Marjolein B. Aerts

CSF α-synuclein does not differentiate between parkinsonian disorders

Differentiating between Parkinsons disease (PD) and atypical Parkinsonism (AP) is clinically relevant but challenging. A timely and correct diagnosis might result in better targeted treatment strategies, adequate patient counseling, and early recognition of disease-specific complications. We aimed to investigate whether cerebrospinal fluid (CSF) concentrations of α-synuclein are of additional diagnostic value. We examined 142 consecutive patients with parkinsonism, mean disease duration 39.7 mo (Parkinsons disease (PD), n = 58; MSA, n = 47; dementia with Lewy bodies (DLB), n = 3; VaP, n = 22; progressive supranuclear palsy (PSP), n = 10; CBD, n = 2). Gold standard was the clinical diagnosis established after 2 years of clinical follow-up. CSF concentrations of α-synuclein, blood pigments and the erythrocyte count were determined. No differences between CSF α-synuclein concentrations of patients with PD with the reference values from our laboratory were observed. We neither found significant differences between patients with PD and AP nor between AP subgroups. Adjustment for age, disease severity or presence of erythrocytes or blood pigments in CSF did not alter these results. Our results imply that CSF α-synuclein is currently unsuitable as biomarker to differentiate between PD and AP.

CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls

Differential diagnosis between Parkinsons disease (PD) and multiple system atrophy (MSA) is difficult, particularly at early disease stages, but is important for therapeutic management. The protein DJ-1 is implicated in the pathology of PD but little is known about its involvement in MSA. We aimed to determine the diagnostic value of CSF DJ-1 and tau proteins for discriminating PD and MSA. DJ-1 and total tau levels were quantified in the CSF of 43 PD patients, 23 MSA patients and 30 non-neurological controls matched for age and gender. Patients were part of a study with a 3-year prospective design with extended case-review follow-up of up to 9 years, ensuring maximum accuracy of the clinical diagnosis. Our results showed that CSF DJ-1 levels could distinguish MSA from PD with a 78% sensitivity and 78% specificity (AUC = 0.84). The combination of DJ-1 and tau proteins significantly improved this discrimination to 82% sensitivity and 81% specificity to identify MSA from PD (AUC = 0.92). Our results highlight the potential benefits of a combination of DJ-1 and total tau as biomarkers for differential diagnosis of MSA and PD.

CSF Neurofilament Light Chain but not FLT3 Ligand Discriminates Parkinsonian Disorders.

The differentiation between multiple system atrophy (MSA) and Parkinson’s disease (PD) is difficult, particularly in early disease stages. Therefore, we aimed to evaluate the diagnostic value of neurofilament light chain (NFL), fms-like tyrosine kinase ligand (FLT3L), and total tau protein (t-tau) in cerebrospinal fluid (CSF) as biomarkers to discriminate MSA from PD. Using commercially available enzyme-linked immunosorbent assays, we measured CSF levels of NFL, FLT3L, and t-tau in a discovery cohort of 36 PD patients, 27 MSA patients, and 57 non-neurological controls and in a validation cohort of 32 PD patients, 25 MSA patients, 15 PSP patients, 5 CBS patients, and 56 non-neurological controls. Cut-offs obtained from individual assays and binary logistic regression models developed from combinations of biomarkers were assessed. CSF levels of NFL were substantially increased in MSA and discriminated between MSA and PD with a sensitivity of 74% and specificity of 92% (AUC = 0.85) in the discovery cohort and with 80% sensitivity and 97% specificity (AUC = 0.94) in the validation cohort. FLT3L levels in CSF were significantly lower in both PD and MSA compared to controls in the discovery cohort, but not in the validation cohort. t-tau levels were significantly higher in MSA than PD and controls. Addition of either FLT3L or t-tau to NFL did not improve discrimination of PD from MSA above NFL alone. Our findings show that increased levels of NFL in CSF offer clinically relevant, high accuracy discrimination between PD and MSA.

Improving the diagnostic accuracy in parkinsonism: a three-pronged approach

Separating Parkinsons disease from the various causes of atypical parkinsonism (AP) is a common and clinically relevant challenge in clinical practice. Distinguishing between the different causes of AP is even more difficult. Here the authors discuss a systematic, clinically based and three-pronged approach that can assist clinicians in establishing the correct diagnosis in the consulting room. The three consecutive steps include: (1) to verify that the clinical syndrome truly represents parkinsonism (hypokinetic–rigid syndrome); (2) to search systematically for ‘red flags’ (alarm signs that may signal the presence of AP); and (3) to integrate these two steps, as a basis for a narrow differential diagnosis and a guide for further ancillary tests.

CSF tau, Aβ42, and MHPG differentiate dementia with Lewy bodies from Alzheimer's disease.

Differentiating dementia with Lewy bodies (DLB) from Alzheimers Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42) in 45 patients with AD (mean age 71.6 years; 34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42, p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB.

