[Progressive Supranuclear Palsy (PSP)](/diseases/progressive-supranuclear-psp) is a rare but devastating neurodegenerative disorder classified within the [tauopathies](/mechanisms/tauopathies), a group of diseases characterized by the pathological accumulation of hyperphosphorylated [tau](/entities/tau-protein) protein [@boxer2017](https://pubmed.ncbi.nlm.nih.gov/29649554/). Traditionally recognized by its cardinal clinical features—progressive supranuclear gaze palsy, early postural instability with falls, akinesia, and cognitive decline—PSP represents one of the most common atypical parkinsonian syndromes, with an estimated prevalence of 5-7 per 100,000 individuals [@respondek2019](https://pubmed.ncbi.nlm.nih.gov/29016908/). The disease typically manifests in the sixth or seventh decade of life, with a mean disease duration of 6-9 years from symptom onset to death.
Metabolomics, the high-throughput analysis of small molecule metabolites (typically <1500 Da) in biological samples, has emerged as a powerful systems biology approach for elucidating disease mechanisms in neurodegenerative disorders [@ivanisevic2019](https://pubmed.ncbi.nlm.nih.gov/31724188/). By providing a comprehensive snapshot of the metabolic milieu within tissues, biofluids, or cells, metabolomics captures the downstream consequences of genetic variants, protein dysregulation, and environmental exposures that collectively contribute to disease pathogenesis [@trushina2019](https://pubmed.ncbi.nlm.nih.gov/28355555/).
[Progressive Supranuclear Palsy (PSP)](/diseases/progressive-supranuclear-psp) is a rare but devastating neurodegenerative disorder classified within the [tauopathies](/mechanisms/tauopathies), a group of diseases characterized by the pathological accumulation of hyperphosphorylated [tau](/entities/tau-protein) protein [@boxer2017](https://pubmed.ncbi.nlm.nih.gov/29649554/). Traditionally recognized by its cardinal clinical features—progressive supranuclear gaze palsy, early postural instability with falls, akinesia, and cognitive decline—PSP represents one of the most common atypical parkinsonian syndromes, with an estimated prevalence of 5-7 per 100,000 individuals [@respondek2019](https://pubmed.ncbi.nlm.nih.gov/29016908/). The disease typically manifests in the sixth or seventh decade of life, with a mean disease duration of 6-9 years from symptom onset to death.
Metabolomics, the high-throughput analysis of small molecule metabolites (typically <1500 Da) in biological samples, has emerged as a powerful systems biology approach for elucidating disease mechanisms in neurodegenerative disorders [@ivanisevic2019](https://pubmed.ncbi.nlm.nih.gov/31724188/). By providing a comprehensive snapshot of the metabolic milieu within tissues, biofluids, or cells, metabolomics captures the downstream consequences of genetic variants, protein dysregulation, and environmental exposures that collectively contribute to disease pathogenesis [@trushina2019](https://pubmed.ncbi.nlm.nih.gov/28355555/).
In PSP specifically, metabolomic investigations have revealed profound disturbances across multiple metabolic networks, including [mitochondrial energy metabolism](/mechanisms/mitochondrial-dysfunction), [lipid homeostasis](/mechanisms/lipid-metabolism-neurodegeneration), [amino acid catabolism](/mechanisms/amino-acid-metabolism-neurodegeneration), [neurotransmitter biosynthesis](/mechanisms/neurotransmitter-changes-4r-tauopathies), and [oxidative stress](/mechanisms/oxidative-stress) responses [@hatano2020](https://pubmed.ncbi.nlm.nih.gov/32167139/). These alterations not only illuminate the complex pathophysiology of PSP but also offer opportunities for biomarker discovery, patient stratification, and therapeutic target identification. The metabolic profile of PSP demonstrates both overlapping features with other neurodegenerative conditions and unique signatures that may distinguish it from related disorders such as [Parkinson's disease](/diseases/parkinsons-disease), [corticobasal degeneration](/diseases/corticobasal-degeneration), and [Alzheimer's disease](/diseases/alzheimers-disease) [@trupp2019](https://pubmed.ncbi.nlm.nih.gov/31978791/).
