Article

Progressive supranuclear palsy: Neuropathologically based diagnostic clinical criteria

March 1995
Journal of Neurology, Neurosurgery, and Psychiatry 58(2):167-73

March 1995
58(2):167-73

DOI:10.1136/jnnp.58.2.167

Source
PubMed

Authors:

All cases examined postmortem at the Mayo Clinic that met the classic neuropathological criteria for progressive supranuclear palsy (PSP) were identified for retrospective clinical analyses. The necropsy material was re-examined by a second neuropathologist to confirm the pathological diagnosis of PSP, yielding 12 cases. A range of clinical signs were documented in these patients, with numerous findings beyond those noted in the original descriptions of this disorder. Atypical clinical findings included absence of supranuclear gaze palsy (two cases), prominent asymmetry (two), arm dystonia (two), upper limb apraxia (two), myoclonus (two), chorea (one), eyelid opening apraxia (one), and respiratory disturbance (one). A definite clinical diagnosis of PSP had been made during life in only eight of the 12 patients. From the retrospective analysis of these 12 cases, a set of clinical criteria were developed for the premortem diagnosis of PSP emphasising differences from other akinetic-rigid disorders.

How to spot ocular abnormalities in progressive supranuclear palsy? A practical review

Article

Full-text available

Dec 2019

Background: For parkinsonian disorders, progressive supranuclear palsy (PSP) continues to be significant for differential diagnosis. PSP presents a range of ocular abnormalities that have been suggested as optional tools for its early detection, apart from the principal characteristic of postural unsteadiness. Nonetheless, such symptoms may be difficult to identify, particularly during the early onset stage of the disorder. It may also be problematic to recognize these symptoms for general practitioners who lack the required experience or physicians who are not specifically educated and proficient in ophthalmology or neurology. Main body: Thus, here, a methodical evaluation was carried out to identify seven oculomotor abnormalities occurring in PSP, comprising square wave jerks, the speed and range of saccades (slow saccades and vertical supranuclear gaze palsy), 'round the houses' sign, decreased blink rate, blepharospasm, and apraxia of eyelid opening. Inspections were conducted using direct visual observation. An approach to distinguish these signs during a bedside examination was also established. When presenting in a patient with parkinsonism or dementia, the existence of such ocular abnormalities could increase the risk of PSP. For the distinction between PSP and other parkinsonian disorders, these signs hold significant value for physicians. Conclusion: The authors urge all concerned physicians to check for such abnormalities with the naked eye in patients with parkinsonism. This method has advantages, including ease of application, reduced time-consumption, and requirement of minimal resources. It will also help physicians to conduct efficient diagnoses since many patients with PSP could intially present with ocular symptoms in busy outpatient clinics.

Progressive Supranuclear Palsy and Corticobasal Degeneration: Pathophysiology and Treatment Options

Article

Full-text available

Aug 2016

Opinion statement: There are currently no disease-modifying treatments for progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD), and no approved pharmacological or therapeutic treatments that are effective in controlling their symptoms. The use of most pharmacological treatment options are based on experience in other disorders or from non-randomized historical controls, case series, or expert opinion. Levodopa may provide some improvement in symptoms of Parkinsonism (specifically bradykinesia and rigidity) in PSP and CBD; however, evidence is conflicting and where present, benefits are often negligible and short lived. In fact, "poor" response to levodopa forms part of the NINDS-SPSP criteria for the diagnosis of PSP and consensus criteria for the diagnosis of CBD (Lang Mov Disord. 20 Suppl 1:S83-91, 2005; Litvan et al. Neurology. 48:119-25, 1997; Armstrong et al. Neurology. 80(5):496-503, 2013). There is some evidence that intrasalivery gland botulinum toxin is useful in managing problematic sialorrhea and that intramuscular botulinum toxin and baclofen are helpful in reducing dystonia, including blepharospasm. Benzodiazepines may also be useful in managing dystonia. Myoclonus may be managed using levetiracetam and benzodiazepines. Pharmacological agents licensed for Alzheimer's disease (such as acetylcholinesterase inhibitors and N-Methyl-D-aspartate receptor antagonists) have been used off-label in PSP, CBD, and other tauopathies with the aim of improving cognition; however, there is limited evidence that they are effective and risk of adverse effects may outweigh benefits. The use of atypical antipsychotics for behavioural symptoms is not recommended in the elderly or those with demetia associated conditions and most antipsychotics will worsen Parkinsonism. Antidepressants may be useful for behavioral symptoms and depression but are often poorly tolerated due to adverse effects. In the absence of an effective drug treatment to target the underlying cause of CBD and PSP, management should focus on optimizing quality of life, relieving symptoms and assisting patients with their activities of daily living (ADL). Patients should be managed by a multidisciplinary team consisting of neurologists, physiotherapists (PT), occupational therapists (OT), speech and language therapists (SALT), dieticians, ophthalmologists, psychologists, and palliative care specialists.

Motor Speech Disorders and Communication Limitations in Progressive Supranuclear Palsy

Article

Mar 2021

Purpose This study describes motor speech disorders and associated communication limitations in six variants of progressive supranuclear palsy (PSP). Method The presence, nature, and severity of dysarthria and apraxia of speech (AOS) were documented, along with scores on the Apraxia of Speech Rating Scale–Version 3 (ASRS-3) for 77 (40 male and 37 female) patients with PSP. Clinician-estimated and patient-estimated communication limitations were rated using the Motor Speech Disorders Severity Rating (MSDSR) Scale and the Communicative Effectiveness Survey (CES), respectively. Descriptive statistics were calculated for each of these dependent variables. One-tailed t tests were conducted to test mean differences in ASRS-3 and CES between participants with and without AOS and between participants with and without dysarthria. Spearman rank correlations were calculated between ASRS-3 scores and clinical judgments of AOS and dysarthria severity and between MSDSR and CES ratings. Results Nine participants (12%) had normal speech. Eighty-seven percent exhibited dysarthria; hypokinetic and mixed hypokinetic–spastic dysarthria were observed most frequently. AOS was observed in 19.5% of participants across all variants, but in only 10% exclusive of the PSP speech and language variant. Nearly half presented with AOS in which neither phonetic nor prosodic features clearly predominated. The mean ASRS-3 score for participants with AOS was significantly higher than for those without and correlated strongly with clinician judgment of AOS severity. Mean ASRS-3 was higher for participants with dysarthria than for those without but correlated weakly with dysarthria severity. Mean MSDSR and CES ratings were lower in participants with AOS compared to those without and moderately correlated with each other. Conclusions Motor speech disorders that negatively impact communicative effectiveness are common in PSP and occur in many variants. This is the first description of motor speech disorders across PSP variants, setting the stage for future research characterizing neuroanatomical correlates, progression of motor speech disorders, and benefits of targeted interventions. Supplemental Material https://doi.org/10.23641/asha.14111837

Progressive supranuclear palsy: Advances in diagnosis and management

Article

May 2020
PARKINSONISM RELAT D

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.

Parálisis supranuclear progresiva: aspectos neurológicos, neuropatológicos y neuropsicológicos

Article

Full-text available

Jan 1999
REV NEUROLOGIA

Saccades in Progressive Supranuclear Palsy-Maladapted, Irregular, Curved, and Slow

Article

Mar 2017

Background and objectives: Slowed and curved rapid eye movements, saccades, are the well-known features of progressive supranuclear palsy (PSP). We hypothesized that the saccades in PSP are not only slow and curved, but they are also irregular and have timing deficits. Methods: We tested this hypothesis in 12 patients with PSP by measuring vertical and horizontal visually guided saccades using a limbus tracker. Results: Both, horizontal and vertical saccades were slow and had irregular trajectory and velocity profiles, but deficits were much more robust in vertical saccades. The irregularity in the saccade velocity was due to premature interruptions that either completely stopped the eyes, or moved the eyes at much slower velocity along or in the opposite direction of the ongoing saccade. The direction of the eyes' trajectory was often changed after the interruption. We simulated a conductance based single-compartment model of the burst neurons embedded in local feedback circuit for saccade generation. This model mimicked anatomical and physiological realism, while allowing the liberty to selectively change the activation of individual burst neurons or the pause neurons. The PSP saccades were comparable to the simulations during reduced activity of the inhibitory and excitatory burst neurons. Conclusion: PSP saccades are due to the paucity in burst generation at the excitatory and imprecise timing signal from the inhibitory burst neurons. Premature discharge of the inhibitory burst neuron further leads to breaks in the saccade trajectory, and maladaptive superior colliculus activity leading to aberrant saccades changing the intended trajectory of the ongoing saccade.

Utility of susceptibility-weighted imaging in Parkinson's disease and atypical Parkinsonian disorders

Article

Full-text available

Oct 2016

In the clinic, the diagnosis of Parkinson's disease (PD) largely depends on clinicians' experience. When the diagnosis is made, approximately 80% of dopaminergic cells in the substantia nigra (SN) have been lost. Additionally, it is rather challenging to differentiate PD from atypical parkinsonian disorders (APD). Clinially-available 3T conventional MRI contributes little to solve these problems. The pathologic alterations of parkinsonism show abnormal brain iron deposition, and therefore susceptibility-weighted imaging (SWI), which is sensitive to iron concentration, has been applied to find iron-related lesions for the diagnosis and differentiation of PD in recent decades. Until now, the majority of research has revealed that in SWI the signal intensity changes in deep brain nuclei, such as the SN, the putamen (PUT), the globus pallidus (GP), the thalamus (TH), the red nucleus (RN) and the caudate nucleus (CN), thereby raising the possibility of early diagnosis and differentiation. Furthermore, the signal changes in SN, PUT and TH sub-regions may settle the issues with higher accuracy. In this article, we review the brain iron deposition of PD, MSA-P and PSP in SWI in the hope of exhibiting a profile of SWI features in PD, MSA and PSP and its clinical values.