Susceptibility-Weighted Imaging Improves the Diagnostic Accuracy of 3T Brain MRI in the Work-Up of Parkinsonism

BACKGROUND AND PURPOSE: The differentiation between Parkinson disease and atypical parkinsonian syndromes can be challenging in clinical practice, especially in early disease stages. Brain MR imaging can help to increase certainty about the diagnosis. Our goal was to evaluate the added value of SWI in relation to conventional 3T brain MR imaging for the diagnostic work-up of early-stage parkinsonism. MATERIALS AND METHODS: This was a prospective observational cohort study of 65 patients presenting with parkinsonism but with an uncertain initial clinical diagnosis. At baseline, 3T brain MR imaging with conventional and SWI sequences was performed. After clinical follow-up, probable diagnoses could be made in 56 patients, 38 patients diagnosed with Parkinson disease and 18 patients diagnosed with atypical parkinsonian syndromes, including 12 patients diagnosed with multiple system atrophy–parkinsonian form. In addition, 13 healthy controls were evaluated with SWI. Abnormal findings on conventional brain MR imaging were grouped into disease-specific scores. SWI was analyzed by a region-of-interest method of different brain structures. One-way ANOVA was performed to analyze group differences. Receiver operating characteristic analyses were performed to evaluate the diagnostic accuracy of conventional brain MR imaging separately and combined with SWI. RESULTS: Disease-specific scores of conventional brain MR imaging had a high specificity for atypical parkinsonian syndromes (80%–90%), but sensitivity was limited (50%–80%). The mean SWI signal intensity of the putamen was significantly lower for multiple system atrophy–parkinsonian form than for Parkinson disease and controls (P < .001). The presence of severe dorsal putaminal hypointensity improved the accuracy of brain MR imaging: The area under the curve was increased from 0.75 to 0.83 for identifying multiple system atrophy–parkinsonian form, and it was increased from 0.76 to 0.82 for identifying atypical parkinsonian syndromes as a group. CONCLUSIONS: SWI improves the diagnostic accuracy of 3T brain MR imaging in the work-up of parkinsonism by identifying severe putaminal hypointensity as a sign indicative of multiple system atrophy–parkinsonian form.

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias.

Overlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimers disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid‐β42 (Aβ42), total tau protein (t‐tau), and phosphorylated tau protein (p‐tau), in combination with 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD.

Cerebrospinal fluid tau and phosphorylated tau protein are elevated in corticobasal syndrome

Differentiating corticobasal syndrome (CBS) from progressive supranuclear palsy (PSP) and idiopathic Parkinsons disease (PD) can be difficult. To investigate the additional value of cerebrospinal fluid (CSF) biomarkers in the diagnostic differentiation of parkinsonism, we analyzed the CSF concentrations of total protein, lactate and brain specific proteins amyloid‐β42 protein, tau protein (t‐tau), and tau protein phosphorylated at Thr181 (p‐tau), in CSF samples from patients with PSP (n = 21), CBS (n = 12), and PD (n = 28). CBS patients demonstrated higher concentrations of t‐tau and p‐tau compared with PSP and PD patients. In discriminating CBS and PD, t‐tau offered the best combination of sensitivity (75%) and specificity (90.9%), followed by p‐tau (sensitivity 87.5% and specificity 75%). The p‐tau/t‐tau ratio resulted in sensitivity of 84.2% and specificity of 66.7% in discriminating PSP and CBS. In conclusion, our results suggest that CSF parameters are of additional value in the diagnostic differentiation of CBS and PD.

Is heart rate variability related to gait impairment in patients with Parkinson's disease? A pilot study

BACKGROUND AND PURPOSE Impairments in gait and autonomic function are common in patients with Parkinsons disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinsons Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms. METHODS Nine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects. RESULTS HRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p>0.129) nor with the UPDRS-motor score (p>0.147). DISCUSSION AND CONCLUSIONS The present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap.

Medio-Lateral Balance Impairment Differentiates between Parkinson's Disease and Atypical Parkinsonism

In early disease stages, it can be difficult to differentiate clinically between Parkinsons disease and the various forms of atypical parkinsonism, like multiple system atrophy or progressive supranuclear palsy. Balance impairment in the medio-lateral plane (i.e. sideways) is often seen in patients with a form of atypical parkinsonism, but not in patients with Parkinsons disease. This is reflected by the distance between the feet during gait, which is typically normal (or even narrow) in Parkinsons disease, but widened in atypical parkinsonism. Estimating this stance width depends on subjective judgement, and is difficult to quantify in clinical practice. Here, we emphasize that this medio-lateral balance impairment can also be revealed using two simple tests: (1) inability to perform tandem gait (taking one or more side steps being abnormal); and (2) self-report by patients who have lost the ability to ride a bicycle. Both tests have a good diagnostic yield in differentiating between Parkinsons disease and atypical parkinsonism, even early in the course of the disease.