The comorbidity and co-medication profile of patients with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. OBJECTIVES: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. METHODS: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®. RESULTS: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions. CONCLUSIONS: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.

Moaning Phenomenon and Rapidly Progressive Dementia in Anti LGI-1 Associated Progressive Supranuclear Palsy Syndrome.

Background: Immunological causes of atypical parkinsonisms linked to neuronal specific antibodies have been recently reported. As these are potentially treatable disorders, it is desirable to identify which clinical features may suggest an autoimmune etiology. Case Report: A 60-year-old-man with progressive supranuclear palsy associated with anti-LGI-1 antibodies presented with rapidly progressive dementia and moaning. Treatment with steroids and immunoglobulin resulted in temporary clinical improvement and disease stabilization. Discussion: Anti-LGI-1 antibodies interfere with normal synaptic activity and maturation in the central nervous system. We suggest that an immune-mediated mechanism might be considered in atypical parkinsonisms with unusual features such as rapidly progressive dementia. Highlights: We present a case of rapidly evolving progressive supranuclear palsy-like parkinsonism associated with anti-LGI-1 antibodies, suggesting that immune-mediated mechanisms might be involved in rapid progression of some atypical parkinsonisms. This case also contributes to the expanding spectrum of moaning-associated disorders.

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders.

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.

Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia.

The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.

Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies.

A diverse group of neurodegenerative diseases - including progressive supranuclear palsy (PSP), corticobasal degeneration and Alzheimer's disease among others, collectively referred to as tauopathies - are characterized by progressive, age-dependent intracellular formations of misfolded protein aggregates that play key roles in the initiation and progression of neuropathogenesis. Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates [J. Alzheimer's Dis. (2009) vol. 16, pp. 433]. Based on our extensive bioavailability, bioactivity and functional preclinical studies, combined with the safety of GSPE in laboratory animals and in humans, we initiated a series of studies exploring the role of GSPE (Meganatural-Az(®) GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP, a neurodegenerative disorder involving the accumulation and deposition of misfolded tau proteins in the brain characterized, in part, by abnormal intracellular tau inclusions in specific anatomical areas involving astrocytes, oligodendrocytes and neurons [J. Neuropathol. Exp. Neurol. (2002) vol. 61, pp. 33]. In this mini-review article, we discuss the biochemical characterization of GSPE in our laboratory and its potential preventative and therapeutic role in model systems of abnormal tau processing pertinent to PSP and related tauopathies.

Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial.

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q(10) (CoQ(10)) is a physiological cofactor of complex I. Therefore, we evaluated the short-term effects of CoQ(10) in PSP. We performed a double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients (stage < or = III) to receive a liquid nanodispersion of CoQ(10) (5 mg/kg/day) or matching placebo. Over a 6-week period, we determined the change in CoQ(10) serum concentration, cerebral energy metabolites (by (31)P- and (1)H-magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Asberg Depression Scale). CoQ(10) was safe and well tolerated. In patients receiving CoQ(10) compared to placebo, the concentration of low-energy phosphates (adenosine-diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high-energy phosphates to low-energy phosphates (adenosine-triphosphate to adenosine-diphosphate, phospho-creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ(10) treatment compared to placebo. Since CoQ(10) appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.

Toward future therapies in progressive supranuclear palsy.

There is a stern therapeutic challenge for progressive supranuclear palsy (PSP) that has not yet been met. The lack of randomized, controlled trials and negative outcomes from the vast majority of studies make it impossible to set therapeutic standards, or to give clear recommendations. We review progress to date in this area and briefly consider future potential therapeutic strategies.

[Effects of tandospirone citrate on frozen gait in patients with early stage of progressive supranuclear palsy, investigated by walk-induced activation single photon emission computed tomography method].

We reported a 64-year-old woman in the early stage of progressive supranuclear palsy presenting as pure akinesia syndrome who showed marked improvement with tandospirone citrate. She revealed bradykinesia, severe frozen gait and disturbance of postural reflex without rigidity or tremor. Treatment with L-dopa and L-threo DOPS was not effective, but tandospirone citrate at a daily dosage of 30 mg significantly lessened the severity of frozen gait. Activation single photon emission computed tomography study with 99mTc-ethyl cysteinate dimer during gait revealed a significant increase in brain activity in the right cingulate cortex after tandospirone citrate treatment. The effect lasted ten months until neck rigidity and ventricular supranuclear palsy were evident.