Diffusion tensor tractography of the corticobulbar tract in a dysphagic patient with progressive supranuclear palsy: A case report

Article

Full-text available

Feb 2023

Rationale: This paper reports the changes over time in the corticobulbar tract (CBT) analyzed using diffusion tensor tractography (DTT) in a dysphagic patient with progressive supranuclear palsy (PSP). Patient concerns: A 53-year-old man initially presented with dysarthria, gait disturbance, and bradykinesia, and approximately 1-year later, downward gaze paralysis appeared. Initially, there was no dysphagia; however, approximately 2 years after visiting the hospital, symptoms of dysphagia, including difficulty swallowing pills, aspiration, and oral movement impairments appeared. The symptoms gradually progressed, and finally, mouth opening was severely damaged to the extent that it was difficult to orally feed. Interventions: We performed diffusion tensor imaging 3 times; at 3-month, 20-month, and 41-month from onset. Outcomes: On 3-month DTT, the left CBT was well reconstructed, whereas the right CBT showed partial tearing. In the 20-month DTT, both CBTs became thinner compared to the 3-month DTT. On 41-month DTT, both CBTs became much thinner than after 3-month and 20-month DTT. Lessons: We observed the degree of CBT injury over time in a dysphagic patient with PSP. These results suggest that the analysis of CBT using DTT is helpful in predicting the degree of dysphagia and prognosis in patients with PSP.

Epidemiology of Progressive Supranuclear Palsy: Real World Data from the Second Largest Health Plan in Israel

Article

Full-text available

Aug 2022
BSRCCS

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder and no disease modifying therapy (DMT) is currently available. This study aims to assess the epidemiology of PSP in Israel and to describe its clinical features. This retrospective analysis identified patients with PSP between 2000 and 2018 over the age of 40 years at first diagnosis (index date). We identified 209 patients with ≥1 diagnosis of PSP. Of those, 88 patients satisfied the inclusion criteria with a mean age at diagnosis of 72 years (SD = 8) and 53% were female. The 2018 prevalence and incidence rates were 5.3 and 1 per 100,000 persons, respectively. Median survival time was 4.9 years (95% CI 3.6–6.1) and median time from initial symptom to diagnosis was 4.2 years. The most common misdiagnoses were Parkinson’s disease, cognitive disorder and depression. The present study demonstrates that the clinic-epidemiological features of PSP in Israel are similar to PSP worldwide. In light of PSP’s rarity, investigation of PSP cohorts in different countries may create a proper platform for upcoming DMT trials.

Relationship between risk and protective factors and clinical features of Parkinson's disease

Article

Apr 2022
PARKINSONISM RELAT D

Background Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. Objective The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample of PD patients. Methods Six hundred ninety-four patients with PD participated. Patients underwent a clinical evaluation assessing motor symptoms and motor complications as well as non-motor symptoms severity. Information regarding pharmacological treatment was also collected. Risk and protective factors were previously identified in the present population and included coffee consumption, cigarette smoking, and physical activity as protective factors and a family history of PD, dyspepsia, and exposure to toxic agents and general anesthesia as risk factors. Multiple regression models were used to investigate the relationship between risk factors and clinical variables. Results Coffee consumption predicted older age at onset (B: 0.527; CI: 0.195; 0.858) and milder motor symptom severity (B: 1.383; CI: 2.646; −0.121). Non-motor symptom severity was more severe in patients with dyspepsia before PD (B: 13.601; CI 5.019; 22.182) and milder in patients who performed physical activity before PD (B: 11.355; CI: 16.443; −6.266). We found no relationship between risk factors and motor complications, motor subtype and pharmacological treatment. Conclusions Risk and protective factors of PD development may influence PD clinical features. This finding may represent the first step in the development of new preventive approaches able to delay disease onset and mitigate the extent of clinical manifestations.

Metabolite and lipoprotein profiles reveal sex-related oxidative stress imbalance in de novo drug-naive Parkinson's disease patients

Article

Feb 2022

Parkinson’s disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress.

Metabolite and lipoprotein profiles reveal sex-related oxidative stress imbalance in de novo drug-naive Parkinson's disease patients

Article

Full-text available

Feb 2022

Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age-and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress. npj Parkinson's Disease (2022) 8:14 ; https://doi.

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care

Article

Full-text available

Jul 2021

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Environmental Risk Factors for Progressive Supranuclear Palsy

Article

Full-text available

May 2021

Typically, progressive supranuclear palsy (PSP) is clinically characterized by slow vertical saccades or supranuclear gaze palsy, levodopa-resistant parkinsonism with predominant axial symptoms, and cognitive executive impairment. Over the past decades, various PSP phenotypes, including PSP with predominant parkinsonism, PSP with corticobasal syndrome, PSP with progressive gait freezing, and PSP with predominant frontal dysfunction, have been identified from pathologically confirmed cases. Expanding knowledge led to new diagnostic criteria for PSP that with increased disease awareness led to increased PSP prevalence estimates. The identification of environmental and modifiable risk factors creates an opportunity to intervene and delay the onset of PSP or slow disease progression. To date, despite the increasing number of publications assessing risk factors for PSP, few articles have focused on environmental and lifestyle risk factors for this disorder. In this article, we reviewed the literature investigating the relationship between PSP and several environmental and other modifiable lifestyle risk factors. In our review, we found that exposures to toxins related to diet, metals, well water, and hypertension were associated with increased PSP risk. In contrast, higher education and statins may be protective. Further case-control studies are encouraged to determine the exact role of these factors in the etiopathogenesis of PSP, which in turn would inform strategies to prevent and reduce the burden of PSP.

Early-Onset Parkinsonism and Early-Onset Parkinson’s Disease: A Population-Based Study (2010-2015)

Article

Mar 2021

Background: Early-onset Parkinson's disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease. Objective: To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties. Methods: A movement-disorder specialist reviewed all the medical records in a 2010-2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes. Results: We identified 27 patients diagnosed at < 50 years with incident Parkinsonism 2010-15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and 3 (11%) other Parkinsonism and 69 incident cases of Parkinsonism < 55 years of age. Overall incidence for Parkinsonism < 50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients < 55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both < 50 years and < 55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases < 55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p = 0.049). Conclusion: The incidence of EOPD < 50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women.

Brain-specific proteins in the diagnosis of dementia

Thesis

Jan 1999

Alison J. E. Green

With the mean age of the population increasing, the number of patients with dementia is likely to increase. Although Alzheimer's disease is the most common form of dementia, it is recognised that other forms of dementia are more prevalent than initially thought. As drug therapies become available, it will become important to obtain an accurate clinical diagnosis. Creutzfeldt-Jakob disease (CJD) is a rare type of dementia but with the emergence of the new variant form of this disease which affects young patients, and is thought to be related to the ingestion of meat or meat products from cattle affected with bovine spongiform encephalopathy (BSE), it is possible that it may become more common. These concerns have led to the search for diagnostic tests which may help in the early diagnosis of these forms of dementia. This study investigated whether measurement of cerebrospinal fluid (CSF) brain- specific proteins could be used in the assessment of patients with dementia. Four proteins were investigated: S-100b, an astrocytic protein; and three neuronal proteins, neurone-specific enolase, tau protein and 14-3-3. A two site sandwich ELISA was developed and evaluated for the measurement of S-100b. Levels of all four brain-specific proteins were raised in the majority of patients with sporadic CJD. The presence of CSF 14-3-3 had the best combination of sensitivity and specificity for detecting sporadic CJD. CSF 14-3-3 has recently been included in the diagnostic criteria for probable sporadic CJD. The value of measurement of these proteins in the new variant, iatrogenic and familial forms of CJD was also investigated. None of the CSF brain-specific proteins investigated was of value in the diagnosis of Alzheimer's disease.

Epidemiology of atypical parkinsonian syndromes

Article

Full-text available

Jan 2021

RaymondY Lo

Atypical parkinsonism or atypical parkinsonian syndromes (APS) refer to a group of neurodegenerative disorders which mimic typical Parkinson's disease but poorly respond to levodopa treatment and deteriorate faster. APS are very rare and among them, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are the three relatively better characterized entities. The prevalence estimates of PSP, MSA, or CBD are mostly <10/105, and the incidence estimates are around 1/105 person-year; both estimates remain stable over the past few decades. The age at onset is relatively young for MSA at late 50s, followed by CBD at early 60s, and then PSP at late 60s. The gender difference is not significant in APS, although slight female predominance in CBD has been reported in literature. Little is known about genetic and environmental risk factors for PSP, MSA, and CBD; although the COQ2 mutation has been identified as a genetic risk for MSA, familial cases are extremely rare. Survival after symptom onset is generally within 10 years, but cases with longer disease duration do exist. Respiratory infection remains the major cause of death for APS, but cardiac arrest should be particularly considered in MSA. In addition to disease rarity, the phenotype-pathology discrepancy in APS makes the epidemiological studies even more challenging. Including biomarkers in future diagnostic criteria and establishing disease registry for collecting sufficient number of APS cases may increase the likelihood of finding modifiable risk factors for prevention and intervention.