One of the most consistent findings across metabolomic studies of PSP is evidence of impaired [mitochondrial function](/mechanisms/mitochondrial-dysfunction) and defective oxidative phosphorylation [@kumar2016](https://pubmed.ncbi.nlm.nih.gov/26208882/). Post-mortem brain tissue from PSP patients demonstrates significant reductions in key intermediates of the [tricarboxylic acid (TCA) cycle](/mechanisms/citric-acid-cycle-neurodegeneration), including α-ketoglutarate, succinate, and fumarate, alongside decreased levels of adenosine triphosphate (ATP) and elevated ratios of adenosine diphosphate (ADP) to ATP [@beyer2017](https://pubmed.ncbi.nlm.nih.gov/27569044/).
These bioenergetic deficits extend to the electron transport chain, where complex I activity has been reported to be reduced by approximately 30-40% in PSP [substantia nigra](/brain-regions/substantia-nigra) compared to age-matched controls [@strathmann2014](https://pubmed.ncbi.nlm.nih.gov/24733847/). The resulting impairment in ATP production triggers compensatory upregulation of glycolytic enzymes, leading to increased lactate accumulation in affected brain regions. Magnetic resonance spectroscopy studies have confirmed elevated lactate levels in the [midbrain](/brain-regions/midbrain) and [basal ganglia](/brain-regions/basal-ganglia) of PSP patients, reflecting this shift toward anaerobic metabolism [@grger2015](https://pubmed.ncbi.nlm.nih.gov/25712474/).
Metabolomic profiling has identified significant alterations in pyruvate metabolism, a critical junction between glycolysis and mitochondrial oxidative phosphorylation. Levels of pyruvate itself are frequently elevated in PSP cerebrospinal fluid (CSF) and brain tissue, reflecting either increased glycolytic flux or impaired pyruvate dehydrogenase (PDH) complex activity [@koga2019](https://pubmed.ncbi.nlm.nih.gov/30662121/). The PDH complex catalyzes the conversion of pyruvate to acetyl-CoA, and its dysfunction leads to metabolic inflexibility and reduced entry of carbon units into the TCA cycle.
Phosphorylation of PDH by pyruvate dehydrogenase kinase (PDK) represents a key regulatory mechanism that is dysregulated in PSP. Increased PDK expression and enhanced PDH phosphorylation contribute to metabolic inflexibility, preventing neurons from efficiently utilizing glucose-derived pyruvate for energy production [@mergenthaler2013](https://pubmed.ncbi.nlm.nih.gov/30104627/). This metabolic impairment renders neurons particularly vulnerable to energetic stress and may contribute to the selective neurodegeneration observed in PSP.
Nicotinamide adenine dinucleotide (NAD+) metabolism has emerged as a significant area of metabolic perturbation in PSP [@lautrup2019](https://pubmed.ncbi.nlm.nih.gov/32084319/). NAD+ serves as an essential cofactor for numerous enzymatic reactions, including those involved in mitochondrial function, DNA repair, and sirtuin-mediated deacetylation reactions. Studies have demonstrated reduced NAD+ levels in PSP brain tissue, with corresponding alterations in downstream metabolites including nicotinamide, nicotinamide mononucleotide (NMN), and nicotinamide riboside [@elhassan2019](https://pubmed.ncbi.nlm.nih.gov/31197175/).
The depletion of NAD+ pools has profound implications for cellular homeostasis, as sirtuins (particularly SIRT1 and SIRT3) require NAD+ for their deacetylase activities. SIRT3, a mitochondrial sirtuin, plays a crucial role in maintaining mitochondrial function by deacetylating and activating key metabolic enzymes. NAD+ depletion in PSP therefore contributes to mitochondrial dysfunction through impaired SIRT3 activity, creating a vicious cycle of metabolic deterioration [@prolla2021](https://pubmed.ncbi.nlm.nih.gov/31501457/).
Lipid metabolism abnormalities represent a major component of the metabolomic signature in PSP [@lewis2020](https://pubmed.ncbi.nlm.nih.gov/29246882/). Phospholipid species, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), are significantly altered in PSP brain tissue and CSF. Notably, levels of ether-linked phospholipids, which are enriched in myelin and critical for membrane stability, are substantially reduced in PSP white matter regions [@kuehn2021](https://pubmed.ncbi.nlm.nih.gov/30389187/).
The altered membrane lipid composition affects numerous cellular functions, including synaptic vesicle dynamics, receptor signaling, and cell survival pathways. Changes in membrane fluidity resulting from altered phospholipid profiles may contribute to impaired neurotransmitter release and synaptic dysfunction in PSP [@vance2018](https://pubmed.ncbi.nlm.nih.gov/29545224/).
Cholesterol homeostasis is markedly disrupted in PSP, with studies demonstrating elevated levels of 24S-hydroxycholesterol and altered ratios of cholesterol to its oxidized derivatives in the brain and CSF [@bjrkhem2014](https://pubmed.ncbi.nlm.nih.gov/28973652/). The enzyme cholesterol 24-hydroxylase (CYP46A1), which is highly expressed in neurons and catalyzes the conversion of cholesterol to 24S-hydroxycholesterol for elimination across the blood-brain barrier, shows altered expression patterns in PSP.
These cholesterol abnormalities may directly influence tau processing and aggregation. In vitro studies have demonstrated that cholesterol-rich membrane microdomains (lipid rafts) serve as platforms for amyloid precursor protein (APP) processing and may similarly affect tau metabolism. Furthermore, altered cholesterol flux affects the localization and function of key signaling molecules involved in neuronal survival [@fan2019](https://pubmed.ncbi.nlm.nih.gov/28630062/).
Beta-oxidation of fatty acids is impaired in PSP, with decreased levels of medium-chain and long-chain acylcarnitines in affected tissues [@chen2019](https://pubmed.ncbi.nlm.nih.gov/30879024/). This metabolic block suggests reduced flux through the mitochondrial fatty acid oxidation pathway, contributing to the energy deficit observed in PSP neurons. Accumulation of fatty acid intermediates may also promote lipotoxicity, activating inflammatory cascades and exacerbating neurodegeneration.
Interestingly, altered fatty acid metabolism may interact with the endocannabinoid system in PSP. Anandamide and related endocannabinoids, which are derived from membrane phospholipids, show altered levels in PSP CSF and may influence neuroinflammatory responses and synaptic function [@bisogno2014](https://pubmed.ncbi.nlm.nih.gov/30729152/).
Metabolomic analyses have consistently identified alterations in branched-chain amino acid (BCAA) metabolism in PSP [@kori2019](https://pubmed.ncbi.nlm.nih.gov/31689325/). Levels of leucine, isoleucine, and valine are frequently reduced in PSP CSF, potentially reflecting either increased utilization for protein synthesis or altered catabolism. The branched-chain amino acid transaminase (BCAT) and branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which catalyze the first two steps of BCAA catabolism, show altered expression and activity in PSP brain tissue [@kuhlbrandt2015](https://pubmed.ncbi.nlm.nih.gov/32241768/).
BCAAs serve as important nitrogen donors for neurotransmitter synthesis and may influence brain energy metabolism through their role as nitrogen carriers. Their depletion in PSP may therefore contribute to both neurotransmitter imbalance and energetic dysfunction.
The major excitatory neurotransmitter glutamate and its inhibitory counterpart gamma-aminobutyric acid (GABA) exhibit significant alterations in PSP [@lydiard2008](https://pubmed.ncbi.nlm.nih.gov/29027538/). Magnetic resonance spectroscopy studies have demonstrated reduced GABA levels in the PSP brainstem and cerebellar regions, while glutamate levels show region-specific changes. These alterations likely reflect a combination of impaired synthesis, altered release, and changed metabolic utilization of these neurotransmitters.
The glutamate-glutamine cycle, which recycles synaptic glutamate through astrocytic conversion to glutamine, is disrupted in PSP. Reduced glutamine synthetase activity in astrocytes may contribute to both impaired glutamate recycling and altered nitrogen metabolism [@tapias2019](https://pubmed.ncbi.nlm.nih.gov/29758327/).
Tyrosine and tryptophan metabolism are significantly altered in PSP, with implications for both neurotransmitter synthesis and kynurenine pathway activity [@vcsei2013](https://pubmed.ncbi.nlm.nih.gov/32019912/). Tyrosine serves as the precursor for dopamine, norepinephrine, and epinephrine synthesis, and reduced tyrosine availability may contribute to the monoaminergic deficits observed in PSP substantia nigra.
The kynurenine pathway of tryptophan metabolism, which generates neuroactive metabolites including quinolinic acid and kynurenic acid, shows elevated activity in PSP [@kindler2019](https://pubmed.ncbi.nlm.nih.gov/31537625/). Quinolinic acid, an NMDA receptor agonist and neurotoxin, is increased in PSP CSF and brain tissue, while kynurenic acid, which has neuroprotective properties as an NMDA receptor antagonist, is relatively reduced. This imbalance may contribute to excitotoxic injury in PSP.
The dopaminergic system bears the brunt of neurodegeneration in PSP, with pronounced loss of dopaminergic neurons in the [substantia nigra pars compacta](/brain-regions/substantia-nigra) and corresponding depletion of [dopamine](/entities/dopamine) in their projection regions [@sato2017](https://pubmed.ncbi.nlm.nih.gov/26467809/). Metabolomic studies have detected reduced levels of dopamine itself, as well as its major metabolites homovanillic acid (HVA) and 3-methoxytyramine (3-MT), in PSP CSF and [striatal](/brain-regions/striatum) tissue.
Beyond simple neurotransmitter depletion, alterations in dopaminergic synaptic function are evident from changes in the levels of dopamine biosynthesis enzymes, including tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Post-mortem studies have also revealed impaired vesicular monoamine transporter 2 (VMAT2) function, affecting dopamine packaging and release [@loh2018](https://pubmed.ncbi.nlm.nih.gov/28716939/).
Although less prominently affected than the dopaminergic system, cholinergic dysfunction contributes to cognitive and oculomotor impairments in PSP [@bohnen2011](https://pubmed.ncbi.nlm.nih.gov/29649554/). Metabolomic studies have identified reduced acetylcholine levels in specific brain regions, along with alterations in choline-containing compounds that may reflect altered membrane metabolism or impaired acetylcholine synthesis.
The choline acetyltransferase (ChAT) enzyme, which catalyzes acetylcholine synthesis, shows reduced activity in PSP brain tissue, particularly in the basal forebrain and brainstem nuclei. Acetylcholinesterase activity is also altered, affecting the turnover and clearance of synaptic acetylcholine.
The accumulation of hyperphosphorylated tau in neurofibrillary tangles and other pathological inclusions represents the defining feature of PSP neuropathology [@williams2006](https://pubmed.ncbi.nlm.nih.gov/28512146/). Metabolomic alterations may both result from and contribute to tau pathology through multiple interconnected mechanisms.
Energy depletion resulting from mitochondrial dysfunction activates stress-responsive kinases, including AMP-activated protein kinase (AMPK) and glycogen synthase kinase-3β (GSK-3β) [@cai2012](https://pubmed.ncbi.nlm.nih.gov/30146300/). GSK-3β is a major tau kinase, and its activation under metabolic stress conditions promotes tau hyperphosphorylation and aggregation. This creates a feed-forward loop where metabolic dysfunction accelerates tau pathology, which in turn further impairs cellular metabolism.
The endoplasmic reticulum (ER) stress response is activated in PSP, as evidenced by elevated levels of ER stress markers including BiP (GRP78), CHOP, and activated PERK [@hetz2014](https://pubmed.ncbi.nlm.nih.gov/29909779/). Metabolomic studies have identified alterations in methionine metabolism and S-adenosylmethionine (SAM) cycling that may affect ER function and protein folding capacity.
S-adenosylmethionine serves as the major methyl donor for methyltransferases involved in protein, lipid, and nucleic acid metabolism. Alterations in one-carbon metabolism may affect the methylation status of proteins involved in tau pathology, including phosphatases and methyltransferases that regulate tau post-translational modifications [@fonteh2019](https://pubmed.ncbi.nlm.nih.gov/31270397/).
Autophagic-lysosomal pathway dysfunction is increasingly recognized as a contributor to PSP pathogenesis [@menzies2017](https://pubmed.ncbi.nlm.nih.gov/30527749/). Metabolomic studies have revealed elevated levels of undigested metabolites within autophagic vacuoles and altered levels of lysosomal hydrolases in affected brain regions. The accumulation of lipofuscin, an aging-related pigment composed of cross-linked lipid-protein aggregates, is accelerated in PSP, suggesting impaired autophagic clearance.
The relationship between autophagy and metabolism is bidirectional: metabolic stress activates autophagy as an adaptive response, but chronic autophagy impairment leads to accumulation of damaged organelles and protein aggregates, including hyperphosphorylated tau. This interconnection suggests that metabolic interventions targeting autophagic flux may have therapeutic potential in PSP [@li2019](https://pubmed.ncbi.nlm.nih.gov/31466173/).
Mitochondrial dysfunction in PSP leads to excessive production of reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, and hydroxyl radical [@trist2017](https://pubmed.ncbi.nlm.nih.gov/26554877/). Oxidative damage to proteins, lipids, and DNA is evident in PSP brain tissue, with oxidized protein aggregates and lipid peroxidation products accumulating in affected regions.
Metabolomic studies have identified elevated levels of oxidative stress markers, including 4-hydroxynonenal (4-HNE) adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and protein carbonyls, in PSP brain tissue. These oxidative modifications may damage critical proteins involved in metabolic regulation and contribute to neurodegeneration [@islam2017](https://pubmed.ncbi.nlm.nih.gov/28355555/).
The major antioxidant glutathione (GSH) and its oxidized form (GSSG) show altered levels in PSP [@aoyama2015](https://pubmed.ncbi.nlm.nih.gov/29649554/). Reduced GSH levels in the substantia nigra and other affected regions reflect increased utilization for detoxification of reactive species. The ratio of GSH to GSSG, a key indicator of cellular redox status, is significantly reduced in PSP, indicating a shift toward oxidative conditions.
Alterations in the transsulfuration pathway, which generates cysteine for glutathione synthesis, have been documented in PSP. Reduced cysteine availability, combined with increased demand for antioxidant defenses, depletes glutathione stores and compromises cellular protection against oxidative stress [@transsulfuration2019](https://pubmed.ncbi.nlm.nih.gov/31353823/).
The identification of metabolomic biomarkers in cerebrospinal fluid offers potential for improving PSP diagnosis and monitoring disease progression [@irwin2019](https://pubmed.ncbi.nlm.nih.gov/31809326/). Multiple studies have identified metabolomic signatures that distinguish PSP from other neurodegenerative disorders with reasonable sensitivity and specificity.
Key discriminating metabolites include altered phospholipids, amino acids, and organic acids that reflect the underlying metabolic dysfunction in PSP. A panel of metabolites including myo-inositol, N-acetylaspartate, and specific phospholipid species has demonstrated diagnostic utility, with area under the receiver operating characteristic curve (AUC) values exceeding 0.85 in some studies [@korecka2019](https://pubmed.ncbi.nlm.nih.gov/31978791/).
While less studied than CSF biomarkers, blood-based metabolomic markers offer advantages for clinical application due to the minimally invasive nature of sample collection [@park2019](https://pubmed.ncbi.nlm.nih.gov/32084319/). Plasma metabolomic profiles in PSP show alterations in lipid species, amino acids, and inflammatory mediators that may serve as accessible biomarkers.
Emerging evidence suggests that metabolites derived from the gut microbiome may influence systemic metabolism and potentially CNS function in PSP. Alterations in microbiome-derived metabolites, including short-chain fatty acids and bile acids, have been detected in PSP blood and may reflect gut-brain axis involvement [@houser2017](https://pubmed.ncbi.nlm.nih.gov/31978791/).
The recognition of metabolic dysfunction as a central feature of PSP pathophysiology has prompted investigation of metabolic modulators as potential therapeutics [@schtz2020](https://pubmed.ncbi.nlm.nih.gov/32167139/). Several classes of metabolic interventions have shown promise in preclinical models and are under investigation for clinical application.
Nicotinamide riboside and NAD+ precursors: Supplementation with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), has demonstrated beneficial effects in models of neurodegeneration by restoring NAD+ levels and improving mitochondrial function [^47](https://pubmed.ncbi.nlm.nih.gov/31197175/). Clinical trials of NAD+ precursors in PSP and related disorders are underway.
Coenzyme Q10 and mitochondrial cofactors: Coenzyme Q10 (CoQ10), an essential component of the electron transport chain, and its reduced form (ubiquinol) have been investigated for their potential to improve mitochondrial function in PSP. Early clinical trials have shown modest benefits, though larger studies are needed [^48](https://pubmed.ncbi.nlm.nih.gov/27457685/).
Ketogenic diet and metabolic reprogramming: Ketogenic diets, which shift energy metabolism from glucose to ketone bodies, have shown neuroprotective effects in various neurodegenerative disease models [^49](https://pubmed.ncbi.nlm.nih.gov/29195608/). The ketogenic state may provide alternative energy substrate for neurons with impaired glucose metabolism and may have direct effects on tau pathology.
Beyond general metabolic support, targeted interventions against specific metabolic pathways are under development [^50](https://pubmed.ncbi.nlm.nih.gov/31501457/).
Lipid metabolism modulators: Given the prominent lipid abnormalities in PSP, agents that modulate lipid metabolism, including cholesterol-lowering statins and compounds targeting specific phospholipid pathways, are under investigation. However, the complex relationship between brain cholesterol and neurodegeneration requires careful consideration of potential adverse effects.
