Nobel Lecture: Prions

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

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The immunology of stroke: from mechanisms to translation

Prions cause transmissible and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Straussler-Scheinker diseases of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein, which is encoded by a chromosomal gene. A posttranslational process, as yet unidentified, converts the cellular prion protein into an abnormal isoform. Scrapie incubation times, neuropathology, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.

https://science.sciencemag.org/content/sci/252/5012/1515.full.pdf

Molecular biology of prion diseases

The visual analogue scale (VAS) is a simple and frequently used method for the assessment of variations in intensity of pain. In clinical practice the percentage of pain relief, assessed by VAS, is often considered as a measure of the efficacy of treatment. However, as illustrated in the present study, the validity of VAS estimates performed by patients with chronic pain may be unsatisfactory. Two types of VAS, an absolute and a comparative scale, were compared with respect to factors influencing the reliability and validity of pain estimates. As shown in this study the absolute type of VAS seems to be less sensitive to bias than the comparative one and is therefore preferable for general clinical use. Moreover, the patients appear to differ considerably in their ability to use the VAS reliably. When assessing efficacy of treatment attention should therefore be paid to several complementary indices of pain relief as well as to the individual's tendency to bias his estimates.

Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale

Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo

Mechanism of placebo analgesia

Mutation in codon 200 of scrapie amyloid precursor gene linked to Creutzfeldt-Jakob disease in Sephardic Jews of Libyan and non-libyan origin

To the Editor:

In a recent article, Chapman et al.1 described a statistical association of the APOE genotype with long-term progression of disability in MS. They showed that the APOE -e4 allele was not associated with higher risk of developing MS, but was associated with accumulation of disability ( p = 0.002); other studies have shown an association between MS disease activity and APOE -e4 as well. It has been shown recently that genetic loci for autoimmune/inflammatory disorders tend to cluster or colocalize throughout the genome,2-5⇓⇓⇓ suggesting, in some cases, common or shared loci involving underlying immune regulatory pathways. The overlap of inflammatory loci is particularly true on chromosome 19q13 at the point …

APOE genotype is a major predictor of long-term progression of disability in MS

Cerebral necrosis following stroke exposes brain antigens to the immune system, potentially initiating an antibody response. The authors measured levels of antibodies to specific neuronal antigens, neurofilaments (NF), and a ubiquitous antigen, cardiolipin (CL), in 45 patients following an acute first-ever stroke, within 48 hours, and 1, 3, and 6 months later. The mean levels of anti-NF antibodies were elevated compared with baseline at 1, 3, and 6, months (p = 0.012, 0.002, and 0.003 by paired t-test). Anti-CL levels did not change significantly.

Antibodies to brain antigens following stroke.

Article abstract-Delusions and other manifestations of psychotic behavior are common side effects in Parkinson9s disease (PD) patients chronically treated with dopaminergic drugs. Clozapine, a dibenzodiazepine derivative, is an antipsychotic drug largely devoid of extrapyramidal side effects. We evaluated the effects of low doses of clozapine on the mental and motor functions in PD patients requiring antipsychotic treatment. Twenty-seven PD patients taking dopaminergic drugs and who had psychotic behavior received clozapine at 12.5 to 75 mg/d. Fifteen patients received clozapine for 1 to 11 months (mean, 6.8 months) and seven received it for 12 to 24 months (mean, 18 months). No patient exhibited motor deterioration, and the psychotic features disappeared immediately, allowing discontinuation of clozapine after several months in 10 patients. Fifteen patients are still receiving clozapine and are free of psychiatric symptoms. The clozapine treatment was discontinued after 5 days (25 mg/d) in two patients because of somnolence. No patient developed neutropenia. Clozapine in low doses is effective in the treatment of drug-induced delusions and hallucinations in PD. NEUROLOGY 1995;45: 432-434

A. D. Korczyn

Papers

Mechanism of placebo analgesia

Mutation in codon 200 of scrapie amyloid precursor gene linked to Creutzfeldt-Jakob disease in Sephardic Jews of Libyan and non-libyan origin

APOE genotype is a major predictor of long-term progression of disability in MS

Antibodies to brain antigens following stroke.

Low-dose Clozapine in the Treatment of Levodopa-Induced Mental Disturbances in Parkinson's Disease