George H. Collins

Association between conformational mutations in neuroserpin and onset and severity of dementia

BACKGROUND The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations. METHODS Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted. FINDINGS Each of the families was heterozygous for an amino acid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons. INTERPRETATION The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation.

Brain Death with Prolonged Somatic Survival

IT is widely held that in patients with brain death who are receiving continued ventilation and full medical care, spontaneous cessation of the heartbeat will ensue within a period of hours or a fe...

The histopathology of freezing injury to the rat spinal cord. A light and electron microscope study. II. Repair and regeneration.

We utilized a recently developed model of spinal cord injury in which freezing of the rat dorsal column produced axonal injury with sparing and proliferation of the supporting tissue. We examined the progress of the reparative and regenerative processes for 15, 30 and 60 days after the injury. In transverse and sagittal sections at the proximal middle, and distal injury zone and at the zone of Wallerian degeneration we have demonstrated an apparent outgrowth of axons which makes its appearance between 15 and 30 days following injury and increases in amount between 30 and 60 days. The myelination of these fibers is bimodal with Schwann cells predominating in the subpial region, and oligodendrocytes in the deeper regions. Growth into the Wallerian zone is significantly less but does occur at 30 days increasing only slightly at 60 days despite extensive clearing of the breakdown products. We believe that the conditions created by this method of injury provide a suitable model for the study of repair and regeneration of mammalian central nervous tissue.

The histopathology of freezing injury to the rat spinal cord. A light microscope study. I: Early degenerative changes

In an effort to develop a method of tissue injury which would provide a model for the study of axonal regrowth in adult mammalian central nervous system (CNS), we have analyzed the effects of freezing in the dorsal columns of more than 200 rat spinal cords. The effects of temperature and time of exposure upon the size, shape, distribution and histologic characteristics of the lesion have been assessed during the first seven days following the injury. The upper threshold for injury occurs at −3°C for 15 minutes. Between −3°C and −12°C the tissue changes vary in extent and characteristics. Selective damage to axons and myelin occurs with sparing of the supportive cells followed by proliferation of a cellular matrix. At seven days, the lesions produced by −8°C for 15 to 60 minutes have neither axons nor myelin sheaths and consist of a dense cellular matrix of macrophages and presumed glial cells. With these tissue characteristics, and the preservation of tissue continuity without obstructive barriers, this model would appear to be potentially suitable for the study of axonal regrowth potential in mammalian CNS.

Pallidonigral pigmentation and spheroid formation with multiple striatal lacunar infarcts

A 72-year-old hypertensive man had focal seizures and mild memory loss. At autopsy, there were many lacunar infarcts, particularly in the neostriatum. Rust-brown discoloration and spheroid formation within the globus pallidus and pars reticulata of the substantia nigra resembled Hallervorden-Spatz disease, in which more detailed analysis of the striatum may be worthwhile.