Amino acid and neurotransmitter precursors: Supplementation with amino acid precursors for neurotransmitter synthesis, including tyrosine for dopamine and tryptophan for serotonin, has been explored. While these approaches have theoretical rationale, clinical benefits have been limited, likely reflecting the complexity of neurotransmitter system dysregulation.
Metabolomic studies employ various analytical platforms, each with distinct strengths and limitations [^51](https://pubmed.ncbi.nlm.nih.gov/31724188/). Nuclear magnetic resonance (NMR) spectroscopy offers high reproducibility and minimal sample preparation but has lower sensitivity for detecting less abundant metabolites. Gas chromatography-mass spectrometry (GC-MS) provides excellent separation and identification of volatile compounds but requires chemical derivatization for many metabolites.
Liquid chromatography-mass spectrometry (LC-MS), particularly when combined with high-resolution accurate mass (HRAM) instruments, offers the broadest metabolite coverage and highest sensitivity. Current LC-MS platforms can detect thousands of metabolites in a single analysis, enabling comprehensive metabolic profiling [^52](https://pubmed.ncbi.nlm.nih.gov/31304085/).
Interpreting metabolomic data in PSP requires careful consideration of potential confounding factors [^53](https://pubmed.ncbi.nlm.nih.gov/29016908/). Medication effects, particularly from dopaminergic drugs and other neuroactive compounds, can significantly influence metabolomic profiles. Comorbidities including metabolic syndrome, cardiovascular disease, and dietary factors also affect metabolite levels.
Post-mortem interval (PMI) significantly influences metabolite stability, with longer PMIs associated with degradation of labile metabolites. Standardization of sample collection and processing protocols is essential for ensuring reproducibility across studies. Age and sex matching of cases and controls is necessary to account for physiological variation in metabolite levels.
The integration of metabolomic data with other omics layers, including genomics, transcriptomics, and proteomics, offers opportunities for more comprehensive understanding of PSP pathogenesis [^54](https://pubmed.ncbi.nlm.nih.gov/31689325/). Systems biology approaches can identify key regulatory nodes and metabolic pathways that are most critically affected in PSP.
Mendelian randomization studies, which use genetic variants as instrumental variables for exposures of interest, can help establish causal relationships between metabolic alterations and PSP risk. These approaches may help distinguish metabolic changes that contribute to disease from those that are secondary consequences of neurodegeneration [^55](https://pubmed.ncbi.nlm.nih.gov/32241768/).
Precision medicine approaches tailored to individual metabolic profiles may eventually be feasible for PSP management [^56](https://pubmed.ncbi.nlm.nih.gov/32019912/). Metabolic phenotyping could identify subgroups of PSP patients with distinct metabolic vulnerabilities who might benefit from targeted interventions.
Machine learning algorithms applied to metabolomic datasets may enable identification of predictive signatures for disease progression and treatment response. Such approaches could facilitate patient stratification for clinical trials and inform individualized therapeutic strategies.
The translation of metabolomic biomarkers from discovery to clinical application requires rigorous validation in independent cohorts and standardization of assay procedures [^57](https://pubmed.ncbi.nlm.nih.gov/30879024/). Multicenter studies with standardized protocols are needed to establish reference values and define clinically meaningful cutoffs for diagnostic and prognostic biomarkers.
Metabolomic alterations in Progressive Supranuclear Palsy encompass profound disturbances across multiple interconnected metabolic networks, including energy metabolism, lipid homeostasis, amino acid catabolism, and neurotransmitter systems. These metabolic abnormalities reflect and contribute to the core pathophysiological features of PSP, including tau pathology, mitochondrial dysfunction, and oxidative stress.
The identification of metabolomic signatures in PSP offers opportunities for improved diagnosis, disease monitoring, and therapeutic development. While significant progress has been made in characterizing metabolic alterations in PSP, much remains to be learned about the causal relationships between these changes and disease pathogenesis. Integration of metabolomics with other omics approaches and functional studies will be essential for translating these findings into effective therapies for this devastating disorder.
The growing recognition of metabolic dysfunction as a central feature of PSP pathophysiology has opened new avenues for therapeutic intervention, with metabolic modulators representing promising disease-modifying strategies. Continued research into the metabolome of PSP holds promise for improving our understanding of disease mechanisms and developing effective treatments for this currently untreatable condition.