Cell models for the study of the association of EIF2AK3/PERK with progressive supranuclear palsy and neurodegeneration

Conference Paper

Oct 2020

Bimali Hapuarachchi

A genome-wide association study (GWAS) identified EIF2AK3 as a risk factor for progressive supranuclear palsy (PSP). EIF2AK3 encodes protein kinase R-like endoplasmic reticulum kinase (PERK), which senses unfolded protein accumulation within the endoplasmic reticulum (ER) lumen. PERK kinase activity has been genetically associated with increased PSP risk. The associated single nuclear polymorphism (SNP), rs7571971, is in linkage disequilibrium with coding SNPs of EIF2AK3: rs867529(Ser136Cys), rs13045(Gln166Arg) and rs1805165(Ala704Ser), forming coding haplotypes of three highly conserved residues; Haplotype A (conserved): S136- R166-S704 and Haplotype B (divergent): Cys136-Gln166-Ala704. A previous study showed that the divergent risk Haplotype B (HapB) has increased PERK activity suggesting that this forms the basis of the genetic risk. The polymorphisms could therefore affect either functional domain (or both). Our aim was to investigate if the two major coding haplotypes of PERK impart differences in the activation of PERK either by impaired homodimerization and/or kinase activity. We generated isogenic HEK293 cell lines for Tet-inducible expression of PERK coding haplotypes with a C-terminal myc-tag to discern from endogenous PERK. With Western blot analyses, we demonstrated robust, inducible expression of myc-tagged PERK. Interestingly, with subsequent passages, the freeze-thawed HapB PERK variants alone underwent C-terminal cleavage as evidenced by loss of the myc-tag which resulted not only in increased PERK protein but also reduced levels of activated p-PERK and p-eIF2a. Myc cleaved HapB cells also showed a significant delayed and impaired kinase activity, alongside increased cell death following induction of the UPR. However, we failed to obtain any evidence for a connection between impaired HapB PERK activity and tau aggregation, even with the more aggregation-prone 2N4Rtau (P301L) and additional seeding with brain lysates from the rTg4510 mouse and with inhibition of ubiquitin proteasome system (UPS) with MG132. In summary, we established stable isogenic cell lines for Tet-inducible expression of PERK functional haplotypes. Although the C-terminus myc tag cleavage of the passage 2 HapB cells resulted in reduced PERK activation leading to an impaired UPR, a necessary further control to validate these conclusions would be to include untagged passage 2 HapB cells. This is essential to clarify as to whether the underlying reduced HapB PERK activity following cell passaging is due to an artefact following myc cleavage or due to posttranslational modifications inherent to HapB PERK.

ЛОГОПЕДИЧНЕ ДОСЛІДЖЕННЯ ПОРУШЕННЯ МОВЛЕННЯ ПРИ ПРОГРЕСУЮЧОМУ НАД’ЯДЕРНОМУ ПАРАЛІЧІ

Article

Sep 2019

Галина Станецька

Falls in Progressive Supranuclear Palsy

Article

Full-text available

Dec 2019

Background: Despite falls being an almost universal clinical feature and central to the presentation and diagnostic criteria of progressive supranuclear palsy, our understanding of falls is surprisingly limited and there are few effective treatment options. Objectives: To provide an overview of the topic of the impact, assessment, mechanism, and management of falls in progressive supranuclear palsy. Methods: We performed a literature search for "falls" and "progressive supranuclear palsy" and included additional relevant literature known to us. We synthesized this literature with experience from clinical practice. Results: We review current understanding of the pathophysiology of falls, highlighting the roles of the indirect pathway and the pedunculopontine nucleus. We go on to identify shortcomings in commonly used assessments to measure falls. We discuss medical and nonmedical fall prevention strategies, and finally we discuss balancing falls risk against promoting independence. Conclusion: Falls are central to progressive supranuclear palsy presentation and diagnosis. Indirect locomotor and pedunculopontine nucleus dysfunction are thought to be the neural substrate of falls in this condition. Attempts to measure and prevent falls, by medical and nonmedical means, are currently limited. A personalized approach is advocated in the management of falls.

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy

Article

Full-text available

Nov 2019

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. Objective: We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. Methods: Eleven PSP patients were compared to 26 age-matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three-dimensional T1 -weighted, diffusion tensor, and neuromelanin-sensitive images) and 7 Tesla (three-dimensional-T2 * images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0-3) were determined. Results: PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin-based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin-based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. Conclusions: These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society.

Dysphagia in Progressive Supranuclear Palsy

Article

Full-text available

Aug 2020
Dysphagia

Progressive supranuclear palsy (PSP) is the most common Parkinson-Plus syndrome and is associated with early onset of dysphagia relative to Parkinson Disease. The current study contributes to the growing understanding of swallowing dysfunction in PSP by describing oropharyngeal swallowing characteristics in a large prospective cohort of participants with PSP employing a nationally standardized videofluoroscopy protocol and a disease severity scale developed expressly for PSP. Participants were 51 adults diagnosed with PSP. Each participant underwent a clinical interview and standardized videofluorographic assessment. Swallowing function was characterized with the Modified Barium Swallow Impairment Scale (MBSImP) and Penetration–Aspiration Scale (PAS). Variables of interest were participant-reported difficulties with liquids and/or solids; overall impression score for each of the 17 individual MBSImP components, as well as Oral Total Sum and Pharyngeal Total Sum; and PAS. Data were described with median interquartile range, counts, and proportions. Spearman’s rank correlations were calculated between MBSImP scores and participant-reported indices, FOIS, and PSP Rating Scale. Approximately two-thirds of participants reported difficulties with liquids, solids, or both, although fewer than 15% reported modifying consistencies. Videofluorographic findings included predominant oral phase impairments, including back and forth rocking motion of the tongue, delayed initiation of the pharyngeal swallow, and oral residue. Pharyngeal phase impairments were relatively infrequent and comparatively mild, with the exception of reduced tongue base retraction contributing to pharyngeal residue, and mildly disrupted laryngeal vestibule closure. Disease severity correlated significantly with oral (r = .0.42, p = .0.002) and pharyngeal (r = 0.41, p = .0.003) total sum scores as well as with the oral phase components of oral transport (r = .0.33, p = .0.02) and initiation of the pharyngeal swallow (r = .0.38, p = .0.007), and PAS for thin liquids (r = .0.44, p = .0.001). The PSP Rating Scale was not more strongly correlated with swallowing impairment than has been reported for other disease severity rating scales. Dysphagia is a common complaint of patients with PSP. The current findings corroborate and expand upon those reported in the literature, detailing relatively more frequent and more severe oral phase impairments and relatively spared hyolaryngeal excursion. Further research is needed to characterize the progression of dysphagia in PSP and to determine whether dysphagia varies in character or in rate of progression across variants of PSP.

Parkinson disease with and without Dementia: A prevalence study and future projections: PD and Prevalence Projections

Article

Jan 2018

Background: Limited population-based information is available on the co-occurrence of dementia and PD. However, projecting the prevalence of PD with and without dementia during the next 50 years is crucial for planning public-health and patient-care initiatives. Objectives: The objective of this study was to project the prevalence of PD with and without dementia in the United States by 2060. Methods: We used the Rochester Epidemiology Project medical records-linkage system to identify all persons with PD with or without dementia residing in Olmsted County, Minnesota, on January 1, 2006. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of PD. We calculated the age- and sex-specific prevalence of PD with and without dementia and projected U.S. prevalence through 2060. Results: We identified 296 persons with PD with and without dementia on the prevalence date (187 men, 109 women); the overall prevalence increased with age from 0.01% (30-39 years) to 2.83% (≥90 years). The prevalence of PD without dementia increased with age from 0.01% (30-39 years) to 1.25% (≥90 years). The prevalence of PD with dementia increased with age from 0.10% (60-69 years) to 1.59% (≥90 years). The prevalence was higher in men than in women for all subtypes and all age groups. We project by 2060 an approximate doubling of the number of persons with PD without dementia and a tripling of the number of persons with PD with dementia in the United States. Conclusions: The prevalence of PD with and without dementia increases with age and is higher in men than women. We project that the number of persons with PD in the United States will increase substantially by 2060. © 2018 International Parkinson and Movement Disorder Society.

Basic and translational neuro-ophthalmology of visually guided saccades: disorders of velocity

Article

Oct 2017

Introduction: Saccades are rapid, yoked eye movements in an effort to direct a target over fovea. The complex circuitry of saccadic eye movements has been exhaustively described. As a result clinicians can elegantly localize the pathology if it falls on the neuraxis responsible for saccades. Traditionally saccades are studied with their quantitative characteristics such as amplitude, velocity, duration, direction, latency and accuracy. Areas covered: Amongst all subtypes, the physiology of the visually guided saccades is most extensively studied. Here we will review the basic and pertinent neuro-anatomy and physiology of visually guided saccade and then discuss common or classic disorders affecting the velocity of visually guided saccades. We will then discuss the basic mechanism for saccade slowing in these disorders. Expert commentary: Prompt appreciation of disorders of saccade velocity is critical to reach appropriate diagnosis. Disorders of midbrain, cerebellum, or basal ganglia can lead to prolonged transition time during gaze shift and decreased saccade velocity.

