tests combined with discriminant analysis may contribute to the differential diagnosis of Parkinsonian syndromes

The differentiation between Parkinsons disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is important for prognostic and therapeutic purposes. In order to evaluate the diagnostic capability of two tests reflecting these items, patients fulfilling strict clinical criteria for PD (n=35), MSA (n=36) and PSP (n=14), were consecutively included. An analysis of neurofilament protein (NFL), a marker of axonal degeneration in the cerebrospinal fluid (CSF) and a levodopa test, recorded with optoelectronic technique were performed. Using discriminant analyses, the tests abilities to predict the clinical PD or non-PD (MSA and PSP) diagnoses were compared. Whereas the CSF-NFL and levodopa tests predicted 79 and 85% correct diagnoses respectively, the combined test predicted 90% correct diagnoses. We conclude that the CSF-NFL and levodopa tests provide detailed information of clinical variables on which the clinical diagnostic criteria are based. As they are pathologically unrelated, the diagnostic precision increases compared to clinical diagnoses when they are combined.

CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders

INTRODUCTIONnThere is an unmet need for biomarkers for Parkinsons 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.nnnMETHODSnWe 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.nnnRESULTSnα-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 (pxa0<xa00.001). Both markers discriminated PD well from controls (pxa0<xa00.0001; area under the curve [AUC]xa0=xa00.82 and 0.89, respectively). Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (pxa0=xa00.015; AUCxa0=xa00.63), whereas CSF UCH-L1 discriminated between PD and APD (pxa0=xa00.0003; AUCxa0=xa00.69). Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies. No correlation was found in controls.nnnCONCLUSIONSnCSF 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.

Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson’s disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs

BACKGROUNDnContinuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinsons disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG.nnnMETHODSnThe seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naïve (Nxa0=xa037), or had previous LCIG treatment for <2 (Nxa0=xa022), or ≥2 (Nxa0=xa018) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinsons Disease Rating Scale (UPDRS), 39-item Parkinsons Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored.nnnRESULTSnMean monthly costs per patient (€8226xa0±xa05952) 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 (nxa0=xa024; UPDRS, pxa0=xa00.033; PDQ-39, pxa0=xa00.049). 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.nnnCONCLUSIONSnCosts 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.