Aetiology
Intracerebral accumulation of abnormally modified tau protein in neurons and glia is the driver of neurodegeneration in progressive supranuclear palsy (PSP). These microtubule-associated tau accumulations occur as neurofibrillary tangles, oligodendrocytic coils, and, specifically, astrocytic tufts. However, it is not yet known what factor(s) trigger this pathological process.[3][14]
In PSP, the group of tau isoforms that has four microtubule-binding repeats - the 4-repeat (4R) tau - predominates in these abnormal intracellular aggregates, hence PSP is a 4R tauopathy. In the normal brain the 4R isomers are in balance with the other group of tau isomers, the 3-repeat (3R) isoforms.
Alzheimer’s disease differs from PSP in being a mixed tauopathy, with tau aggregates that contain both 3R and 4R isoforms.
Genome-wide association studies have confirmed the H1c sub-haplotype of the tau gene as the major genetic risk factor for PSP but have also found single nucleotide polymorphisms (SNPs) in at least six other genes to be associated with PSP.[15][16][17][18][19] The role of these factors in the pathogenesis of PSP is yet to be investigated.
The H1 haplotype of the microtubule-associated protein tau (MAPT) gene is the most important genetic susceptibility factor for sporadic PSP, with an odds ratio (OR) of 5.5.[16] It is thought to cause an increase in tau expression and imbalance in tau isoforms that are more prone to aggregation. However, because it is also present in up to 60% of the general population, genetic testing for the H1 tau haplotype is not recommended to support the clinical diagnosis.
A meta-analysis of genome-wide association studies identified various SNPs (in STX6, EIF2AK3, MOBP, SLCO1A2, DUSP10, and RUNX2 genes) found to be associated with PSP, with an OR <2 for each polymorphism.[18][19] Some of them are likely related to neuroinflammation mechanisms.
A few genetic and environmental risk factors have been postulated to be associated with an increased risk of PSP. These include environmental exposure to pesticides/herbicides (e.g., from well water use), low level of education, heavy metal exposure, contamination from chromate and phosphate ore processing (used in textile dyeing and tanning industries), firearm use (suggesting the possibility of an aetiological role for lead), and severely stressful life events.[20][21][22][23][24]
However, only one study included a large sample of the PSP population and it found only well water use and low education to be significantly associated with higher PSP frequency.[21]
Pathophysiology
PSP is a primary tauopathy in which hyperphosphorylated tau protein accumulates in neurons and glia leading to neuronal loss and gliosis.[25]
Various aetio-pathogenesis mechanisms have been proposed, including abnormal tau protein production and modification pathways, mitochondrial dysfunction, neuroinflammation, and prion-like spread.
However, none of these mechanisms per se can explain all the pathological changes seen in PSP; therefore, a mix of mechanisms is probably involved in the development of PSP pathology in each individual patient.
The pattern of brain involvement explains the variation in constellation of symptoms between the different PSP phenotypes.[14] In the Richardson’s syndrome phenotype (PSP-RS), which is the most common PSP subtype, tau accumulation and neurodegeneration most prominently involve the brainstem, especially midbrain structures, the basal ganglia (in particular, the globus pallidus and subthalamic nucleus), and the cerebellar dentate nucleus. Of the cortical areas, the frontal lobes are more prominently involved while hippocampal, temporal, and occipital areas are relatively spared.[26][27]
In PSP-parkinsonism (PSP-P) and PSP with progressive gait freezing (PSP-PGF), the involvement is less severe and is brainstem-predominant.[27]
In other PSP phenotypes including PSP with frontal presentation (PSP-F), PSP with speech/language disorders (PSP-SL), and PSP-corticobasal syndrome (PSP-CBS), frontal and fronto-parietal areas are more severely involved.[27]
Classification
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