Survival and Causes of Death Among People With Clinically Diagnosed Synucleinopathies With Parkinsonism: A Population-Based Study

Article

May 2017

Importance To our knowledge, a comprehensive study of the survival and causes of death of persons with synucleinopathies compared with the general population has not been conducted. Understanding the long-term outcomes of these conditions may inform patients and caregivers of the expected disease duration and may help with care planning. Objective To compare survival rates and causes of death among patients with incident, clinically diagnosed synucleinopathies and age- and sex-matched referent participants. Design, Setting, and Participants This population-based study used the Rochester Epidemiology Project medical records–linkage system to identify all residents in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from 1991 through 2010. A movement-disorders specialist reviewed the medical records of each individual to confirm the presence of parkinsonism and determine the type of synucleinopathy. For each confirmed patient, an age- and sex-matched Olmsted County resident without parkinsonism was also identified. Main Outcomes and Measures We determined the age- and sex-adjusted risk of death for each type of synucleinopathy, the median time from diagnosis to death, and the causes of death. Results Of the 461 patients with synucleinopathies, 279 (60.5%) were men, and of the 452 referent participants, 272 (60.2%) were men. From 1991 through 2010, 461 individuals received a diagnosis of a synucleinopathy (309 [67%] of Parkinson disease, 81 [17.6%] of dementia with Lewy bodies, 55 [11.9%] of Parkinson disease dementia, and 16 [3.5%] of multiple system atrophy with parkinsonism). During follow-up, 68.6% (n = 316) of the patients with synucleinopathies and 48.7% (n = 220) of the referent participants died. Patients with any synucleinopathy died a median of 2 years earlier than referent participants. Patients with multiple system atrophy with parkinsonism (hazard ratio, 10.51; 95% CI, 2.92-37.82) had the highest risk of death compared with referent participants, followed by those with dementia with Lewy bodies (hazard ratio, 3.94; 95% CI, 2.61-5.94), Parkinson disease with dementia (hazard ratio, 3.86; 95% CI, 2.36-6.30), and Parkinson disease (hazard ratio, 1.75; 95% CI, 1.39-2.21). Neurodegenerative disease was the most frequent cause of death listed on the death certificate for patients, and cardiovascular disease was the most frequent cause of death among referent participants. Conclusions and Relevance Individuals with multiple system atrophy with parkinsonism, dementia with Lewy bodies, and Parkinson disease dementia have increased mortality compared with the general population. The mortality among persons with Parkinson disease is only moderately increased compared with the general population.

Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study

Article

Full-text available

Oct 2016
MOVEMENT DISORD

Background: Epidemiological studies of drug-induced parkinsonism remain limited. Objectives: To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population. Methods: We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine-blocking or dopamine-depleting medications. Results: Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug-induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. Conclusions: The incidence of drug-induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cerebral peduncle angle: Unreliable in differentiating progressive supranuclear palsy from other neurodegenerative diseases

Article

Aug 2016

Introduction The significant symptom overlap between progressive supranuclear palsy (PSP) and other parkinsonian neurodegenerative diseases frequently results in misdiagnosis. However, neuroimaging can be used to quantify disease-related morphological changes and specific markers. The cerebral peduncle angle (CPA) has been shown to differentiate clinically diagnosed PSP from other parkinsonian diseases but this result has yet to be confirmed in autopsy-proven disease. Methods Magnetic resonance imaging (MRI) scans were obtained for 168 patients representing 69 medical facilities. Following randomization, the images were divided into two groups (Type 1 and Type 2) based upon midbrain morphological differences. Two readers were blinded and independently measured the CPA of 146 patients with autopsy-proven progressive supranuclear palsy (PSP; n = 54), corticobasal degeneration (n = 16), multiple system atrophy (MSA; n = 11) and Lewy body disease (n = 65). Results Applying two separate measurement techniques revealed no statistically significant differences in CPA measurements among any study groups regardless of classification measurement approach. The interobserver agreement showed significant differences in measurements using the Type 2 approach. Conclusion Measuring the CPA on MRI is not a reliable way of differentiating among patients with PSP, corticobasal degeneration, MSA, or Lewy body disease.

A Review of Treatment Options for Progressive Supranuclear Palsy

Article

May 2016

Progressive supranuclear palsy (PSP) is an atypical parkinsonian condition characterized by a symmetric akinetic–rigid syndrome, early falls, supranuclear gaze palsy, and a frontotemporal behavioral syndrome. The typical phenotype is termed Richardson’s syndrome, but numerous other phenotypes have been described. The pathophysiology of PSP is not fully understood, but dysfunction of the tau protein seems to play a central role. Despite exciting new knowledge on the pathophysiology of PSP, there is still no highly effective symptomatic or disease-modifying treatment. We review the evidence on pharmacotherapy and experimental therapies in PSP and provide levels of recommendation for the off-label use of commonly used drugs in this disorder.

The differential diagnosis of parkinsonism: A clinical approach

Chapter

Mar 2011

Carlo Colosimo

Improved diagnostic sophistication is increasingly enabling neurologists to differentiate between Parkinson's disease and other atypical parkinsonism (AP), such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The Handbook of Atypical Parkinsonism is a comprehensive survey of all diseases of this category, providing an authoritative guide to the recognition, diagnosis and management of these disorders. Each chapter follows a common structure, commencing with the full basic science of the disorder under consideration, followed by descriptions of the clinical picture and differential diagnosis. Subsequent chapters discuss current and future therapeutic approaches to these difficult conditions. Written and edited by leading practitioners in the field, clinicians in neurology and other specialties will find this book essential to the understanding and diagnosis of this complex group of disorders.

Management Strategies for Atypical Parkinsonism

Article

Full-text available

Mar 2024

Purpose of Review Atypical parkinsonism is a term usually used to describe three neurodegenerative parkinsonian disorders: progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). In contrast to Parkinson’s disease, these disorders have a poor prognosis and present with a multitude of diverse symptoms, including parkinsonism, dystonia, myoclonus, gait disorders, dysarthria, dysphagia, sleep, cognitive, and behavioral disorders. In the absence of an approved disease-modifying treatment, symptomatic treatment is the mainstay of management. The purpose of this review is to present an overview of the management of these complex disorders, with a particular focus on a holistic and multidisciplinary approach. Recent Findings In addition to presenting the most significant pharmacological interventions for symptom management, data regarding non-pharmacological interventions are analyzed. Important non-pharmacological clinical practice questions such as breaking the news, palliative care, and end-of-life issues are discussed, in an effort to present an overview of the management of atypical parkinsonism from diagnosis to the most advanced stages of these diseases. Summary Management of atypical parkinsonian disorders includes symptomatic pharmacological and non-pharmacological interventions, in addition to addressing issues such as informing the patient of the diagnosis, palliative care, and end-of-life issues, which require a multidisciplinary approach.

Atypical findings: Atypical parkinsonian syndromes or Atypical parkinsonian syndromes look-alikes

Article

Sep 2023
CLIN NEUROL NEUROSUR

Diagnosing Methods of Parkinson's Disease: Revolutionary Techniques

Chapter

Jun 2023

Parkinson's disease is known by tremor, rigidity, and bradykinesia. Non-motor symptoms also manifest during the disease course or even predate the appearance of motor-symptoms and that can be as troublesome as motor features. At the cellular level, the degeneration of substantia nigra neurons and the low levels of dopamine caused by intracytoplasmic inclusions of Lewy bodies that consist of α-synuclein were recognized as the putative cause of the disease and therefore physical symptoms. PD is a slow-moving illness and detection of that disease is not easy because of delayed symptoms, variation in clinical manifestations, course of progression, and biomarker profiles from person to person. Early diagnosis of PD plays a critical role in effective disease management. Here, the authors aim to give an overview of different methods of diagnosing PD with emphasis on clinical differential diagnosis that differentiate it from other parkinsonian disorders, challenges, and a brief description of new approaches of artificial intelligence technologies as a tool for better prediction of that disease.

Accurate measurement of magnetic resonance parkinsonism index by a fully automatic and deep learning quantification pipeline

Article

Jul 2023
EUR RADIOL

Objectives: This study aims at a fully automatic pipeline for measuring the magnetic resonance parkinsonism index (MRPI) using deep learning methods. Methods: MRPI is defined as the product of the pons area to the midbrain area ratio and the middle cerebellar peduncle (MCP) width to the superior cerebellar peduncle (SCP) width ratio. In our proposed pipeline, we first used nnUNet to segment the brainstem and then employed HRNet to identify two key boundary points so as to sub-divide the whole brainstem into midbrain and pons. HRNet was also employed to predict the MCP endpoints for measuring the MCP width. Finally, we segmented the SCP on an oblique coronal plane and calculated its width. A total of 400 T1-weighted magnetic resonance images (MRIs) were used to train the nnUNet and HRNet models. Five-fold cross-validation was conducted to evaluate our proposed pipeline's performance on the training dataset. We also evaluated the performance of our proposed pipeline on three external datasets. Two of them had two raters manually measuring the MRPI values, providing insights into automatic accuracy versus inter-rater variability. Results: We obtained average absolute percentage errors (APEs) of 17.21%, 18.17%, 20.83%, and 22.83% on the training dataset and the three external validation datasets, while the inter-rater average APE measured on the first two external validation datasets was 11.31%. Our proposed pipeline significantly improved the MRPI quantification accuracy over a representative state-of-the-art traditional approach (p < 0.001). Conclusion: The proposed automatic pipeline can accurately predict MRPI that is comparable with manual measurement. Clinical relevance statement: This study presents an automated magnetic resonance parkinsonism index measurement tool that can analyze large amounts of magnetic resonance images, enhance the efficiency of Parkinsonism-Plus syndrome diagnosis, reduce the workload of clinicians, and minimize the impact of human factors on diagnosis. Key points: • We propose an automatic pipeline for measuring the magnetic resonance parkinsonism index from magnetic resonance images. • The effectiveness of the proposed pipeline is successfully established on multiple datasets and comparisons with inter-rater measurements. • The proposed pipeline significantly outperforms a state-of-the-art quantification approach, being much closer to ground truth.

