RESUMEN
We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson's disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson's disease (i.e. Parkinson's disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson's disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson's disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson's disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson's disease mimic versus typical Parkinson's disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson's disease or progressive supranuclear palsy (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson's disease or progressive supranuclear palsy.
Asunto(s)
Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/patología , Parálisis Supranuclear Progresiva/patologíaRESUMEN
Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.
Asunto(s)
Hipocampo/metabolismo , Atrofia de Múltiples Sistemas/fisiopatología , alfa-Sinucleína/metabolismo , Adulto , Anciano , Secreciones Corporales/metabolismo , Encéfalo/patología , Cognición/fisiología , Disfunción Cognitiva/etiología , Demencia/complicaciones , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/fisiología , Masculino , Memoria , Trastornos de la Memoria/complicaciones , Persona de Mediana Edad , Neuronas/metabolismoRESUMEN
Impulsive compulsive behaviours in Parkinson's disease have been linked to increased dopaminergic release in the ventral striatum and excessive stimulation of dopamine D3 receptors. Thirty-one patients with impulsive compulsive behaviours and Parkinson's disease who donated their brains to the Queen Square Brain Bank for Neurological Disorders were assessed for α-synuclein neuropathological load and tyrosine hydroxylase levels in the nucleus accumbens, dorsal putamen and caudate using immunohistochemistry. Dopamine D2 and dopamine D3 receptors protein levels in the nucleus accumbens, frontal cortex and putamen were determined using western blotting. Results were compared to 29 Parkinson's disease cases without impulsive compulsive behaviours matched by age, sex, disease duration, age at Parkinson's disease onset and disease duration. The majority of patients with impulsive compulsive behaviours had dopamine dysregulation syndrome. Patients with Parkinson's disease and impulsive compulsive behaviours had lower α-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. No differences were seen between groups in the other brain areas and in the analysis of tyrosine hydroxylase and dopamine D2 receptor levels. Lower α-synuclein load in the nucleus accumbens of individuals with Parkinson's disease and impulsive compulsive behaviours was confirmed on western blotting. Downregulation of the dopamine D3 receptor levels may have occurred either as a consequence of the degenerative process or of a pre-morbid trait. The lower levels of α-synuclein may have contributed to an excessive stimulation of the ventral striatum resulting in impulsive compulsive behaviours.
Asunto(s)
Conducta Compulsiva/metabolismo , Conducta Compulsiva/psicología , Conducta Impulsiva , Núcleo Accumbens/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/psicología , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , alfa-Sinucleína/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Autopsia , Conducta Compulsiva/patología , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Núcleo Accumbens/patología , Enfermedad de Parkinson/patología , Receptores de Dopamina D2/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Pagano and collaborators have recently reported lower ventral striatum D3 receptor availability in Parkinson's disease using PET scan. Our group conducted the first postmortem study of individuals with PD who had ICD and related behaviours in life and reported lower alpha-synuclein pathology and D3R levels in the nucleus accumbens of such individuals. The findings by Pagano and co-authors of low D3R binding in PD patients at baseline, when taken together with our findings of lower Lewy pathology and D3R in the nucleus accumbens, favour the hypothesis that D3R levels are downregulated because of excessive synaptic dopamine.
Asunto(s)
Trastornos Disruptivos, del Control de Impulso y de la Conducta , Enfermedad de Parkinson , Estriado Ventral , Radioisótopos de Carbono , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Receptores de Dopamina D3 , Estriado Ventral/diagnóstico por imagenRESUMEN
Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species ("seeds") containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Anticuerpos Monoclonales/inmunología , Inmunización Pasiva/métodos , Proteínas tau/genética , Proteínas tau/inmunología , Enfermedad de Alzheimer/patología , Animales , Anticuerpos Monoclonales/farmacología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Inmunoglobulina G/inmunología , Inmunoglobulina G/farmacología , Masculino , Ratones Transgénicos , Agregación Patológica de Proteínas/inmunología , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/farmacologíaRESUMEN
NKX3.1, a member of the NK class of homeodomain proteins, is expressed primarily in the adult prostate and has growth suppression and differentiating effects in prostate epithelial cells. A C-->T polymorphism at nucleotide 154 (NKX3.1 C154T) is present in approximately 11% of healthy men with equal distribution among whites and blacks. In a cohort of 1253 prostate cancer patients and age-matched controls, the presence of the polymorphism was associated with a 1.8-fold risk of having stage C or D prostate cancer or Gleason score > or =7 (confidence interval, 1.01-3.22). The NKX3.1 C154T polymorphism codes for a variant protein that contains an arginine-to-cysteine substitution at amino acid 52 (R52C) adjacent to a protein kinase C phosphorylation site at serine 48. Substitution of cysteine for arginine 52 or of alanine for serine 48 (S48A) reduced phosphorylation at serine 48 in vitro and in vivo. Phosphorylation of wild-type NKX3.1, but not of NKX3.1 R52C or NKX3.1 S48A, diminished binding in vitro to a high-affinity DNA binding sequence. NKX3.1 also serves as a transcriptional coactivator of serum response factor. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate to phosphorylate NKX3.1 had no effect on NKX3.1 coactivation of serum response factor. Neither the R52C nor the S48A substitution affected serum response factor coactivation by NKX3.1 We conclude that the polymorphic NKX3.1 allele codes for a variant protein with altered DNA binding activity that may affect prostate cancer risk.
Asunto(s)
Proteínas de Homeodominio/fisiología , Neoplasias de la Próstata/genética , Factores de Transcripción/fisiología , ADN de Neoplasias/metabolismo , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Fosforilación , Polimorfismo Genético , Neoplasias de la Próstata/metabolismo , Proteína Quinasa C/metabolismo , Serina/genética , Serina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación TranscripcionalRESUMEN
The clinical syndrome of pure akinesia has most often been associated with progressive supranuclear palsy (PSP) and is characterized by difficulty initiating gait and "freezing" during walking, writing and speaking. Similar syndromes have been described under the rubrics of primary progressive freezing gait and primary gait ignition failure. We investigated the specificity of the clinical syndrome of pure akinesia with gait freezing (PAGF) for PSP-tau pathology. Among 749 patients archived at the QSBB, only 7 fulfilled proposed diagnostic criteria of: gradual onset of freezing of gait or speech; absent limb rigidity and tremor; no sustained response to levodopa; and no dementia or ophthalmoplegia in the first 5 years of disease. In these cases detailed pathological examination was performed. PSP was the pathological diagnosis in six patients, and Parkinson's disease (PD) in the seventh. As defined, this syndrome had a positive predictive value of 86% for PSP-tau pathology. In the cases with PSP there were no additional features of coexistent vascular or PD and the median PSP-tau score was 3, reflecting relative mild tau load. The clinical syndrome of PAGF appears to have a high specificity for PSP-tau pathology. This relatively uncommon presentation of PSP-tau pathology has less severe tau accumulation than in the more common, "classic" PSP clinical phenotype: Richardson's disease.