Sniffing the diagnosis: Olfactory testing in neurodegenerative parkinsonism.

OBJECTIVE: To determine the diagnostic utility of olfactory testing in patients with neurodegenerative parkinsonism. METHODS: The Sniffin' Sticks test battery for assessment of odor identification, discrimination, and threshold was applied to patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) as well as healthy controls (HC). Two different cohorts were analyzed: A PD/healthy control that included PD patients and HC as well as a PD/diseased control cohort for which patients PD, MSA and PSP were recruited. The former cohort was exploited to calculate cut-off values that discriminate PD patients from HC with a sensitivity (sensitivity-weighted cut-off) or specificity (specificity-weighted cut-off) exceeding 95%, respectively. The PD/diseased controls cohort was used to determine the diagnostic accuracy using these cut-off values in discriminating patients with neurodegenerative parkinsonism. RESULTS: PD patients (n = 67) performed significantly worse in olfactory testing than HC (n = 41) and patients with MSA (n = 23) or PSP (n = 23). There was no significant difference in olfactory function between MSA and PSP patients. Diagnostic performance of the identification subscore was similar to the sum score of the Sniffin' Sticks test (AUC identification test 0.94, AUC sum score 0.96), while threshold and discrimination subscores were inferior. In patients with parkinsonism, the specificity-weighted cut-off predicted a diagnosis of PD with a sensitivity and specificity of 76.6 and 87.0%, respectively. The discriminative value of this cut-off in separating PD from MSA was 76.7% (sensitivity) and 95.7% (specificity). The corresponding, prevalence-adjusted positive predictive value of olfactory testing exceeded 95%. CONCLUSIONS: Our data suggest that assessment of olfactory function, particularly odor identification, can be useful to discriminate PD from atypical parkinsonian disorders, particularly MSA patients.

The PRIPS study: screening battery for subjects at risk for Parkinson's disease.

BACKGROUND AND PURPOSE: Screening batteries to narrow down a target-at-risk population are essential for trials testing neuroprotective compounds aiming to delay or prevent onset of Parkinson's disease (PD). METHODS: The PRIPS study focuses on early detection of incident PD in 1847 at baseline PD-free subjects, and assessed age, male gender, positive family history, hyposmia, subtle motor impairment and enlarged substantia nigra hyperechogenicity (SN+). RESULTS: After 3 years follow-up 11 subjects had developed PD. In this analysis of the secondary outcome parameters, sensitivity and specificity of baseline markers for incident PD were calculated in 1352 subjects with complete datasets (10 PD patients). The best approach for prediction of incident PD comprised three steps: (i) prescreening for age, (ii) primary screening for positive family history and/or hyposmia, and (iii) secondary screening for SN+. CONCLUSION: With this approach, one out of 16 positively screened participants developed PD compared to one out of 135 in the original cohort. This corresponds to a sensitivity of 80.0%, a specificity of 90.6% and a positive predictive value of 6.1%. These values are higher than for any single screening instrument but still too low for a feasible and cost-effective screening strategy which might require longer follow-up intervals and application of additional instruments.

[Differential diagnosis of parkinsonian syndromes using MRI]. / Differenzialdiagnose der Parkinson-Syndrome mittels MRT.

The differential diagnosis of parkinsonian syndromes is considered one of the most challenging in clinical neurology. Despite published consensus operational criteria for the diagnosis of Parkinson's disease (PD) and the various atypical parkinsonian disorders (APD), such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration (CBD), the clinical separation of APDs from PD carries a high rate of misdiagnosis. However, the early differentiation between APD and PD, each characterized by a very different natural history, is crucial for determining the prognosis and choosing a treatment strategy. Despite limitations the various modern magnetic resonance imaging (MRI) techniques have undoubtedly added to the differential diagnosis of neurodegenerative parkinsonism. In clinical practice conventional MRI with visual assessment of T2 and T1-weighted imaging is a well established method for the exclusion of symptomatic parkinsonism due to other pathologies and may also point to the diagnosis of APD. Furthermore, advances in MRI techniques, such as diffusion-weighted imaging (DWI), have enabled abnormalities in the basal ganglia and infratentorial brain structures in APD to be quantitatively illustrated.

Inhibition of transmitter release from rat sympathetic neurons via presynaptic M(1) muscarinic acetylcholine receptors.

BACKGROUND AND PURPOSE: M(2), M(3) and/or M(4) muscarinic acetylcholine receptors have been reported to mediate presynaptic inhibition in sympathetic neurons. M(1) receptors mediate an inhibition of K(v)7, Ca(V)1 and Ca(V)2.2 channels. These effects cause increases and decreases in transmitter release, respectively, but presynaptic M(1) receptors are generally considered facilitatory. Here, we searched for inhibitory presynaptic M(1) receptors. EXPERIMENTAL APPROACH: In primary cultures of rat superior cervical ganglion neurons, Ca(2+) currents were recorded via the perforated patch-clamp technique, and the release of [(3)H]-noradrenaline was determined. KEY RESULTS: The muscarinic agonist oxotremorine M (OxoM) transiently enhanced (3)H outflow and reduced electrically evoked release, once the stimulant effect had faded. The stimulant effect was enhanced by pertussis toxin (PTX) and was abolished by blocking M(1) receptors, by opening K(v)7 channels and by preventing action potential propagation. The inhibitory effect was not altered by preventing action potentials or by opening K(v)7 channels, but was reduced by PTX and omega-conotoxin GVIA. The inhibition remaining after PTX treatment was abolished by blockage of M(1) receptors or inhibition of phospholipase C. When [(3)H]-noradrenaline release was triggered independently of voltage-activated Ca(2+) channels (VACCs), OxoM failed to cause any inhibition. The inhibition of Ca(2+) currents by OxoM was also reduced by omega-conotoxin and PTX and was abolished by M(1) antagonism in PTX-treated neurons. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that M(1), in addition to M(2), M(3) and M(4), receptors mediate presynaptic inhibition in sympathetic neurons using phospholipase C to close VACCs.