Interventional trials in atypical parkinsonism

Eschlböck, Sabine; Krismer, Florian; Wenning, Gregor K.

doi:10.1016/j.parkreldis.2015.09.038

Cited by 20 publications

(17 citation statements)

References 44 publications

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“…The APSs comprise multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which are a heterogeneous group of neurodegenerative disorders characterized by levodopa-refractory parkinsonism and distinctive atypical clinical features (10). In cases of MSA, one may observe various combinations of progressive autonomic failure, parkinsonian, cerebellar features, and pyramidal features.…”

Section: Apssmentioning

confidence: 99%

“…The current focus of drug therapy for APSs is still primarily alleviation of symptoms, for which the therapy is often ineffective (10). Available data on interventional therapies in APSs are sparse: small case series highlight the risk of clinical worsening after deep-brain stimulation in histologically proven MSA patients and strongly discourage its use (26).…”

Section: Treatment and Prognosismentioning

confidence: 99%

“…At present, no effective treatment exists to delay disease progression in APSs. In turn, disease-modifying trials with rasagiline and rifampicin for MSA or tideglusib and davunetide for PSP yielded negative results (10). Strategies to enhance trial success have been proposed, such as an enrichment design for novel disease-specific molecularly targeted therapeutics or identification of preclinical stages of parkinsonism, allowing for primary prevention and early disease-modifying trials.…”

Section: Treatment and Prognosismentioning

confidence: 99%

“…In fact, the mean time span between onset of dementia and death appears to be only about 2-4 y (33,34). Compared with PD, APSs are characterized by the early presence of additional debilitating symptoms and a more rapid progression to death (10). According to clinicopathologic studies, APSs share a comparably short survival of about 7-8 y from symptom onset, or less than 3-4 y from the typically somewhat delayed clinical diagnosis (32).…”

Section: Treatment and Prognosismentioning

confidence: 99%

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¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

et al. 2017

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Learning Objectives: On successful completion of this activity, participants should be able to (1) describe the clinical demand and rationale for differential diagnosis in parkinsonism, (2) recognize and differentiate the disease-specific patterns of regional glucose metabolism associated with Parkinson disease and the different atypical parkinsonian syndromes, and (3) identify regional metabolic changes that predict cognitive decline in Parkinson disease.Financial Disclosure: Dr. Meyer receives support from GE and Piramal for a research study outside the present topic. The authors of this article have indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA category 1 credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through December 2020.Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. In addition, with the development of invasive therapies and novel disease-specific therapies, strategies for patient enrichment in trial populations are of growing importance. Imaging disease-specific patterns of regional glucose metabolism with PET and 18 F-FDG allows for a highly accurate distinction between Parkinson disease (PD) and atypical parkinsonian syndromes, including multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. On the basis of a preliminary metaanalysis of currently available studies with inclusion of multiple disease groups, we estimated that the diagnostic sensitivity and specificity for visual PET readings supported by voxel-based statistical analyses for diagnosis of atypical parkinsonian syndromes are 91.4% and 90.6%, respectively. The diagnostic specificity of 18 F-FDG PET for diagnosing multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration was consistently shown to be high (.90%), whereas sensitivity was more variable (.75%). It is increasingly acknowledged that cognitive impairment represents a major challenge in PD, with mild cognitive impairment being a prodromal stage of PD with dementia (PDD). In line with clinical and neuropsychologic studies, recent PET studies demonstrated that posterior cortical dysfunction in nondemented PD patients precedes cognitive decline and the development of PDD by several years. Taken together, the current literature underscores the utility of 18 F-FDG PET for diagnostic evaluation of parkinsonism and the promising role of 18 F-FDG PET for assessment and risk stratification of cognitive impairment in PD.

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Section: Apssmentioning

confidence: 99%

Section: Treatment and Prognosismentioning

confidence: 99%

Section: Treatment and Prognosismentioning

confidence: 99%

Section: Treatment and Prognosismentioning

confidence: 99%

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¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

et al. 2017

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“…From onset of symptoms, the median survival is less than 10 years [32]. Importantly, there are currently no efficient symptomatic or disease-modifying therapies available [13]. MSA patients present with a heterogeneous combination of autonomic dysfunction, parkinsonism, cerebellar ataxia, and pyramidal features as a consequence of pronounced neurodegenerative changes.…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

et al. 2016

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Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths in order to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

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Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

Heras‐Garvin

Weckbecker²,

Ryazanov

et al. 2018

Movement Disorders

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Background MSA is a fatal neurodegenerative disease characterized by autonomic failure and severe motor impairment. Its main pathological hallmark is the accumulation of α‐synuclein in oligodendrocytes, leading to glial and neuronal dysfunction and neurodegeneration. These features are recapitulated in the PLP‐hαSyn mouse model expressing human α‐synuclein in oligodendrocytes. At present, there is no effective disease‐modifying therapy. Previous experiments have shown that the aggregation inhibitor, anle138b, reduces neurodegeneration and behavioral deficits in mouse models of other proteinopathies. Objectives To test the therapeutic potential of anle138b in a mouse model of MSA. Methods Two‐month‐old PLP‐hαSyn mice were fed over a period of 4 months with pellets containing anle138b at two different doses (0.6 and 2 g/kg) and compared to healthy controls and PLP‐hαSyn mice fed with placebo pellets. At the end of the treatment, behavioral and histological analyses were performed. Results We observed a reversal of motor function to healthy control levels when PLP‐hαSyn mice were treated with both doses of anle138b. Histological and molecular analyses showed a significant reduction in α‐synuclein oligomers and glial cytoplasmic inclusions in animals fed with anle138b compared to nontreated mice. These animals also present preservation of dopaminergic neurons and reduction in microglial activation in SN correlating with the α‐synuclein reduction observed. Conclusions Anle138b reduces α‐synuclein accumulation in PLP‐hαSyn mice, leading to neuroprotection, reduction of microglial activation, and preservation of motor function supporting the use of anle138b in a future clinical trial for MSA. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Interventional trials in atypical parkinsonism

Cited by 20 publications

References 44 publications

¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

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Interventional trials in atypical parkinsonism

Cited by 20 publications

References 44 publications

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

Contact Info

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¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

¹⁸F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment