• NEUROPATHOLOGY
• DEMENTIA
• ALS
• ALZHEIMER-S DISEASE
• PARKINSON-S DISEASE

How is any neurological disease defined? Detailed medical case reports are accessible in publications going back at least 200 years. Pre-eminent figures of the 19th century, such as Gowers and Charcot (to name only two among many across the globe), were great observers and painstaking taxonomists. It is testament to the detail of many of the descriptions from this period, including exquisite drawings in many cases, that the neurological syndromes are often easily recognisable and distinguishable today without the advances in molecular biology and neuroimaging that emerged only over the last 50 years. These original pioneers grounded their clinical observations alongside (necessarily) postmortem histology. Neuropathology continues to be the ‘gold standard’ in delineating and finding common molecular pathways for what, in life, are often syndromes with considerable clinical overlap.

In this issue, Cullinane et al present a review of the core histopathology of the neurodegenerative disorders (accompanied by an excellent macroscopic tissue video demonstration).1 Specific protein aggregates are undoubtedly the common thread across the neurodegenerative disorders. Just as association and causation are a pitfall of epidemiology, it is important to consider that protein aggregation might, to some extent, reflect those cells doing their best to mitigate other primary drivers of neurodegeneration. After all, those cells failing in that task won’t be visible. For what are essentially disorders whose incidence increases with age, there is a broader concept of loss of protein ‘quality control’ or ‘cellular tolerance’ in neurodegeneration. This is self-evident in monogenetically mediated forms where gene variants are present from the time of conception, yet the disease is not manifest …