Influences of motor speech impairments on the presentation of dysphagia in progressive supranuclear palsy

Article

Jun 2023

Purpose: The purpose of this study was to examine whether differences in motor speech features are related to presentations of dysphagia in progressive supranuclear palsy (PSP) given the sparsity of data examining this relationship. Method: Motor speech disorder (MSD) type and severity along with specific swallowing variables were analysed to obtain insights among these relationships in 73 participants with PSP. Result: Results revealed that most participants (93%) had dysarthria, with 19% having co-occurring apraxia of speech (AOS). Greater MSD severity was related to more severe pharyngeal phase impairments (95% CI [-0.917, -0.146], p = 0.008). While certain motor speech and swallowing scores varied minimally across participants, incremental changes in these functions were more likely to occur when specific MSD features were present. A trend for participants with spastic dysarthria and/or AOS to exhibit more severe dysphagia was observed. Conclusion: This study points to the need for thorough neurological evaluation, with inclusion of speech-language pathology consultation, in the standard of care for PSP. Comprehensive assessment of both motor speech and swallowing functions can inform differential diagnosis and assist patients/families facing decisions regarding modalities for communication and nutrition in the setting of neurodegenerative disease. Additional research may yield greater insights about relevant assessment and intervention considerations in PSP.

Non-pharmacological treatment for atypical parkinsonism

Chapter

Mar 2011

Progressive Supranuclear Palsy and Corticobasal Degeneration

Chapter

Jan 2021
ADV EXP MED BIOL

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.

Progressive supranuclear palsy

Chapter

Jun 2005

Lawrence I. Golbe

Atypical parkinsonism, parkinsonism-plus syndromes, and secondary parkinsonian disorders

Chapter

Jan 2011

Eye movement disorders

Chapter

Jan 2010

Slow Saccades

Chapter

Jan 2019

Rapid and yoked eye movements made to direct the target over fovea, saccades, are critical aspects of visual scanning behavior. Elegant physiological, anatomical, and computational studies have described the complex circuitry of saccadic eye movements. These basic science examinations have facilitated our ability to confidently localize central pathology affecting the saccade generation. Amplitude, velocity, duration, direction, latency, and accuracy are traditional measures of saccadic eye movements. The visually guided saccades are very commonly studied eye movements. In this chapter, we will outline pertinent anatomy and physiology of saccades. We will also discuss disorders affecting the velocity of visually guided saccades. Finally, we will discuss the mechanistic underpinning of slowing of saccade velocity in context of these neurological disorders.

Klinická charakteristika ochorení podmienených patologickým hromadením tau proteínu

Book

Full-text available

Oct 2019

Ján Necpál

Survival and Progression in Synucleinopathy Phenotypes With Parkinsonism

Article

Aug 2019

Objective: To compare survival by the presenting parkinsonism symptoms at diagnosis among patients with incident clinically diagnosed synucleinopathies. Patients and methods: Using the Rochester Epidemiology Project medical records-linkage system, we identified all persons residing in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from January 1, 1991, through December 31, 2010. A movement disorder specialist reviewed the complete medical records of each individual to confirm the presence of parkinsonism, determine the type of synucleinopathy, and identify the onset dates of each cardinal symptom (tremor at rest, bradykinesia, rigidity, and impaired postural reflexes). We determined the median time from age at diagnosis to death or censoring (June 30, 2015) for each presenting symptom and the age- and sex-adjusted risk of death. Results: From 1991 through 2010, a total of 433 individuals had a synucleinopathy diagnosed (301 [69.5%], Parkinson disease; 68 [15.7%], dementia with Lewy bodies; 52 [12.0%], Parkinson disease dementia; and 12 [2.8%], multiple systems atrophy with parkinsonism). Overall, the risk of death in the tremor-predominant group was less than that in the bradykinesia/rigidity-only group (hazard ratio [HR], 0.59; 95% CI, 0.40-0.87; P=.007). Similarly, risk of death in the bradykinesia/rigidity-only group was significantly greater than in the tremor-predominant group (HR, 1.75; 95% CI, 1.23-2.51; P=.002) and compared with tremor before bradykinesia (HR, 1.75; 95% CI, 1.24-2.47; P=.001). Conclusion: Patients with tremor as a presenting symptom have longer survival. In contrast, the presence of bradykinesia/rigidity as a presenting symptom correlates with reduced survival across all types of synucleinopathies.

Neuropathology of Movement Disorders

Article

Apr 1998
NEUROSURG CLIN N AM

Kurt Jellinger

Movement Disorders

Chapter

Jan 2005

Teresella Gondolo

Clinicopathologic discrepancies in a population‐based incidence study of parkinsonism in olmsted county: 1991‐2010

Article

Aug 2017
MOVEMENT DISORD

Objective: The purpose of this study was to examine the discrepancies between the clinical diagnosis of parkinsonism and neuropathological findings in a population-based cohort with parkinsonian disorders. Background: The specific clinical diagnosis of parkinsonism is challenging, and definite confirmation requires neuropathological evaluation. Currently, autopsies are seldom performed, and most brain autopsies represent atypical or diagnostically unresolved cases. Methods: We used a defined population-based incidence cohort with clinical parkinsonism (n = 669) from the Rochester Epidemiology Project in Olmsted County, Minnesota, 1991-2010. We reviewed reports of all patients who underwent neuropathologic examination at autopsy (n = 60; 9%) and applied consensus pathologic guidelines for neurodegenerative disease diagnosis. Results: Among the 60 patients examined pathologically, the median time from the last recorded clinical diagnosis to death was 7 years (range from 2 to 17 years). Clinical-pathological concordance was found in 52 cases (86.7%), whereas 8 (13.3%) had a clinical-pathological discrepancy. Four patients with a clinical diagnosis of idiopathic Parkinson's disease had no pathological evidence of Lewy bodies or α-synucleinopathy; of these, pathological diagnoses were Alzheimer's disease (2 cases), progressive supranuclear palsy (1 case), and vascular parkinsonism (1 case). Two patients with clinical diagnoses of "dementia with Lewy bodies" and one patient with an "unspecified parkinsonism" had a pathological diagnosis of Alzheimer's disease without concomitant α-synuclein lesions. One patient with clinically diagnosed "progressive supranuclear palsy" had indeterminate pathological findings without α-synuclein or Aβ- or tau-immunoreactive lesions at autopsy. Conclusions: Overall, the clinical diagnoses of parkinsonian subtypes had good concordance with pathological confirmation (86.7%). However, clinical-pathological discrepancies were documented in 13.3%. © 2017 International Parkinson and Movement Disorder Society.

Advances in the Clinical Differential Diagnosis

Article

Mar 2017
INT REV NEUROBIOL

The differential diagnosis of Parkinson's disease has widened considerably in recent years. This chapter aims to summarize the current knowledge on the clinical differential diagnoses of sporadic Parkinson's disease. As the number of monogenic familial Parkinson's disease variants and risk factors is growing, so is the number of appreciated etiologies of atypical parkinsonian and other pallidopyramidal syndromes. This work aims at summarizing the current knowledge on both motor and nonmotor neurological signs and symptoms that aid the clinical diagnosis of Parkinson's disease and its differential diagnoses.

Parkinsonism and tremor disorders. A clinical approach

Article

Jun 2007

Hani T S Benamer

Time Trends in the Incidence of Parkinson Disease

Article

Jun 2016

Importance Changes over time in the incidence of parkinsonism and Parkinson disease (PD) remain uncertain. Objective To investigate secular trends (period effects) and birth cohort trends in the incidence of parkinsonism and PD over 30 years in a geographically defined American population. Design, Setting, and Participants We used the medical records–linkage system of the Rochester Epidemiology Project to identify incidence cases of PD and other types of parkinsonism in Olmsted County, Minnesota, from 1976 to 2005. All cases were classified by a movement disorder specialist using defined criteria through the review of the complete medical records within the system. The analyses for this study were conducted between May 2015 and January 2016. Main Outcomes and Measures Incidence rates of parkinsonism and PD over 30 years. We tested for secular trends (period effects) using negative binomial regression models and for birth cohort effects using age–period-cohort models. Results Of 906 patients with parkinsonism, 501 were men, and the median age at onset was 74 years (interquartile range, 66-81 years). Of the 464 patients with PD, 275 were men, and the median age at onset was 73 years (interquartile range, 64-80 years). The overall incidence rates increased significantly over 30 years in men for both parkinsonism (relative risk [RR], 1.17 per decade; 95% CI, 1.03-1.33) and PD (RR, 1.24 per decade; 95% CI, 1.08-1.43). These trends were driven primarily by the older age groups. In particular, for men 70 years or older, incidence rates increased for both parkinsonism (RR, 1.24 per decade; 95% CI, 1.07-1.44) and PD (RR, 1.35 per decade; 95% CI, 1.10-1.65). The secular trends were not significant for women overall or in age strata. We observed an increased risk for both men and women born in the 1920 cohort (1915-1924). However, this birth cohort effect was significant only for PD and only in men. Conclusions and Revelance Our study suggests that the incidence of parkinsonism and PD may have increased between 1976 and 2005, particularly in men 70 years and older. These trends may be associated with the dramatic changes in smoking behavior that took place in the second half of the 20th century or with other lifestyle or environmental changes. However, the trends could be spurious and need to be confirmed in other populations.

Supranuclear and Internuclear Disorders

Chapter

Apr 2013

Fiona Rowe

Saccadic Movement Disorders Smooth Pursuit Movement Disorders Vergence Movement Disorders Gaze Palsy Optokinetic Movement Disorders Vestibular Movement Disorders Brainstem Syndromes Skew Deviation Ocular Tilt Reaction Ocular Investigation Management Options References Further Reading

Functional Changes Associated with the Aging Nervous System

Chapter

Mar 2014

The brain and other parts of the nervous system undergo complex changes with age. Loss of brain weight and volume, changes in neurons and synapses, and oxidative, inflammatory, and biochemical changes have all been described in the aging brain. Moreover, the aging brain and nervous system show an increased vulnerability to a variety of distinct pathologies, particularly degenerative and vascular. This chapter provides an overview of the neuropathology of the aging brain, including "normal" aging, the pathology of cognitive impairment and dementia, movements disorders, brain tumors, vascular disease, motor impairments, and other common geriatric brain conditions, such as toxic metabolic conditions, neoplasms, infections, and traumatic injury that may affect the elderly. The section on cognitive impairment and dementia explains the neuropathology of Alzheimer's disease (AD), mild cognitive impairment (MCI), mixed dementias, vascular dementia (also known as vascular cognitive impairment), and dementia with Lewy bodies (DLB).

Diffuse Lewy body disease presenting with supranuclear gaze palsy

Article

Full-text available

Mar 1991

A patient with diffuse Lewy body disease presented with supranuclear vertical and horizontal ophthalmoplegia, dementia, axial rigidity and falls, bradykinesia and pyramidal signs. This broadens the clinical presentation of this pathological diagnosis and re-emphasises the heterogeneity of patients diagnosed clinically as progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome).

Pure akinesia: An atypical manifestation of progressive supranuclear palsy

Article

Full-text available

Jun 1991

Two patients with "pure akinesia" who showed the characteristic changes of progressive supranuclear palsy (PSP) at necropsy are described. They had akinesia but no rigidity or tremor, and ophthalmoplegia was not observed during the course of illness. The symptoms of "pure akinesia" was not improved by levodopa therapy but was considerably improved by L-threo-3,4-dihydroxy-phenylserine. At necropsy, pathological findings were not different from those reported for PSP. It is suggested that "pure akinesia" is an atypical manifestation of PSP, and that norepinephrinergic neurons may be involved in some types of PSP.

Subcortical dementia. Frontal cortex hypometabolism detected by positron tomography in patients with progressive supranuclear palsy

Article

Full-text available

Oct 1985

The dementia associated with progressive supranuclear palsy (PSP) is considered to be subcortical because the cerebral cortex, unlike the subcortical structures, is usually free from major neuropathological lesions; the characteristic symptoms point to a dysfunction of the prefrontal lobe. The regional cerebral metabolic rate of glucose (rCMR Glu) was studied by positron emission tomography and 18F-fluoro-2-deoxyglucose18FDG in 6 patients presumed to have PSP and was compared with values found in 8 control subjects of similar age. The results obtained showed a highly significant rCMR Glu decrease in the prefrontal cortex of our patients. The loss of several subcortical afferents to prefrontal cortex may be responsible for the frontal cortical hypometabolism present in PSP.

Clinical features and investigation of the primary autonomic failure syndromes

Article

Jan 1992

Research on progressive supranuclear palsy

Article

Feb 2011

Progressive Supranuclear Palsy: Clinical and Research Approaches

Article

Jun 1993

Robert B. Daroff

Positron Emission Tomography Study in Progressive Supranuclear Palsy

Article

Jul 1990
ARCH NEUROL-CHICAGO

Jerôme Blin

• In 41 patients with progressive supranuclear palsy (PSP) that was diagnosed on the basis of eight clinical criteria (25 patients with all eight criteria [probable PSP] and 16 with six or seven criteria [possible PSP]), we studied cerebral energy metabolism by using positron emission tomography and the fludeoxyglucose F 18 or the oxygen 15 method. Compared with age-matched controls, each of the cortical and subcortical metabolic values was significantly reduced, with a predominance in the frontal cortex, in both groups of patients with probable and possible PSP, without a difference between these two groups, suggesting similar underlying disease. The frontal metabolic value decreased with disease duration, but the relative frontal hypometabolism (expressed as the fronto-occipital metabolic ratio) was apparently already present in the early stages of the disease. The parkinsonian motor score was correlated with the caudate and thalamic metabolic values. The intellectual deterioration index was significantly correlated with both the frontal and the nonfrontal metabolic values. Finally, the frontal neuropsychological score was significantly correlated with only the fronto-occipital metabolic ratio. Hence, in PSP, a degenerative brain disease with subcortical lesions, the prominent frontal lobe-like syndrome essentially depends on the relative hypometabolism of the frontal cortex.

Progressive Supranuclear Palsy

Article

Apr 1964
ARCH NEUROL-CHICAGO

John Charles Steele

Introduction In this report we are describing a progressive brain disease featured by supranuclear ophthalmoplegia affecting chiefly vertical gaze, pseudobulbar palsy, dysarthria, dystonic rigidity of the neck and upper trunk, and other less constant cerebellar and pyramidal symptoms. Dementia has usually remained mild. This disease would appear to be predominantly a nerve cell degeneration centered chiefly in the brain stem.The fully developed clinical picture presented by this disease seems to follow a fairly definitive pattern and does not conform to the classical system degenerations such as motor neurone disease, paralysis agitans, cerebellar degeneration, Creuzfeldt-Jakob disease, or the presenile dementias. Yet it would seem unlikely that the disease shown by our cases is a new one, and similar earlier cases may well have been accepted as arteriosclerotic parkinsonism when that diagnosis was used in a very broad sense such as in Critchley's monograph of 1929.1 There are some resemblances to

Progressive Supranuclear Palsy: A Heterogeneous Degeneration Involving the Brain Stem, Basal Ganglia and Cerebellum With Vertical Gaze and Pseudobulbar Palsy, Nuchal Dystonia and Dementia

Article

Apr 1964
ARCH NEUROL-CHICAGO

We have described nine patients who displayed an unusual progressive neurological disorder with ocular, motor, and mental features. The clinical picture was characterized by supranuclear ophthalmoplegia, particularly of downward gaze, pseudobulbar palsy, dysarthria, dystonic rigidity of the neck and upper trunk, and dementia. There were less constant cerebellar and pyramidal symptoms. Commonly, the disease started in the sixth decade and led to death within several years. Seven patients have died. Pathological investigation showed the presence of cell loss, gliosis, neurofibrillary tangles, granulovacuolar degeneration and demyelination in various regions of the basal ganglia, brain stem, and cerebellum. The most severely affected areas included the globus pallidus, subthalamic nucleus, red nucleus, substantia nigra, superior colliculi, nuclei cuneiformis and subcuneiformis, periaqueductal gray matter, pontine tegmentum, and the dentate nucleus. The inflammatory response was seen extremely rarely. Individual cases similar to those reported by us have been described in the literature, but it has not been hitherto recognized that they form a distinct clinicopathological syndrome. While we have not been able to establish a definite etiology, we suggest a degenerative process or viral infection. The histopathological features bear a striking resemblance to those seen in postencephalitic parkinsonism and in Hiranos parkinsonisra-dementia syndrome, but the distribution of lesions is different in our cases. We believe that the clinicopathological syndrome described by us is not uncommon and that the awareness of its occurrence will lead to its wider recognition. The highly specific clinical syndrome of our cases is dependent on the similar localization of lesions. It is possible that further observations may broaden the clinical spectrum of the disease. In other cases, the distribution of pathological changes may be different, and thereby the clinical picture would be modified. Patient 6 was under the care of Dr. H. J. M. Barnett who provided us with the clinical records. Drs. H. H. Hyland and J. L. Silversides added some clinical data on cases 2, 3, and 4. Drs. F. McNaughton and G. Mathieson provided the clinical and pathological material of case 7.

Progressive Supranuclear Ophthalmoplegia: Association With Cricopharyngeal Dysfunction and Recurrent Pneumonia

Article

Apr 1977

Problems in the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)

Article

Jun 1978

Five patients with progressive supranuclear palsy are described, in whom the ophthalmoplegia developed late in the course of the disease. In two, an internuclear component was identified in the ophthalmoplegia, and one patient had an alternating nystagmus of a type not previously described in this condition. The late appearance of the ophthalmoplegia, with a corresponding delay in establishing the diagnosis, is compared to the similar experience of Pfaffenbach et al (1972) in six patients. Other clinical features, previously seldom described, have been encountered. Dysphasia was seen in two cases, both of whom had evidence of cortical atrophy on neuro-radiological investigation. The evidence that cortical changes, in particular the presence of neurofibrillary tangles, may be a specific morphological characteristic of the disease rather than a chance association is discussed. Disorders of respiratory rhythm in four patients were similar to those described by Mastaglia et al. (1973), and indistinguishable from those occurring after encephalitis lethargica. A review of cases resembling progressive supranuclear palsy in the early part of the century fails to show any with post-encephalitic features, nor does a search of reviews of eye movement disorders in encephalitis lethargica and post-encephalitic Parkinsonism provide comparable cases. None of the forty patients with post encephalitic Parkinsonism examined at the Highlands Hospital had a clinical picture resembling progressive supranuclear palsy. It is suggested that neither on clinical nor pathological grounds is it justifiable to equate this disorder with known postencephalitic syndromes.

Autonomic involvement in extrap ramidal and cerebellar disorders

Article

Jul 1991

We reviewed the clinical and autonomic features of all patients with extrapyramidal and cerebellar disorders studied in the Mayo Autonomic Reflex Laboratory from 1983 to 1989. Patients were grouped into the following categories (number in parentheses): Parkinson's disease (35); parkinsonism-plus (54); multiple system atrophy (75); hereditary multisystem degenerations (eleven); progressive supranuclear palsy (32); non-familial cerebellar degeneration (eleven); nonspecific sporadic multisystem degeneration (73). Severe autonomic failure occurred in 97% of patients with multiple system atrophy and 53% of the nonspecific sporadic multisystem degeneration patients respectively. Autonomic involvement was mild or absent in Parkinson's disease while parkinsonism-plus and non-familial cerebellar degeneration patients had moderate autonomic failure. Orthostatic blood pressure reduction, percentage of anhidrosis on thermoregulatory sweat test, quantitative sudomotor axon reflex test, forearm response and heart rate response to deep breathing strongly regressed with severity. A response to levodopa treatment in patients with parkinsonism was more likely if cerebellar signs and cognitive deficits were absent. The presence of levodopa induced dyskinesia was also a marker for a clinically favourable levodopa response. We conclude that there is a spectrum of autonomic involvement in these degenerative disorders and that autonomic studies are useful in separating them and monitoring their course.

