Philipp Mahlknecht

Diagnostic accuracy of the magnetic resonance Parkinsonism index and the midbrain‐to‐pontine area ratio to differentiate progressive supranuclear palsy from Parkinson's disease and the Parkinson variant of multiple system atrophy

Using magnetic resonance (MR) planimetry, both the midbrain‐to‐pontine area ratio (m/p‐ratio) and the MR parkinsonism index (MRPI) have been shown to assist in the differential diagnosis of progressive supranuclear palsy (PSP) from Parkinsons disease (PD) and the Parkinson variant of multiple system atrophy (MSA‐P). The aim of this study was to determine the diagnostic accuracy of the MRPI compared with the m/p‐ratio in a large cohort of 123 patients with neurodegenerative parkinsonism including patients with PSP, PD, and MSA‐P. Patients with PSP had significant higher MRPI values and significant smaller m/p‐ratios compared with the other groups with overlapping individual values. Overall predictive accuracy was similar for the m/p‐ratio (87.0%) and the MRPI (80.5%) with a predictive accuracy for PSP from MSA‐P being significantly better for the MRPI (87.5%) compared with the m/p‐ratio (75%) as well as a predictive accuracy for PSP from PD being significantly better for the m/p‐ratio (87.6%) compared with the MRPI (77.3%). Both the m/p‐ratio and the MRPI may assist the clinical differential diagnosis in neurodegenerative parkinsonism.

Probable RBD and association with neurodegenerative disease markers: A population‐based study

The prevalence of rapid eye movement sleep behavior disorder (RBD) and its association with markers of neurodegeneration in the general population are poorly defined.

Prevalence and burden of gait disorders in elderly men and women aged 60-97 years: a population-based study

Background Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined. Methods In a cross-sectional investigation of the population-based Bruneck Study cohort, 488 community-residing elderly aged 60–97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored. Results Overall, 32.2% (95% confidence interval [CI] 28.2%–36.4%) of participants presented with impaired gait. Prevalence increased with age (p<0.001), but 38.3% (95%CI 30.1%–47.3%) of the subjects aged 80 years or older still had a normally preserved gait. A total of 24.0% (95%CI 20.4%–28.0%) manifested neurological gait disorders, 17.4% (14.3%–21.0%) non-neurological gait problems, and 9.2% (6.9%–12.1%) a combination of both. While there was no association of neurological gait disorders with gender, non-neurological gait disorders were more frequent in women (pu200a=u200a0.012). Within the group of neurological gait disorders 69.2% (95%CI 60.3%–76.9%) had a single distinct entity and 30.8% (23.1%–39.7%) had multiple neurological causes for gait impairment. Gait disorders had a significant negative impact on quantitative gait measures, but only neurological gait disorders were associated with recurrent falls (odds ratio 3.3; 95%CI 1.4–7.5; pu200a=u200a0.005 for single and 7.1; 2.7–18.7; p<0.001 for multiple neurological gait disorders). Finally, we detected a significant association of gait disorders, in particular neurological gait disorders, with depressed mood, cognitive dysfunction, and compromised quality of life. Conclusions Gait disorders are common in the general elderly population and are associated with reduced mobility. Neurological gait disorders in particular are associated with recurrent falls, lower cognitive function, depressed mood, and diminished quality of life.

The Concept of Prodromal Parkinson's Disease.

Parkinson’s disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials.

Correlation of dopaminergic terminal dysfunction and microstructural abnormalities of the basal ganglia and the olfactory tract in Parkinson’s disease

Signal abnormalities of the substantia nigra and the olfactory tract detected either by diffusion tensor imaging, including measurements of mean diffusivity, a parameter of brain tissue integrity, and fractional anisotropy, a parameter of neuronal fibre integrity, or transcranial sonography, were recently reported in the early stages of Parkinsons disease. In this study, changes in the nigral and olfactory diffusion tensor signal, as well as nigral echogenicity, were correlated with clinical scales of motor disability, odour function and putaminal dopamine storage capacity measured with 6-[(18)F] fluorolevodopa positron emission tomography in early and advanced stages of Parkinsons disease. Diffusion tensor imaging, transcranial sonography and positron emission tomography were performed on 16 patients with Parkinsons disease (mean disease duration 3.7 ± 3.7 years, Hoehn and Yahr stage 1 to 4) and 14 age-matched healthy control subjects. Odour function was measured by the standardized Sniffin Sticks Test. Mean putaminal 6-[(18)F] fluorolevodopa influx constant, mean nigral echogenicity, mean diffusivity and fractional anisotropy values of the substantia nigra and the olfactory tract were identified by region of interest analysis. When compared with the healthy control group, the Parkinsons disease group showed significant signal changes in the caudate and putamen by 6-[(18)F] fluorolevodopa positron emission tomography, in the substantia nigra by transcranial sonography, mean diffusivity and fractional anisotropy (P < 0.001, P < 0.01, P < 0.05, respectively) and in the olfactory tract by mean diffusivity (P < 0.05). Regional mean diffusivity values of the substantia nigra and the olfactory tract correlated significantly with putaminal 6-[(18)F] fluorolevodopa uptake (r = -0.52, P < 0.05 and r = -0.71, P < 0.01). Significant correlations were also found between nigral mean diffusivity values and the Unified Parkinsons Disease Rating Scale motor score (r = -0.48, P < 0.01) and between mean putaminal 6-[(18)F] fluorolevodopa uptake and the total odour score (r = 0.58; P < 0.05) as well as the Unified Parkinsons Disease Rating Scale motor score (r = -0.53, P < 0.05). This study reports a significant association between increased mean diffusivity signal and decreased 6-[(18)F] fluorolevodopa uptake, indicating that microstructural degradation of the substantia nigra and the olfactory tract parallels progression of putaminal dopaminergic dysfunction in Parkinsons disease. Since increases in nigral mean diffusivity signal also correlated with motor dysfunction, diffusion tensor imaging may serve as a surrogate marker for disease progression in future studies of putative disease modifying therapies.

