Post-mortem neuropathological examination of five cases of Niemann-Pick disease type C revealed neurofibrillary tangles in many parts of the brain. Tangles were a consistent finding in the hippocampus, hypothalamus, substantia innominata, midbrain pons and medulla. Other regions of the brain in which tangles were present included neocortex, basal ganglia, thalamus, cerebellar cortex in one case, and dentate nucleus in another. The tangles were argyrophilic, fluoresced under ultraviolet light when stained with thioflavin S, and reacted strongly with antibody to tau protein. Some of the tangles could be immunostained for ubiquitin. Electron microscopy, performed in one of the cases, showed the tangles to consist of paired helical filaments ultrastructurally identical to those of Alzheimer's disease. The distribution of the tangles in the central nervous system as a whole and also within many individual neurons corresponded fairly closely with that of the abnormal storage material. Both the tangles and the storage material extended into, and distended, the proximal parts of many dendrites and axons. No A4/beta protein, either in the form of plaques or in the walls of blood vessels, was detected in any of the cases. Our findings suggest that neurofibrillary tangles are a common feature of Niemann-Pick disease type C and that their formation may be a reaction to the abnormal storage material.

Spinal cord teratoma is a rare, mainly benign tumour, which could be associated with vertebral anomaly. The pathogenesis of this tumour is controversial, possibly due to germinal cell aberration.

Regional variation in the distribution of SP and NFT within the brain is well documented. Consideration of such variation is potentially of help in formulating models of disease progression. Several models propose that pathological changes in Alzheimer's disease (AD) progress in a step-wise fashion along neuronally connected regions. In this study, we measured tau, Abeta and betaAPP load in different brain regions and examined our results against models of AD progression. Blocks of brain tissue from 45 AD and 15 control cases were immunolabelled for tau, Abeta and betaAPP. Immunolabelled areas were measured as a proportion of the area of the field. Tau load was almost twice as great in the entorhinal cortex than elsewhere in the brain and was least in the cingulate gyrus. In contrast, Abeta was greatest in the cingulate gyrus and least in the entorhinal cortex. BetaAPP rankings were similar to those of tau. Thus the site with the greatest Abeta load (cingulate cortex) had the least tau and the site with the greatest tau load (entorhinal cortex) had the least Abeta. The entorhinal and cingulate cortex are neuronally interconnected. Our results might be explained on the basis that a neurone with its cell body in the entorhinal cortex and axonal terminals in the cingulate cortex shows predominately tau pathology in relation to the cell body and predominately Abeta pathology in relation to its axonal terminals. We conclude that our observations are consistent with previously described models of AD progression. It is possible that tau-rich neurones are associated through their projections to Abeta rich sites. Further work of this kind analysing differential pathological profiles in interconnected brain regions may contribute to refining this model.

ObjectivesTo test whether collagen 4A1 in cerebral small arteries associated with age, hypertension or small vessel disease (SVD).DesignNeuropathology cohort study.SubjectsOlder people age >65 years with minimal Alzheimer’s Disease.MethodsWe examined subcortical white matter in archived brain tissue from older people (n=34, 15F/19M, median age 84, range 65–99 y) and from experimental non-human primates (NHP, Macaca mulatta) that were young adults (n=9, age 6.2–8.3 y) or older adults (n=8, age 17.0–22.7 y). Some of the primates (5 young, 3 older) were chronically hypertensive. Vascular collagen 4A1 immunohistochemical labelling was examined qualitatively and quantified as percent area fraction.ResultsCollagen 4A1 labelling was common in arterial myocytes and in the adventitial layer in human and primate brain arteries, as well as in basement membrane, which frequently exhibited replication. Among older people, collagen 4A1 associated with neuropathological SVD severity (sclerotic index; r=−0.461, p=0.0409, least squares) and with radiological SVD severity (leukoaraiosis; p=0.0455, 1-way ANOVA) but not with age or clinical history of hypertension. In NHP, age but not hypertension was significantly associated with collagen-4A1 labelling (p=0.0396, 0.232 respectively, 2-way ANOVA).ConclusionsIn this small cohort, vascular collagen 4A1 was related to SVD severity in older humans, in accord with genetic associations of COL4A1 with SVD phenotypes.