Parkinsonism and extraocular motor abnormalities with unusual neuropathological findings

Article

Jan 1991

Parkinsonian patients with ocular motility abnormalities are usually considered to have progressive supranuclear palsy. However, a number of other conditions have been noted to have the combination of parkinsonism and ocular problems. We report a case of rigid akinetic parkinsonism, oculomotor palsy, and eyelid apraxia with postmortem examination. Our findings are unusual in that there was marked gliosis of the substantia nigra with a large amount of free extracellular neuromelanin despite a 3-year clinical course. Only rare hyaline inclusion bodies and no neurofibrillary tangles were seen in the brainstem. Excessive calcification of the vessels of the globus pallidus were also noted. This case represents another example of the diversity of conditions producing parkinsonism with extraocular motor abnormalities.

Ageing and Parkinson's disease: Substantia Nigra regional selectivity

Article

Nov 1991

The micro-architecture of the substantia nigra was studied in control cases of varying age and patients with parkinsonism. A single 7 mu section stained with haematoxylin and eosin was examined at a specific level within the caudal nigra using strict criteria. The pars compacta was divided into a ventral and a dorsal tier, and each tier was further subdivided into 3 regions. In 36 control cases there was a linear fallout of pigmented neurons with advancing age in the pars compacta of the caudal substantia nigra at a rate of 4.7% per decade. Regionally, the lateral ventral tier was relatively spared (2.1% loss per decade) compared with the medial ventral tier (5.4%) and the dorsal tier (6.9%). In 20 Parkinson's disease (PD) cases of varying disease duration there was an exponential loss of pigmented neurons with a 45% loss in the first decade. Regionally, the pattern was opposite to ageing. Loss was greatest in the lateral ventral tier (average loss 91%) followed by the medial ventral tier (71%) and the dorsal tier (56%). The presymptomatic phase of PD from the onset of neuronal loss was estimated to be about 5 yrs. This phase is represented by incidental Lewy body cases: individuals who die without clinical signs of PD or dementia, but who are found to have Lewy bodies at post-mortem. In 7 cases cell loss was confined to the lateral ventral tier (average loss 52%) congruent with the lateral ventral selectivity of symptomatic PD. It was calculated that at the onset of symptoms there was a 68% cell loss in the lateral ventral tier and a 48% loss in the caudal nigra as a whole. The regional selectivity of PD is relatively specific. In 15 cases of striatonigral degeneration the distribution of cell loss was similar, but the loss in the dorsal tier was greater than PD by 21%. In 14 cases of Steele-Richardson-Olszewski syndrome (SRO) there was no predilection for the lateral ventral tier, but a tendency to involve the medial nigra and spare the lateral. These findings suggest that age-related attrition of pigmented nigral cells is not an important factor in the pathogenesis of PD.

Cortical-basal ganglionic degeneration

Article

Sep 1990

We report our experience with 15 patients believed to have cortical-basal ganglionic degeneration. The clinical picture is distinctive, comprising features referable to both cortical and basal ganglionic dysfunction. Characteristic manifestations include cortical sensory loss, focal reflex myoclonus, "alien limb" phenomena, apraxia, rigidity and akinesia, a postural-action tremor, limb dystonia, hyperreflexia, and postural instability. The asymmetry of symptoms and signs is often striking. Brain imaging may demonstrate greater abnormalities contralateral to the more affected side. Postmortem studies in 2 patients revealed the characteristic pathologic features of swollen, poorly staining (achromatic) neurons and degeneration of cerebral cortex and substantia nigra. Biochemical analysis of 1 brain showed a severe, diffuse loss of dopamine in the striatum. This condition is more frequent than previously believed, and the diagnosis can be predicted during life on the basis of clinical findings. However, as with other "degenerative" diseases of the nervous system, a definitive diagnosis of cortical-basal ganglionic degeneration requires confirmation by autopsy.

Corticobasal degeneration

Article

Nov 1989

Three patients with clinical and pathological features of corticobasal degeneration are described. They presented with a progressive disease bearing some clinical resemblance to Steele-Richardson-Olszewski syndrome and displaying some pathological features of Pick's disease. Their illness began at the age of 59 to 66 yrs with focal dystonia and myoclonus of an arm, the 'alien hand' sign, or an akinetic-rigid syndrome. They developed a supranuclear gaze palsy, parkinsonian features and mild cerebellar signs. Two patients showed constructional dyspraxia when using the arms. The duration of disease to death was 4 to 6 yrs. Pathological examination showed frontoparietal atrophy with cortical cell loss, gliosis and Pick cells, but there was no significant hippocampal disease or Pick bodies in this region. There was nerve cell loss and gliosis in the thalamus, lentiform nucleus, subthalamic nucleus, red nucleus, midbrain tegmentum, substantia nigra and locus coeruleus. Neuronal inclusions in the substantia nigra, termed corticobasal inclusions, were reminiscent of the globose neurofibrillary tangle of Steele-Richardson-Olszewski syndrome, and other pale inclusions resembled the pale body of Parkinson's disease, but Lewy bodies and neurofibrillary tangles were generally absent. Some nigral inclusions were similar to those in Pick's disease. Despite some pathological similarities to Pick's disease we suggest that the distribution of nerve cell loss and the corticobasal inclusion are unique to corticobasal degeneration.

Multiple system atrophy--the nature of the beast

Article

Jul 1989

Quinn NP

Multiple system atrophy (MSA) is generally considered a rare disease, but may account for up to 10% of patients with Parkinsonism. The profusion of names for this disease, which may present to general physicians, psychiatrists, cardiologists, autonomic specialists, general neurologists and those with a special interest in Parkinsonism (this author's own perspective) or cerebellar disorders, together with ignorance of its protean manifestations, may account for its underrecognition and misdiagnosis. In this article, the history and nosology of the condition are considered, and provisional diagnostic criteria are advanced. The usefulness (or otherwise) of ancillary investigations is addressed, and the shortcomings of current methods of treatment are stressed. As with idiopathic Parkinson's disease, the ultimate goal of eradicating the disease entails better diagnosis in order to establish the cause, and thence to develop a radical treatment capable of preventing or arresting the disease process.

Magnetic resonance imaging in Parkinson's disease and Parkinsonian syndromes

Article

Dec 1989

High field strength magnetic resonance imaging (MRI) provides a noninvasive means of evaluating patients with parkinsonism. Using strict clinical criteria, we began a prospective study of patients with Parkinson's disease (PD) and parkinsonian syndromes (PS) including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and atypical parkinsonism (ATYP). We detected moderate to severe putaminal hypointensity more frequently in PS than in PD and controls, although putaminal hypointensity did not distinguish between MSA, PSP, or ATYP. Signal intensity in the lateral substantia nigra did not differ significantly among patients with PD, PS, or controls and was therefore not a useful MRI marker. Pars compacta width was significantly narrower in both PD and PS. Subcortical and periventricular hyperintense foci were more abundant in PD and PS than controls. Atrophy of the brainstem occurred only in patients with PS.

Steele-Richardson-Olszewski syndrome. Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography

Article

Jul 1988

Brain function was measured in 5 patients with clinically diagnosed Steele-Richardson-Olszewski syndrome using positron emission tomography and tracers of dopamine metabolism, blood flow and oxygen metabolism. A global decrease in blood flow and oxygen utilization compared with normal values was found but the decrease was more marked in the frontal regions. The degree of impairment in oxygen utilization in the frontal region paralleled roughly the duration of the disease. Blood flow was impaired to a greater extent than oxygen utilization, resulting in raised oxygen extraction. This can partially be explained by a lower pCO2 in the patients. Alternatively it may imply involvement of brain vasculature in the pathophysiology of the disease in addition to neuronal degeneration. Striatal dopamine formation and storage, as indicated by L-(18F)fluorodopa uptake, was significantly decreased compared with control values. The severity of this decrease paralleled the degree of reduction in frontal cerebral blood flow. The results suggest that the impairment of cerebral function in Steele-Richardson-Olszewski syndrome is determined to a large extent by brainstem pathology.

Prevalence and natural history of progressive supranuclear palsy

Article

Aug 1988

We surveyed neurologists and chronic care facilities in and near two New Jersey counties with a combined population of 799,022, regarding cases of progressive supranuclear palsy. All suspected cases were examined personally, using rigid criteria. The prevalence ratio was 1.39/100,000. A total of 50 New Jersey cases yielded median intervals to onset of requiring gait assistance, 3.1 years; visual symptoms, 3.9 years; dysarthria, 3.4 years; dysphagia, 4.4 years; requiring wheelchair, 8.2 years; and death, 9.7 years.

Limb dystonia in progressive supranuclear paly

Article

Oct 1987

Progressive limb dystonia contributed to disability in 8 of 30 patients with progressive supranuclear palsy (PSP). In five, it was present when the patients were on no medication. In four, it had been present before the distinctive ophthalmoplegia permitted a correct diagnosis. The severity of limb dystonia did not correlate with the severity of either ophthalmoplegia or neck dystonia. The importance of dystonia in the pathophysiology of PSP is emphasized, with regard to both the branchial dystonia that underlies several cardinal features of the disease, and to the frequent occurrence of limb dystonia as an early sign.

The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy)

Article

Aug 1986

We analyzed the clinical features and natural history of 52 consecutive patients with the Steele-Richardson-Olszewski syndrome. The most common symptoms at onset were unsteady gait, backward falls because of poor balance, visual disturbances, slurred speech, and forgetfulness. The median duration from onset to death was 5.9 years, with a median survival after diagnosis of only 1.8 years. Bronchopneumonia was the usual cause of death recorded on death certificates.

