Cognitive Disorder

Cognitive disorders encompass a wide range of conditions characterized by significant impairments in cognitive functions such as memory, attention, language, and executive function. These impairments can manifest as challenges with learning new information, solving problems, or performing daily tasks. Cognitive function is a complex trait influenced by both environmental factors and a strong genetic component, having been shown to be highly heritable^[1].

Biological Basis

The biological underpinnings of cognitive disorders are complex, involving various genetic and neurological pathways. Research indicates that memory and cognitive problems are characteristic of many common psychiatric and neurological disorders ^[1]. Cognitive measures are increasingly viewed as ‘endophenotypes’ for neuropsychiatric diseases, meaning they are measurable, heritable traits that lie on the causal pathway between genes and clinical disease^[1].

Early genome-wide association studies (GWAS) investigating common genetic variation in memory identified genes such as KIBRA and CAMTA1, although subsequent replication efforts have yielded mixed results ^[1]. Beyond these, hundreds of studies have explored associations between specific genetic polymorphisms and memory ^[1]. Genes implicated in related neurological conditions also show relevance to cognitive function. For instance, PDE4D and LTA4H have been associated with stroke, while NGFB, NTRK2, and NTRK3, which are neural growth factor genes, have been linked to memory tasks in animal studies^[1]. Genes like BACE1, PRNP, and A2M are associated with Alzheimer’s disease, VLDLR with dementia, and LRRK2 with Parkinson’s disease and tau pathology, all of which involve cognitive decline^[1]. More specific associations include SORL1, which plays a role in amyloid precursor protein processing and has been linked to abstract reasoning and Alzheimer’s disease risk, and CDH4, associated with total cerebral brain volume^[1]. Additionally, studies have suggested a role for rare genetic variation, with genes like NRXN1 showing associations with cognition ^[1].

Clinical Relevance

Cognitive impairments are a hallmark of numerous clinical conditions, impacting diagnosis, prognosis, and treatment outcomes. Patients with psychiatric disorders like schizophrenia and bipolar disorder frequently experience cognitive deficits that are often unresponsive to conventional treatments^[1]. The severity of these cognitive impairments can correlate with the overall functional outcome of the illness ^[1]. Furthermore, studies indicate that cognitive impairments associated with neuropsychiatric disorders are also present in unaffected relatives at a higher rate than in the general population, and can persist in patients even when the illness is not active ^[1]. Understanding the genetic basis of these endophenotypes is crucial for developing targeted interventions.

Social Importance

The widespread impact of cognitive disorders underscores their significant social importance. These conditions affect millions globally, leading to substantial personal, family, and societal burdens. Research into the genetic underpinnings of cognitive function aims to improve early identification of individuals at risk, facilitate the development of more effective diagnostic tools, and pave the way for novel therapeutic strategies. By studying the genetic architecture of cognitive endophenotypes in healthy individuals, researchers hope to gain insights into the mechanisms underlying complex brain disorders, ultimately enhancing the quality of life for those affected and reducing the societal cost of these debilitating conditions.

Limitations

Research into cognitive disorders, while critical for understanding and developing treatments, faces several inherent limitations that influence the interpretation and generalizability of findings. These challenges span methodological design, the complexity of phenotypes, and the intricate genetic architecture underlying these conditions.

Methodological and Statistical Constraints

Many studies investigating cognitive disorders have historically faced methodological and statistical limitations. The interpretation of findings has often been hampered by issues such as small sample sizes, publication bias ^[2] and ^[3], and insufficient correction for population stratification ^[4]. These factors can lead to inflated effect sizes and an overall lack of replication across different datasets, making it difficult to identify robust genetic associations. Furthermore, despite the application of whole-genome technologies, consistently replicating strong associations for neurocognitive traits has proven challenging ^[5] and ^[6]. The power of current study designs may be insufficient to detect associations with certain genetic variants, especially if effects are subtle or mediated by complex interactions ^[5], highlighting the inherent difficulty in uncovering the genetic architecture of these complex traits.

Challenges in Phenotype Assessment and Generalizability

Generalizing findings to the broader population is often constrained by the specific characteristics of study cohorts. For instance, studies predominantly including individuals with higher education and those under 40 years of age may limit the ability to detect genetic associations specific to older or less-educated populations. Even with advanced methods like EIGENSTRAT applied for correcting population stratification, residual genetic differences between distinct ancestral groups, such as Asian and European populations, could still diminish the power to identify genuinely associated variants or introduce spurious findings. The diverse nature of cognitive functions also presents a challenge, as findings from assessments of specific cognitive domains may not generalize to other aspects of cognition. Many types of learning and memory, including delayed or remote memory, are often not assessed, and these could potentially be under different genetic controls, requiring caution when broadly applying conclusions.

Unaccounted Genetic Architecture and Knowledge Gaps

Research into cognitive disorders continues to face challenges in fully elucidating the underlying genetic architecture. It is considered a likely explanation for some findings that the genetic variation contributing to neurocognitive traits might be too rare to be reliably detected with current genotyping platforms, which are often geared towards common variants. Another possibility is that genetic contributions stem from hundreds of common variants, each with an exceedingly small effect size. Such a scenario makes individual variant detection challenging and contributes to the phenomenon of “missing heritability” in complex traits. These knowledge gaps underscore the need for continued exploration into diverse genetic mechanisms and improved detection technologies to fully understand the genetic underpinnings of cognitive function and dysfunction.

