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Practical Neurology Oct 2021Treating patients with progressive supranuclear palsy (PSP) is both effective and rewarding. This review aims to share our experience in the proactive management of PSP,... (Review)
Review
Treating patients with progressive supranuclear palsy (PSP) is both effective and rewarding. This review aims to share our experience in the proactive management of PSP, considering the patient, the family and the medical context in which the illness unfolds. There are many opportunities to assist your patients, ameliorate their symptoms, reduce their risks and harm, and guide them through the complex medical, social and legal minefield that characterises life with chronic neurological illness. We summarise the challenges of early diagnosis, consider PSP mimics and the role of investigations in excluding these, and discuss the available pharmacological and non-pharmacological treatment strategies to tackle the common and challenging symptoms of PSP. The best treatment will be patient centred and as part of a multidisciplinary team.
Topics: Diagnosis, Differential; Humans; Supranuclear Palsy, Progressive
PubMed: 34215700
DOI: 10.1136/practneurol-2020-002794 -
Parkinsonism & Related Disorders Apr 2020Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed... (Review)
Review
Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed at autopsy. Growing understanding of the phenotypic diversity of PSP has led to expanded clinical criteria and new insights into etiopathogenesis that coupled with improved in vivo biomarkers makes increased access to current clinical trials possible. Current standard-of-care treatment of PSP is multidisciplinary, supportive and symptomatic, and several trials of potentially disease modulating agents have already been completed with disappointing results. Current ongoing clinical trials target the abnormal aggregation of tau through a variety of mechanisms including immunotherapy and gene therapy offer a more direct method of treatment. Here we review PSP clinicopathologic correlations, in vivo biomarkers including MRI, PET, and CSF biomarkers. We additionally review current pharmacologic and non-pharmacologic methods of treatment, prior and ongoing clinical trials in PSP. Newly expanded clinical criteria and improved specific biomarkers will aid in identifying patients with PSP earlier and more accurately and expand access to these potentially beneficial clinical trials.
Topics: Drug Therapy; Genetic Therapy; Humans; Immunotherapy; Supranuclear Palsy, Progressive
PubMed: 32487421
DOI: 10.1016/j.parkreldis.2020.04.014 -
RoFo : Fortschritte Auf Dem Gebiete Der... Dec 2021Diagnosis of Parkinson's disease and atypical parkinsonism is based on clinical evaluation of the patient's symptoms and on magnetic resonance imaging (MRI) of the... (Review)
Review
BACKGROUND
Diagnosis of Parkinson's disease and atypical parkinsonism is based on clinical evaluation of the patient's symptoms and on magnetic resonance imaging (MRI) of the brain, which can be supplemented by nuclear medicine techniques. MRI plays a leading role in the differentiation between Parkinson's disease and atypical parkinsonism. While atypical parkinsonism is characterized by relatively specific MRI signs, imaging of Parkinson's disease previously lacked such signs. However, high-field MRI and new optimized MRI sequences now make it possible to define specific MRI signs of Parkinson's disease and have significant potential regarding differentiated imaging, early diagnosis, and imaging of disease progression.
METHODS
PubMed was selectively searched for literature regarding the definition and discussion of specific MRI signs of Parkinson's disease, as well as the most common types of atypical parkinsonism with a leading motor component. No time frame was set, but the search was particularly focused on current literature.
RESULTS
This review article discusses the different MRI signs of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. The pathogenesis of the MRI signs is described, and imaging examples are given. The technical aspects of image acquisition are briefly defined, and the different signs are discussed and compared with regard to their diagnostic significance according to current literature.
CONCLUSION
The MRI signs of Parkinson's disease, which can be defined with high-field MRI and new optimized MRI sequences, enable differentiated structural image interpretation and consecutive diagnostic workup. Despite the fact that the signs are in need of further validation by bigger studies, they have the potential to achieve significant diagnostic relevance regarding the imaging of Parkinson's disease and atypical parkinsonism.
KEY POINTS
· High-field MRI and specialized sequences make it possible to define specific MRI signs for neurodegenerative disorders. · Cerebral alterations can be detected in prodromal stages of Parkinson's disease. · The combination of specific MRI signs makes it possible to differentiate between Parkinson's disease and atypical parkinsonism.
CITATION FORMAT
· Aludin S, Schmill LA. MRI Signs of Parkinson's Disease and Atypical Parkinsonism. Fortschr Röntgenstr 2021; 193: 1403 - 1410.
Topics: Humans; Magnetic Resonance Imaging; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive
PubMed: 34034347
DOI: 10.1055/a-1460-8795 -
Handbook of Clinical Neurology 2023Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct... (Review)
Review
Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns-Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO). Intriguingly, many of those nuclear DNA pathogenic variants impair maintenance of the mitochondrial genome causing downstream mtDNA multiple deletions and depletion. In addition, numerous genetic causes of nonmitochondrial PEO have been identified.
Topics: Humans; Ophthalmoplegia, Chronic Progressive External; DNA, Mitochondrial; Ophthalmoplegia; Muscle, Skeletal; Syndrome
PubMed: 36813323
DOI: 10.1016/B978-0-12-821751-1.00018-X -
Journal of Neurology Nov 2020Disturbances of balance, gait and posture are a hallmark of parkinsonian syndromes. Recognition of these axial features can provide important and often early clues to... (Review)
Review
Disturbances of balance, gait and posture are a hallmark of parkinsonian syndromes. Recognition of these axial features can provide important and often early clues to the nature of the underlying disorder, and, therefore, help to disentangle Parkinson's disease from vascular parkinsonism and various forms of atypical parkinsonism, including multiple system atrophy, progressive supranuclear palsy, and corticobasal syndrome. Careful assessment of axial features is also essential for initiating appropriate treatment strategies and for documenting the outcome of such interventions. In this article, we provide an overview of balance, gait and postural impairment in parkinsonian disorders, focusing on differential diagnostic aspects.
Topics: Gait; Humans; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive
PubMed: 31119450
DOI: 10.1007/s00415-019-09382-1 -
Orphanet Journal of Rare Diseases Oct 2022Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in... (Review)
Review
Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.
Topics: Anemia; Child, Preschool; Congenital Bone Marrow Failure Syndromes; DNA, Mitochondrial; Humans; Infant; Kearns-Sayre Syndrome; Lipid Metabolism, Inborn Errors; Mitochondrial Diseases; Muscular Diseases
PubMed: 36253820
DOI: 10.1186/s13023-022-02538-9 -
Acta Neuropathologica Aug 2020Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical...
Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.
Topics: Aged; Brain; Cohort Studies; Female; Humans; Male; Middle Aged; Supranuclear Palsy, Progressive; tau Proteins
PubMed: 32383020
DOI: 10.1007/s00401-020-02158-2 -
JAMA Neurology Mar 2020Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult...
IMPORTANCE
Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.
OBJECTIVE
To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.
DESIGN, SETTING, PARTICIPANTS
This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.
MAIN OUTCOMES AND MEASURES
Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.
RESULTS
A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).
CONCLUSIONS AND RELEVANCE
These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.
Topics: Aged; Cohort Studies; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Supranuclear Palsy, Progressive
PubMed: 31860007
DOI: 10.1001/jamaneurol.2019.4347 -
Blood Nov 2020CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by...
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Autoantibodies; B-Lymphocytes; Cryoglobulins; Female; France; Hematologic Neoplasms; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Ophthalmoplegia; Paraproteinemias; Paresthesia; Retrospective Studies; Rituximab; Syndrome; Waldenstrom Macroglobulinemia
PubMed: 32959046
DOI: 10.1182/blood.2020007092 -
Cell May 2024Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we...
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
Topics: Humans; Induced Pluripotent Stem Cells; tau Proteins; Tauopathies; Neurons; Animals; Mice; Alzheimer Disease; Brain; Supranuclear Palsy, Progressive; Cell Differentiation; Mutation; Autophagy
PubMed: 38582079
DOI: 10.1016/j.cell.2024.03.015