"Pure akinesia" and the later added supranuclear ophthalmoplegia

Article

Feb 1987
Adv Neurol

Atypical presentation of progressive supranuclear palsy

Article

Apr 1985

Four pathologically documented cases of progressive supranuclear palsy are reported. Two patients exhibited severe dementia and 2 parkinsonism; none had the classic ophthalmoplegia. On retrospective analysis, clues to the diagnosis included early prominent gait disturbance, apraxia of eyelid opening in 1 patient, lack of tremor, poor response to levodopa-carbidopa, and severe rigidity with a posture of neck extension terminally in 1 patient. The clinical presentation of progressive supranuclear palsy, therefore, is not as stereotyped as previously thought, and the diagnosis can be overlooked if one adheres rigidly to the classic diagnostic criteria.

Clinical Diagnosis of the Dyskinesias

Article

Dec 1972
MED CLIN N AM

RC Duvoisin

Progressive supranuclear palsy

Article

Feb 1972

John Charles Steele

Ocular Manifestations in Progressive Supranuclear Palsy

Article

Jan 1973
AM J OPHTHALMOL

In 44 cases of progressive supranuclear palsy, progressive loss of vertical conjugate gaze formed the basis for most of the ocular complaints. This paresis of vertical movement is characteristic and essential to the establishment of the diagnosis.

Observations on the Efficacy of L-Dopa in Progressive Supranuclear Palsy

Article

Feb 1971

The long-term effect of L-dopa in 3 patients with progressive supranuclear palsy is described and 10 other cases previously reported are summarized. L-dopa has a significant effect on the parkinsonian features of PSP but does not have any significant effect on the specific non-parkinsonian features such as ophthalmoplegia and neck dystonia. The implications of this difference are discussed in relation to the pathophysiology of the separate symptoms.Copyright © 1971 S. Karger AG, Basel

Restriction in Upward Gaze with Advancing Age

Article

Feb 1970
Trans Am Ophthalmol Soc

Webb Chamberlain

There has been documented a progressive symmetrical limitation in upward gaze with advancing years. This limitation of elevation is most apparent in the elderly but is a measurable restriction which can be demonstrated even in young adults. The symmetrical restriction of upward gaze simulates a supranuclear paralysis. When there is a marked inability to elevate either eye, it is not possible to test the function of the individual muscles which elevate the globe. In evaluating older patients it is important to recognize that symmetrical limitation of upward gaze may be a "normal" finding related to the age of the individual. The normal upward rotation in young children in the five through the 14-year decade is 40 degrees, but in elderly patients in the 75- to 84-year bracket the average is only 16 degrees, with many scarcely able to elevate 10 degrees. It would seem that the relative ineffectiveness of up gaze may relate to the reduced use of the eyes in the upper field with advancing years. There is a significant and progressive symmetrical limitation to upward gaze with advancing age which must be considered in evaluating ocular motility in the middle aged or elderly.

Corticodentatonigral Degeneration With Neuronal Achromasia

Article

Feb 1968
ARCH NEUROL-CHICAGO

IN RECENT years staff members of the Neurology Service at the Massachusetts General Hospital have had the opportunity of examining three adult patients suffering from a slowly progressive neurological illness that defied all attempts at exact diagnosis and effective treatment. This strange disorder was characterized by severe impairment in the control of muscular movements, by abnormalities in posture and by involuntary motor activity. Despite serious disability, there was little muscular weakness, and mental faculties were relatively spared until the end. After years of increasing incapacity, all three patients died of the effects of the illness. Postmortem neuropathological studies showed a disease process in the central nervous system that was unlike any that we had previously seen or had been described by others. Since it appears to us that we may be dealing with a hitherto unrecognized disorder of the central nervous system, we feel justified in reporting our findings

Further observations in progressive supranuclear palsy

Article

May 1968

Progressive Supranuclear Palsy: Clinico-Pathological and Biochemical Studies

Article

Feb 1980
J NEURAL TRANSM-SUPP

Ten autopsy cases of Progressive Supranuclear Palsy (PSP) are reported. Age at onset ranged from 16 to 67 years and the duration of illness 3 to 24 years. The clinical features were aggressive mental retardation in 4 cases with early onset, paroxysmal dysequilibrium, ophthalmoplegia, rigidity and akinesia, pseudobulbar palsy and variable degrees of dementia. Neuropathology showed widespread neurofibrillary degeneration associated with system-bound neuronal loss and gliosis in subcortical areas, particularly affecting the subthalamic nucleus, substantia nigra, brainstem tegmentum and dentate nuclei, with no or little involvement of the cerebral cortex. The distribution of the lesions and the ultrastructure of the neurofibrillary tangles made of 15 nm straight filaments (seen in one case) in PSP are different from postencephalitic parkinsonism, Guam Parkinson-dementia complex and brainstem affection in (pre)senile dementia. Post-mortem biochemical analysis of two brains disclosed severe reduction of tyrosine hydroxylase, the key synthetic enzyme of the catecholamine pathway, not only in the nigrostriatal system as seen in Parkinson's disease, but in most areas of the brain-stem and limbic system. The implication and possible pathogenic and therapeutic significance of these biochemical findings are discussed. The etiology of PSP and its nosological position within the degenerative extrapyramidal disorders remain unknown.

Blink rates and disorders of movement

Article

Jun 1984

Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).

Progressive supranuclear palsy: Clinical features and response to treatment in 16 patients

Article

Mar 1983

Among 415 patients with parkinsonism, 16 (3.9%) had findings of progressive supranuclear palsy (PSP). This report reviews the clinical features and response to drug therapy in those 16 patients. Anticholinergic drugs failed to benefit any of the 5 patients treated, while presynaptic dopaminergic drugs (Sinemet or amantadine) were beneficial in only 5 of 22 patient trials. Alternatively, dopamine agonists (bromocriptine and pergolide) caused improvement in 9 of 14 patient trials despite the fact that all but 1 of these patients had previously failed to respond to presynaptic dopaminergic drugs. Dopamine agonists such as bromocriptine and pergolide may be useful in some patients with PSP.

Pallido-nigro-luysial atrophy with massive appearance of corpora amylacea in the CNS

Article

Feb 1981

A case of pallido-nigro-luysial atrophy, characterized by symptoms typical of progressive supranuclear palsy, presented (1) severe symmetrical abiotrophic degeneration of the globus pallidus, substantia nigra, and subthalamic nucleus and (2) widespread accumulations of corpora amylacea in the CNS. The former is thought to be consistent with pallido-nigro-luysial atrophy and we regard it as a combined system degeneration of both the pallido-nigral and the pallido-luysial systems. The significance of the latter is quite obscure. As far as we know, only three cases of pallido-nigro-luysial atrophy have been reported. However, there is no reported case of this disorder with such widespread and massive accumulations of corpora amylacea as in our case.

Progressive supranuclear palsy 1979: An overview

Article

Nov 1980

Without Abstract

Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)

Article

May 1996

We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele-Richardson-Olszewski syndrome, rated 105 autopsy-proven cases of PSP (n = 24), Lewy body disease (n = 29), corticobasal ganglionic degeneration (n = 10), postencephalitic parkinsonism (n = 7), multiple system atrophy (n = 16), Pick's disease (n = 7), and other parkinsonian or dementia disorders (n = 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.

Subcortical dementia: frontal cortex hypometabolism

R Antona
Jc Baron
Y Samson
M Serdaru

Antona R, Baron JC, Samson Y, Serdaru M, et al. Subcortical dementia: frontal cortex hypometabolism

Restriction in upward gaze with advanc-ing age Cortico-dentatonigral degeneration with neuronal achromasia

Jan 1968
234-4420

W Chamberlain
Rebeiz Jn
Eh Kolodny
Richardson

Chamberlain W. Restriction in upward gaze with advanc-ing age. Trans Am Ophthalmol Soc 1970;68:234-44. 25 Rebeiz Jn, Kolodny EH, Richardson EP. Cortico-dentatonigral degeneration with neuronal achromasia. Arch Neurol 1968;18:20-33.

Further observations in PSP

Jan 1968
349-56

David Nj Mackey
Ea
Smith
Jl

David NJ, Mackey EA, Smith JL. Further observations in PSP. Neurology 1968;18:349-56.

Computed tomography and magnetic resonance imaging Progressive supranuclear palsy: clinical and research approaches

Jan 1992
110-131

S Schonfeld

Schonfeld S. Computed tomography and magnetic resonance imaging. In: Litvan I, Agid Y, eds. Progressive supranuclear palsy: clinical and research approaches. New York: Oxford University Press, 1992; 110-21.

Progressive supranuclear palsy ophthalmoplegia; association with cricopharyngeal dysfunction and recurrent pneumonia. _AMA 1 977

994-999

Ma Schleider
Jt Nagumey

11 Schleider MA, Nagumey JT. Progressive supranuclear palsy ophthalmoplegia; association with cricopharyngeal dysfunction and recurrent pneumonia. _AMA 1 977;237: 994-5.

Progressive supranuclear * Bradykinesia * Rigidity, neck > limbs * Staring, non-blinking facies * Wide based, shuffling gait * Retrocollis or dystonic arm * Sitting "en bloc

Ja Jackson
J Jankovic
J Ford

Jackson JA, Jankovic J, Ford J. Progressive supranuclear * Bradykinesia * Rigidity, neck > limbs * Staring, non-blinking facies * Wide based, shuffling gait * Retrocollis or dystonic arm * Sitting "en bloc"

The Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy)

Jan 1987
272

A J Lees
Lees, A.J.

Progressive supranuclear palsy: Neuropathologically based diagnostic clinical criteria

Abstract

No full-text available

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