Diabetes: a tipping point in neurodegenerative diseases.

Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.

Biological and Clinical Implications of Sex-Specific Differences in Alzheimer's Disease.

Mounting evidence indicates that the female sex is a risk factor for Alzheimer's disease (AD), the most common cause of dementia worldwide. Decades of research suggest that sex-specific differences in genetics, environmental factors, hormones, comorbidities, and brain structure and function may contribute to AD development. However, although significant progress has been made in uncovering specific genetic factors and biological pathways, the precise mechanisms underlying sex-biased differences are not fully characterized. Here, we review several lines of evidence, including epidemiological, clinical, and molecular studies addressing sex differences in AD. In addition, we discuss the challenges and future directions in advancing personalized treatments for AD.

Diet and lifestyle impact the development and progression of Alzheimer's dementia.

Dementia is a growing public health concern, with an estimated prevalence of 57 million adults worldwide. Alzheimer's disease (AD) accounts for 60-80% of the cases. Clinical trials testing potential drugs and neuroprotective agents have proven futile, and currently approved drugs only provide symptomatic benefits. Emerging epidemiological and clinical studies suggest that lifestyle changes, including diet and physical activity, offer an alternative therapeutic route for slowing and preventing cognitive decline and dementia. Age is the single most common risk factor for dementia, and it is associated with slowing cellular bioenergetics and metabolic processes. Therefore, a nutrient-rich diet is critical for optimal brain health. Furthermore, type 2 diabetes (T2D) is a risk factor for AD, and diets that reduce the risk of T2D may confer neuroprotection. Foods predominant in Mediterranean, MIND, and DASH diets, including fruits, leafy green vegetables, fish, nuts, and olive oil, may prevent or slow cognitive decline. The mechanisms by which these nutrients promote brain health, however, are not yet completely understood. Other dietary approaches and eating regimes, including ketogenic and intermittent fasting, are also emerging as beneficial for brain health. This review summarizes the pathophysiology, associated risk factors, and the potential neuroprotective pathways activated by several diets and eating regimes that have shown promising results in promoting brain health and preventing dementia.

Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.

Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.

Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases.

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-ß, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

Sex-specific transcriptional rewiring in the brain of Alzheimer's disease patients.

Sex-specific differences may contribute to Alzheimer's disease (AD) development. AD is more prevalent in women worldwide, and female sex has been suggested as a disease risk factor. Nevertheless, the molecular mechanisms underlying sex-biased differences in AD remain poorly characterized. To this end, we analyzed the transcriptional changes in the entorhinal cortex of symptomatic and asymptomatic AD patients stratified by sex. Co-expression network analysis implemented by SWItchMiner software identified sex-specific signatures of switch genes responsible for drastic transcriptional changes in the brain of AD and asymptomatic AD individuals. Pathway analysis of the switch genes revealed that morphine addiction, retrograde endocannabinoid signaling, and autophagy are associated with both females with AD (F-AD) and males with (M-AD). In contrast, nicotine addiction, cell adhesion molecules, oxytocin signaling, adipocytokine signaling, prolactin signaling, and alcoholism are uniquely associated with M-AD. Similarly, some of the unique pathways associated with F-AD switch genes are viral myocarditis, Hippo signaling pathway, endometrial cancer, insulin signaling, and PI3K-AKT signaling. Together these results reveal that there are many sex-specific pathways that may lead to AD. Approximately 20-30% of the elderly have an accumulation of amyloid beta in the brain, but show no cognitive deficit. Asymptomatic females (F-asymAD) and males (M-asymAD) both shared dysregulation of endocytosis. In contrast, pathways uniquely associated with F-asymAD switch genes are insulin secretion, progesterone-mediated oocyte maturation, axon guidance, renal cell carcinoma, and ErbB signaling pathway. Similarly, pathways uniquely associated with M-asymAD switch genes are fluid shear stress and atherosclerosis, FcγR mediated phagocytosis, and proteoglycans in cancer. These results reveal for the first time unique pathways associated with either disease progression or cognitive resilience in asymptomatic individuals. Additionally, we identified numerous sex-specific transcription factors and potential neurotoxic chemicals that may be involved in the pathogenesis of AD. Together these results reveal likely molecular drivers of sex differences in the brain of AD patients. Future molecular studies dissecting the functional role of these switch genes in driving sex differences in AD are warranted.

Physical Activity Rewires the Human Brain against Neurodegeneration.

Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for disease management. Here we employed several bioinformatic methods to dissect the molecular underpinnings of physical activity in brain health. Network analysis identified 'switch genes' associated with drastic hippocampal transcriptional changes in aged cognitively intact individuals. Switch genes are key genes associated with dramatic transcriptional changes and thus may play a fundamental role in disease pathogenesis. Switch genes are associated with protein processing pathways and the metabolic control of glucose, lipids, and fatty acids. Correlation analysis showed that transcriptional patterns associated with physical activity significantly overlapped and negatively correlated with those of neurodegenerative diseases. Functional analysis revealed that physical activity might confer neuroprotection in Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases via the upregulation of synaptic signaling pathways. In contrast, in frontotemporal dementia (FTD) its effects are mediated by restoring mitochondrial function and energy precursors. Additionally, physical activity is associated with the downregulation of genes involved in inflammation in AD, neurogenesis in FTD, regulation of growth and transcriptional repression in PD, and glial cell differentiation in HD. Collectively, these findings suggest that physical activity directs transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases. These results provide new evidence on the unique and shared mechanisms between physical activity and neurodegenerative diseases.

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no modifying treatments available. The molecular mechanisms underpinning disease pathogenesis are not fully understood. Recent studies have employed co-expression networks to identify key genes, known as "switch genes", responsible for dramatic transcriptional changes in the blood of ALS patients. In this study, we directly investigate the root cause of ALS by examining the changes in gene expression in motor neurons that degenerate in patients. Co-expression networks identified in ALS patients' spinal cord motor neurons revealed 610 switch genes in seven independent microarrays. Switch genes were enriched in several pathways, including viral carcinogenesis, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Transcription factors ELK1 and GATA2 were identified as key master regulators of the switch genes. Protein-chemical network analysis identified valproic acid, cyclosporine, estradiol, acetaminophen, quercetin, and carbamazepine as potential therapeutics for ALS. Furthermore, the chemical analysis identified metals and organic compounds including, arsenic, copper, nickel, and benzo(a)pyrene as possible mediators of neurodegeneration. The identification of switch genes provides insights into previously unknown biological pathways associated with ALS.

Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias.

Frontotemporal lobar degeneration (FTLD), also known as frontotemporal dementia (FTD), results in a progressive decline in executive function, leading to behavioral changes, speech problems, and movement disorders. FTD is the second most common cause of young-onset dementia affecting approximately 50-60,000 Americans. FTD exists in familial and sporadic forms, with GRN progranulin and C9orf72 mutations being the most common causes. In this study, we compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann's area 8 of patients with FTD to determine genes and pathways involved in the disease process. Most dysregulated genes expression occurred in the frontal cortex and Brodmann's area 8 for genetic and sporadic forms of FTD, respectively. A meta-analysis revealed 50 genes and 95 genes are dysregulated in at least three brain regions in patients with familial mutations and sporadic FTD patients, respectively. Familial FTD genes centered on the Wnt signaling pathway, whereas genes associated with the sporadic form of FTD centered on MAPK signaling. The results reveal the similarities and differences between sporadic and familial FTD. In addition, valproic acid and additional therapeutic agents may be beneficial in treating patients with FTD.

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients.

Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.

Key Disease Mechanisms Linked to Alzheimer's Disease in the Entorhinal Cortex.

Alzheimer's disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain's entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor γ (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical-protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing.

The Impact of Disease Comorbidities in Alzheimer's Disease.

A wide range of comorbid diseases is associated with Alzheimer's disease (AD), the most common neurodegenerative disease worldwide. Evidence from clinical and molecular studies suggest that chronic diseases, including diabetes, cardiovascular disease, depression, and inflammatory bowel disease, may be associated with an increased risk of AD in different populations. Disruption in several shared biological pathways has been proposed as the underlying mechanism for the association between AD and these comorbidities. Notably, inflammation is a common dysregulated pathway shared by most of the comorbidities associated with AD. Some drugs commonly prescribed to patients with diabetes and cardiovascular disease have shown promising results in AD patients. Systems-based biology studies have identified common genetic factors and dysregulated pathways that may explain the relationship of comorbid disorders in AD. Nonetheless, the precise mechanisms for the occurrence of disease comorbidities in AD are not entirely understood. Here, we discuss the impact of the most common comorbidities in the clinical management of AD patients.

A Comparison of Gene Expression Changes in the Blood of Individuals Consuming Diets Supplemented with Olives, Nuts or Long-Chain Omega-3 Fatty Acids.

BACKGROUND: The Mediterranean diet, which is rich in olive oil, nuts, and fish, is considered healthy and may reduce the risk of chronic diseases. METHODS: Here, we compared the transcriptome from the blood of subjects with diets supplemented with olives, nuts, or long-chain omega-3 fatty acids and identified the genes differentially expressed. The dietary genes obtained were subjected to network analysis to determine the main pathways, as well as the transcription factors and microRNA interaction network to elucidate their regulation. Finally, a gene-associated disease interaction network was performed. RESULTS: We identified several genes whose expression is altered after the intake of components of the Mediterranean diets compared to controls. These genes were associated with infection and inflammation. Transcription factors and miRNAs were identified as potential regulators of the dietary genes. Interestingly, caspase 1 and sialophorin are differentially expressed in the opposite direction after the intake of supplements compared to Alzheimer's disease patients. In addition, ten transcription factors were identified that regulated gene expression in supplemented diets, mild cognitive impairment, and Alzheimer's disease. CONCLUSIONS: We determine genes whose expression is altered after the intake of the supplements as well as the transcription factors and miRNA involved in their regulation. These genes are associated with schizophrenia, neoplasms, and rheumatic arthritis, suggesting that the Mediterranean diet may be beneficial in reducing these diseases. In addition, the results suggest that the Mediterranean diet may also be beneficial in reducing the risk of dementia.

Bioinformatic Analysis Reveals Phosphodiesterase 4D-Interacting Protein as a Key Frontal Cortex Dementia Switch Gene.

: The mechanisms that initiate dementia are poorly understood and there are currently no treatments that can slow their progression. The identification of key genes and molecular pathways that may trigger dementia should help reveal potential therapeutic reagents. In this study, SWItch Miner software was used to identify phosphodiesterase 4D-interacting protein as a key factor that may lead to the development of Alzheimer's disease, vascular dementia, and frontotemporal dementia. Inflammation, PI3K-AKT, and ubiquitin-mediated proteolysis were identified as the main pathways that are dysregulated in these dementias. All of these dementias are regulated by 12 shared transcription factors. Protein-chemical interaction network analysis of dementia switch genes revealed that valproic acid may be neuroprotective for these dementias. Collectively, we identified shared and unique dysregulated gene expression, pathways and regulatory factors among dementias. New key mechanisms that lead to the development of dementia were revealed and it is expected that these data will advance personalized medicine for patients.

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders.

BACKGROUND: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer's disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. METHODS: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. RESULTS: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. CONCLUSIONS: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer's Disease.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are among the most prevalent chronic diseases affecting the aging population. Extensive research evidence indicates that T2D is a well-established risk factor for AD; however, the molecular mechanisms underlying this association have not been fully elucidated. Furthermore, how T2D may contribute to the progression of AD is a subject of extensive investigation. In this study, we compared the blood transcriptome of patients with mild cognitive impairment (MCI), AD, and advanced AD to those afflicted with T2D to unveil shared and unique pathways and potential therapeutic targets. Blood transcriptomic analyses revealed a positive correlation between gene expression profiles of MCI, AD, and T2D in seven independent microarrays. Interestingly, gene expression profiles from women with advanced AD correlated negatively with T2D, suggesting sex-specific differences in T2D as a risk factor for AD. Network and pathway analysis revealed that shared molecular networks between MCI and T2D were predominantly enriched in inflammation and infectious diseases whereas those networks shared between overt AD and T2D were involved in the phosphatidylinositol 3-kinase and protein kinase B/Akt (PI3K-AKT) signaling pathway, a major mediator of insulin signaling in the body. The PI3K-AKT signaling pathway became more significantly dysregulated in the advanced AD and T2D shared network. Furthermore, endocrine resistance and atherosclerosis pathways emerged as dysregulated pathways in the advanced AD and T2D shared network. Interestingly, network analysis of shared differentially expressed genes between children with T2D and MCI subjects identified forkhead box O3 (FOXO3) as a central transcriptional regulator, suggesting that it may be a potential therapeutic target for early intervention in AD. Collectively, these results suggest that T2D may be implicated at different stages of AD through different molecular pathways disrupted during the preclinical phase of AD and more advanced stages of the disease.

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer's Disease Dementia.

BACKGROUND: Dementia is a major public health concern affecting approximately 47 million people worldwide. Mild cognitive impairment (MCI) is one form of dementia that affects an individual's memory with or without affecting their daily life. Alzheimer's disease dementia (ADD) is a more severe form of dementia that usually affects elderly individuals. It remains unclear whether MCI is a distinct disorder from or an early stage of ADD. METHODS: Gene expression data from blood were analyzed to identify potential biomarkers that may be useful for distinguishing between these two forms of dementia. RESULTS: A meta-analysis revealed 91 genes dysregulated in individuals with MCI and 387 genes dysregulated in ADD. Pathway analysis identified seven pathways shared between MCI and ADD and nine ADD-specific pathways. Fifteen transcription factors were associated with MCI and ADD, whereas seven transcription factors were specific for ADD. Mir-335-5p was specific for ADD, suggesting that it may be useful as a biomarker. Diseases that are associated with MCI and ADD included developmental delays, cognition impairment, and movement disorders. CONCLUSION: These results provide a better molecular understanding of peripheral changes that occur in MCI and ADD patients and may be useful in the identification of diagnostic and prognostic biomarkers.

Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer's patients.

The dementia epidemic is likely to expand worldwide as the aging population continues to grow. A better understanding of the molecular mechanisms that lead to dementia is expected to reveal potentially modifiable risk factors that could contribute to the development of prevention strategies. Alzheimer's disease is the most prevalent form of dementia. Currently we only partially understand some of the pathophysiological mechanisms that lead to development of the disease in aging individuals. In this study, Switch Miner software was used to identify key switch genes in the brain whose expression may lead to the development of Alzheimer's disease. The results indicate that switch genes are enriched in pathways involved in the proteasome, oxidative phosphorylation, Parkinson's disease, Huntington's disease, Alzheimer's disease and metabolism in the hippocampus and posterior cingulate cortex. Network analysis identified the krupel like factor 9 (KLF9), potassium channel tetramerization domain 2 (KCTD2), Sp1 transcription factor (SP1) and chromodomain helicase DNA binding protein 1 (CHD1) as key transcriptional regulators of switch genes in the brain of AD patients. These transcriptions factors have been implicated in conditions associated with Alzheimer's disease, including diabetes, glucocorticoid signaling, stroke, and sleep disorders. The specific pathways affected reveal potential modifiable risk factors by lifestyle changes.

PTPRC Expression in Blood is Downregulated in Parkinson's and Progressive Supranuclear Palsy Disorders.

BACKGROUND: Parkinson's disease (PD) shares pathological and clinical features with progressive supranuclear palsy (PSP) patients making the diagnosis challenging. Distinguishing PD from PSP is crucial given differences in disease course, treatment and clinical management. OBJECTIVE: Although some progress has been made in the discovery of biomarkers for PD and PSP, there is an urgent need to identify additional biomarkers capable of distinguishing between these diseases. METHODS: In this study, we tested the phosphatases DUSP8 and PTPRC for their diagnostic potential using quantitative PCR assays, in blood of 138 samples from participants nested in the Parkinson's Disease Biomarkers Program. RESULTS: Relative abundance of PTPRC mRNA was downregulated in PSP patients compared to PD and healthy controls, whereas there was no significant difference in the expression of DUSP8. Interestingly, PTPRC mRNA correlated with the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score and MDS-UPDRS- part III, thus indicating it might be useful as part of a biosignature to stratify patients according to disease severity and progression. CONCLUSIONS: Collectively, these results suggest that PTPRC expression may be useful for distinguishing PD from PSP patients as part of a biosignature. Evaluation of PTPRC along with additional biomarkers in a larger and well-characterized longitudinal study is warranted.

Evaluation of RNA Blood Biomarkers in the Parkinson's Disease Biomarkers Program.

There is a high misdiagnosis rate between Parkinson's disease (PD) and atypical parkinsonian disorders (APD), such as progressive supranuclear palsy (PSP), the second most common parkinsonian syndrome. In our earlier studies, we identified and replicated RNA blood biomarkers in several independent cohorts, however, replication in a cohort that includes PSP patients has not yet been performed. To this end, we evaluated the diagnostic potential of nine previously identified RNA biomarkers using quantitative PCR assays in 138 blood samples at baseline from PD, PSP and healthy controls (HCs) nested in the PD Biomarkers Program. Linear discriminant analysis showed that COPZ1 and PTPN1 distinguished PD from PSP patients with 62.5% accuracy. Five biomarkers, PTPN1, COPZ1, FAXDC2, SLC14A1s and NAMPT were useful for distinguishing PSP from controls with 69% accuracy. Several biomarkers correlated with clinical features in PD patients. SLC14A1-s correlated with Unified Parkinson's Disease Rating Scale total and part III scores. In addition, COPZ1, PTPN1 and MLST8, correlated with Montreal Cognitive Assessment (MoCA). Interestingly, COPZ1, EFTUD2 and PTPN1 were downregulated in cognitively impaired (CI) compared to normal subjects. Linear discriminant analysis showed that age, PTPN1, COPZ1, FAXDC2, EFTUD2 and MLST8 distinguished CI from normal subjects with 65.9% accuracy. These results suggest that COPZ1 and PTPN1 are useful for distinguishing PD from PSP patients. In addition, the combination of PTPN1, COPZ1, FAXDC2, EFTUD2 and MLST8 is a useful signature for cognitive impairment. Evaluation of these biomarkers in a larger study will be a key to advancing these biomarkers into the clinic.