Neurodegeneration is a Blend of Damage and Symptoms, Not Nice Neat Categories of Disease and Mechanism

The common neurodegenerative conditions are associated with various different forms of protein aggregation; a few proteins in the body have toxic alternative forms that can spread and cause harm to cells. Alzheimer's disease is associated with amyloid-β and tau, Parkinson's disease with α-synuclein, and so forth. But the decay of the aging brain is not a nice neat process in which one individual exhibits one clear-cut pathology with clear-cut symptoms indicative of that pathology. All protein aggregates occur in every aged person to some degree, and they interact with one another, alongside other mechanisms such as vascular issues in the brain. Diagnosis of a dementia is a case of crudely trying to fit a broad category of symptoms to a broad category of pathology. Just because the situation looks like Alzheimer's doesn't mean it is Alzheimer's by the textbook definition. It is inevitably a messy, complex situation.

"One of the things that we've learned in the last decade or so is that a lot of people that we think have dementia from Alzheimer's disease, actually don't. There are other brain diseases that cause the same kind of symptoms as Alzheimer's, including some that we only recently figured out existed." Researchers used brain autopsy data from 375 older adults. This work builds on the work last year to discover another form of dementia caused by TDP-43 proteinopathy now known as LATE.

Misfolded TDP-43 protein, which was discovered in 2006, is the "newest brain bad guy." Although TDP-43 exists normally in a non-disease causing form, it is seen in multiple debilitating diseases in addition to LATE, including ALS and frontotemporal dementia. As researchers reviewed clinical and brain autopsy data for research participants, they noticed there were significantly more people than expected that had not only Alzheimer's pathology but also pathology indicating Lewy bodies (alpha synuclein) and TDP-43. "They had every neurodegeneration causing pathology that we know about. There was not a name for this, so we came up with one: quadruple misfolded proteins, or QMP."

The group then obtained more data to conduct a study of how often QMP occurred and what that meant for the participant with QMP. The study found that about 20% of the participants with dementia had QMP, and their dementia was the most severe. "This is not great news, because it means that even if we could completely cure Alzheimer's disease, we still have to deal with TDP-43 and alpha synuclein, and they are common in old age. But, we have to understand exactly what we are up against as we try to stop dementia. We still have so much to learn."



"They had every neurodegeneration causing pathology that we know about. There was not a name for this, so we came up with one: quadruple misfolded proteins, or QMP."

This is becoming increasingly silly. The FDA should allow to trial and sell drugs that simply address root damage types (misfolded a-beta, misfolded tau, etc.) instead of consequences grouped around a named disease (memory deficit, neuron death, brain atrophy, etc.).

Posted by: Antonio at July 3rd, 2020 5:16 PM
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