Physical activity and exercise in dementia: clinical relevance and emerging insights.

Progressive Supranuclear Palsy Syndrome (PSP-S) is a rapidly progressive neurodegenerative disorder with clinical manifestations of gait disturbance, vertical gaze palsy, recurrent falls, akinesia, and cognitive dysfunction (). Pathologically, PSP-S is defined by the accumulation of hyperphosphorylated tau protein leading to neuronal loss in the basal ganglia, brainstem, cerebellum and, to a lesser extent, the cerebral cortex, which is consistent across the autopsy studies (, ). The heterogeneous nature of the disease, as well as variability of progression and predominant symptomatology, has led to the classification of several clinical variants of PSP-S (, , ). Despite the advances in genetic, epigenetic, and neuropathological understanding, the precise mechanistic basis of PSP-S remains inadequately understood. Emerging studies suggest a pivotal role of neuroinflammation in toxic tau accumulation and the progression of tauopathies (–). Microglia activation and subsequent neuroinflammation, oxidative stress, neurotoxicity, and neurodegeneration have been implicated in PSP-S and other tauopathies (, ). Evidence of neuroinflammation also emerged from studies reporting significantly elevated levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the cerebrospinal fluid (CSF) and upregulated transcript levels in the substantia nigra of PSP-S brains (, ). Besides neuroinflammation, a few recent studies have also indicated altered peripheral immune cells and molecules in PSP-S (, ). A higher neutrophil-to-lymphocyte ratio (NLR), a general indicator of peripheral inflammation, was reported in PSP-S (, ). The differences in the plasma and CSF levels of IL-1β and IL-6 were reported between PSP-P and PSP-RS and such distinct inflammatory patterns were suggested to contribute to various PSP-S phenotypes and clinical course (). It is noteworthy that the peripheral immune markers were shown to be associated with greater clinical severity, higher expression of neurodegeneration markers, and more pronounced region-specific brain atrophy in PSP-S (). In an interesting study, elevated peripheral immune parameters such as IL-1β, NLR, and platelet-to-lymphocyte ratio (PLR) were associated with lower Montreal Cognitive Assessment (MoCA) test score, implying an impact of peripheral inflammation on cognitive decline in PSP-S (). In a recent genome-wide association study (GWAS), a novel susceptibility locus was identified at complement factor 4A (C4A) and C4A was found to co-localize with abnormal tau species in oligodendrocytes (). These findings indicate involvement of innate immunity in PSP-S pathobiology. It is important to note that several factors and mechanisms such as genetic background, metabolic pathways, neurotrophic factors, and glial cells are crucially involved in the regulation of immune and inflammatory responses. A pivotal role of genetic regulation of immune and inflammatory responses is also becoming increasingly apparent in PSP-S (). Glial activation, altered expression of neurotrophic factors like glial cell-derived neurotrophic factor (GDNF) and an impact of inflammatory as well as neurotrophic factors on quality of life in patients with PSP-S were reported in recent studies (, , ). Increased leukocyte metabolism leading to its metabolic reprogramming and activation of NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response was demonstrated in PSP-S (). Despite these advances, a question remained pertinent and unanswered for decades is whether systemic inflammation contributes to neuroinflammatory changes in neurodegenerative diseases. In an interesting recent study, peripheral inflammation was shown to be associated with neuroinflammation and worse clinical outcome in frontotemporal lobar degeneration (). On the contrary, a neuroimaging study conducted on a small cohort has raised doubt about unequivocal role of non-specific inflammatory markers in neurodegenerative changes in PSP-S (). Overall, a peripheral to central inflammation continuum model seems to operate in tauopathies. However, this proposition has not yet been empirically examined in PSP-S. Further, the currently available data on immune dysregulations in PSP-S are discrete in nature and do not inform the involvement of any specific immune pathway(s). The inflammatory sequelae are mediated by a cascade of immune events, including activation of nuclear factor-κB (NF-κB), inflammasome, and inflammatory T lymphocytes. To delineate the immunopathogenesis of PSP-S, it is important to examine the implications of the crucial inducers, regulators (positive and negative) and effectors of inflammation. Inflammasomes are the most potent inducers of inflammation and are implicated in the neuroinflammatory and neurodegenerative diseases (). NF-κB is a family of inducible transcription factors and comprises five structurally related members (NF-κB1, NF-κB2, RelA, RelB, and c-Rel). NF-κB regulates the expression and function of