Retrospective study of drug response in 87 patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease that responds poorly to pharmacologic intervention despite its clinical, neurochemical, and pathologic similarity to Parkinson's disease. We reviewed our experience with drugs used in the treatment of patients with PSP who were followed in the Department of Neurology, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School. Of 136 patients identified, adequate drug-response data were available for 87 (64%). Benefit and adverse effects of therapy were graded on a 4-point scale: 0, none; 1, minimal; 2, moderate; 3, marked. The three most frequently used drugs were amitriptyline (32% of patients benefited), imipramine (28% of patients benefited) and levodopa/carbidopa (Sinemet) (38% of patients benefited). Levodopa/carbidopa, amantadine, selegiline, and amitriptyline gave the best risk/benefit ratios. Monotherapy tended to show more benefit and fewer adverse effects than polypharmacy.

Paralisia supranuclear progressiva (síndrome de Steele-Richardson-Olszewski): apresentaçäo de caso e revisäo da literatura / Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of a case and review of the literature

Paralisia supranuclear progressiva (PSP) foi inicialmente identificada como entidade distinta por Richardson, Steele e Olszewski há cerca de 25 anos. Observaçöes clínicas subsequentes näo apenas têm confirmado mas, também acrescentaram novas informaçöes aos relatos pioneiros. PSP pode ser descrita como transtorno neurológico gradualmente incapacitante com rigidez extrapiramidal, bradicinesia, dificuldade na marcha com quedas frequentes, paralisia pseudo-bulbar, demência e oftalmoplegia supranuclear característica. Incide em pessoas na meia idade ou idosas, sem distinçäo racial ou sexual. PSP é importante causa de parkinsonismo e sua etiologia permanece obscura. Neste registro é apresentado o caso de um paciente de Santa Catarina, exibindo inequívoca evidência clínica da PSP. Este é o primeiro caso descrito neste Estado onde, baseando-se em recentes premissas epidemiológicas, poderemos supor a existência de pelo menos mais 50 pacientes com PSP. Em complementaçäo, é apresentada revisäo da literatura, com ênfase a aspectos clínicos e terapêuticos da PSP

[Progressive supranuclear palsy: clinical report on 7 cases and review of literature].

Progressive supranuclear palsy is sufficiently rare and difficult to diagnose that it escaped clinical recognition until 1964, when Steele, Richardson, and Olszewski clarified it as a pathologic entity. From January 1981 to June 1989, 7 patients who fulfilled the Golbe's criteria of progressive supranuclear palsy were admitted to the neurological department of National Taiwan University Hospital. The mean age at onset was 60 years (range: 53-69 years), and the mean age at diagnosis was 63 years), and the mean age at diagnosis was 63 years (range: 55-71 years). The study failed to identify any specific risk factors associated with progressive supranuclear palsy. Unsteady gait, vertical gaze palsy, pseudobulbar palsy, parkinsonian features and dementia were noted in all cases. The brain computed tomography revealed mild cortical atrophy and ventricular dilatation in 5 patients. Additionally, electroencephalography revealed diffuse theta waves in 4 patients and temporal theta waves in 2 patients, but these findings were nonspecific. Nystagmograms were performed in 3 patients, and hypometric saccades were noted in all of these patients, and uninhibited neurogenic bladder was proven by cystometry in 2 of these patients. All patients were treated with levodopa, but none of the patients showed any beneficial effects. Two patients died of aspiration pneumonia; the average duration from onset to death was about 4 years.

[A case of Steel-Richardson-Olszewski syndrome]. / Przypadek choroby Steela-Richardsona-Olszewskiego.

A case of Steele-Richardson-Olszewski disease is reported calling attention to diagnostic difficulties in cases of chronic dementia with neurological signs. The authors propose including therapy with antiviral and antiparkinsonian drugs in S-R-O disease. The presented case confirms the effectiveness of this treatment.