Prodromal Parkinson's disease as defined per MDS research criteria in the general elderly community.

Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinsons disease (PD), but to date their predictive value has not yet been tested in population‐based cohorts.

Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments

AbstractModern deep brain stimulation (DBS) has become a routine therapy for patients with movement disorders such as Parkinson’s disease, generalized or segmental dystonia and for multiple forms of tremor. Growing numbers of publications also report beneficial effects in other movement disorders such as Tourette’s syndrome, various forms of chorea and DBS is even being studied for Parkinson’s-related dementia. While exerting remarkable effects on many motor symptoms, DBS does not restore normal neurophysiology and therefore may also have undesirable side effects including speech and gait deterioration. nFurthermore, its efficacy might be compromised in the long term, due to progression of the underlying disease. Various programming strategies have been studied to try and address these issues, e.g., the use of low-frequency rather than high-frequency stimulation or the targeting of alternative brain structures such as the pedunculopontine nucleus. In addition, further technical developments will soon provide clinicians with an expanded choice of hardware such as segmented electrodes allowing for a steering of the current to optimize beneficial effects and reduce side effects as well as the possibility of adaptive stimulation systems based on closed-loop concepts with or without accompanying advances in programming and imaging software. In the present article, we will provide an update on the most recent achievements and discoveries relevant to the application of DBS in the treatment of movement disorder patients and give an outlook on future clinical and technical developments.

Sniffing the diagnosis: Olfactory testing in neurodegenerative parkinsonism

OBJECTIVEnTo determine the diagnostic utility of olfactory testing in patients with neurodegenerative parkinsonism.nnnMETHODSnThe Sniffin Sticks test battery for assessment of odor identification, discrimination, and threshold was applied to patients with Parkinsons 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.nnnRESULTSnPD patients (nxa0=xa067) performed significantly worse in olfactory testing than HC (nxa0=xa041) and patients with MSA (nxa0=xa023) or PSP (nxa0=xa023). 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%.nnnCONCLUSIONSnOur data suggest that assessment of olfactory function, particularly odor identification, can be useful to discriminate PD from atypical parkinsonian disorders, particularly MSA patients.

Predictors for mild parkinsonian signs: A prospective population-based study

OBJECTIVEnMild parkinsonian signs (MPS) are common in the elderly population and are associated with a wide range of adverse health outcomes, including incident Parkinsons disease (PD). We aimed to prospectively evaluate potential risk factors for incident MPS.nnnMETHODSnParticipants of the population-based Bruneck Study representative for the general elderly community underwent a baseline assessment of substantia nigra (SN)-echogenicity with transcranial sonography, olfactory function with the Sniffin Sticks identification test and vascular risk according to the Framingham risk score as well as a baseline and 5-year follow-up neurological examination. MPS were defined according to established criteria based on the entire motor section of the Unified PD Rating Scale. Participants with PD at baseline or follow-up and subjects with MPS at baseline were excluded. A logistic regression analysis adjusted for age and sex was used to detect risk factors for incident MPS in the remaining 393 participants.nnnRESULTSnSN-hyperechogenicity and hyposmia were related to the development of MPS with odds ratios of 2.0 (95%CI, 1.1-3.7) and 1.6 (95%CI, 1.0-2.7), respectively, while increased vascular risk was not. Having both, SN-hyperechogenicity and hyposmia, was associated with an odds ratio of 3.0 (95%CI, 1.2-7.7) for incident MPS. Among the various motor domains, increased SN-echogenicity predicted the development of bradykinesia and rigidity, whereas diminished olfactory function predicted the development of impaired axial motor function.nnnCONCLUSIONSnIn addition to their established roles as risk factors for PD, SN-hyperechogenicity and hyposmia are associated with an increased risk for MPS in the general elderly community.

Optimizing odor identification testing as quick and accurate diagnostic tool for Parkinson's disease

The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD.