In this paper, we claim that those limitations are mostly caused by the fact that existing metrics and heuristics are not sensitive to primitive concern properties, such as either their degree of tangling and scattering or their specific structural shapes.
This is a novel finding suggesting that BPAN may be considered as a tauopathy and further strengthening the link between tauopathies and other forms of NBIA such as PKAN, PLAN and MPAN in which a degree of neurofibrillary tangle pathology is a feature in some cases although extensive tau pathology is more often associated with PLAN [ 2, 10– 13].
Previous studies suggested a relationship between severity of symptoms and the degree of neurofibrillary tangles (NFTs) clustering in different areas of the cortex in Alzheimer's disease (AD).
The key findings were firstly, that Dynamin1 levels in prefrontal cortex were correlated with rate of cognitive (MMSE) decline in all three dementia groups despite mean concentrations being no different from controls, and secondly, that CaMKII levels in parietal cortex were correlated with degree of plaque and tangle formation.
Synaptic loss correlates with cognitive decline and is more associated with the degree of dementia compared to plaques and tangles [ 5- 8], especially within certain areas of the brain, such as the hippocampus [ 7, 9].
These features are often observed before the appearance of plaque and tangle pathology, and the degree of inflammatory cell activation correlates with pathology development and neuronal death in mouse models of AD.
Ghost tangles were visible on HE-stained sections suggesting the death of tangle bearing neurons (Fig. 6c, black arrows).
Basic and clinical studies in recent years have shown that senile plaque and neurofibrillary tangle are not related to the degree of cognitive decline.
However, there is only a weak correlation between the degree of cognitive impairment and the presence of plaques or neurofibrillary tangles (Price et al., 2009) and thus, it is necessary for us to better understand this association.
Furthermore, in AD, a higher density of tangles occurs in the more plastic regions and is correlated with the degree of minicolumn disruption [ 26].
In addition to plaques and tangles, it was found that AD cases displayed a degree of cerebral artery (circle of Willis) occlusion that was significantly greater than in controls, and there was a positive correlation between the degree of arterial stenosis and NFT score [ 15].