The APOEgene, located on chromosome 17, plays a crucial role in lipid metabolism and transport within the brain and body. It is essential for the packaging and transport of cholesterol and other fats, which are vital for neuronal function and repair. The single nucleotide polymorphism (SNP)rs429358 , along with another SNP, rs7412 , determines the three major isoforms or alleles of the APOEgene: ε2, ε3, and ε4. These alleles have distinct effects on cognitive health, with the ε4 allele being the most well-known genetic risk factor for late-onset Alzheimer’s disease (AD) and other cognitive impairments. The presence of thers429358 (C) allele, in combination with rs7412 (C), defines the ε4 isoform, leading to structural and functional differences in the APOE protein that impair the clearance of amyloid-beta plaques from the brain, a hallmark of AD pathology.

Individuals carrying one or two copies of the APOE ε4 allele (defined by rs429358 (C)) face an increased risk of developing AD and often experience an earlier age of onset compared to those with other APOEgenotypes. The ε4 allele is associated with poorer cognitive performance in various domains, including memory and executive function. Conversely, theAPOE ε2 allele (defined by rs429358 (T) and rs7412 (T)) is generally considered protective against AD, potentially by promoting more efficient lipid processing and amyloid-beta clearance, thereby supporting better brain health and cognitive function into older age. The ε3 allele (defined byrs429358 (T) and rs7412 (C)) is the most common and is generally considered neutral in terms of AD risk.

Beyond APOE, other genetic variants contribute to the complex landscape of cognitive disorders. For instance, variants within the SORL1 (Sortilin-related receptor 1) gene, such as rs1131497 and rs726601 , have shown strong associations with performance on abstract reasoning tests. SORL1functions as an apolipoprotein E receptor and is involved in the processing of amyloid precursor protein (APP), a key player in the development of Alzheimer’s disease. Its role in regulating APP processing and retrograde protein transport means that variations inSORL1can influence the accumulation of amyloid-beta, impacting cognitive function and contributing to AD risk.

Further illustrating the multifactorial nature of cognitive health, the CDH4 (Cadherin 4) gene, through its variant rs1970546 , has been associated with Total Cerebral Brain Volume (TCBV). TCBV is an important measure of overall brain size and a proxy for neuronal integrity, with reduced volume often correlating with cognitive decline and neurodegenerative processes. Similarly, theKIBRA gene, with its variant rs17070145 , has been linked to verbal memory performance, highlighting its role in synaptic plasticity and the formation of new memories. These diverse genetic factors, ranging from lipid transport and amyloid processing to brain structure and synaptic function, collectively influence an individual’s susceptibility to cognitive disorders and the trajectory of brain aging.

Cognitive Disorder: Classification, Definition, and Terminology

Definition

A cognitive disorder is characterized by cognitive impairments, which are deficits in mental functions. These impairments are associated with clinical diseases, brain aging, stroke, and neurodegenerative diseases such as Alzheimer’s disease (AD). Cognitive measures are also studied as endophenotypes for psychiatric disorders, indicating heritable traits that may increase the risk of developing these conditions.

Terminology and Related Concepts

• Cognitive Impairments: Observable difficulties in cognitive functions. For example, psychiatric disorders like schizophrenia are commonly accompanied by cognitive impairments that are crucial to functional outcome.
• Cognitive Phenotypes: Measurable characteristics or traits related to cognitive function. These are defined and collected for research, such as in genome-wide association studies.
• Cognitive Test Performance: The quantitative results obtained from standardized tests designed to assess various cognitive abilities. These scores are often combined or analyzed individually to characterize specific cognitive domains.
• Cognitive Domains: Distinct areas of mental function. The research identifies specific domains based on test performance:
  • Verbal Memory (Factor 1, F1): Relates to the ability to recall and recognize verbal information.
  • Visual Memory and Organization (Factor 2, F2): Involves the ability to remember and structure visual and spatial information.
  • Attention and Executive Function (Factor 3, F3): Encompasses mental processes such as focused attention, planning, problem-solving, and cognitive flexibility.
• Endophenotypes: In the context of psychiatric disorders, cognitive measures can serve as endophenotypes. These are intermediate traits that are heritable and associated with clinical disease, with the potential for a clearer genetic basis.

Classification

Cognitive abilities are classified into specific domains, often derived from performance on a battery of tests. In studies, cognitive test performance is frequently grouped into factors representing these domains:

• Factor 1 (F1): Represents Verbal Memory.
• Factor 2 (F2): Represents Visual Memory and Organization.
• Factor 3 (F3): Represents Attention and Executive Function.

Individual cognitive tests are also utilized to assess particular aspects of cognitive function:

• Boston Naming Test (Nam): A test assessing naming ability.
• Similarities (Sim): A measure of abstract reasoning.
• Wide-Range Achievement Test (WRAT): A test often used to assess basic academic skills.

Conditions associated with cognitive disorders include:

• Neurodegenerative diseases: Such as Alzheimer’s disease (AD).
• Vascular conditions: Such as stroke.
• Brain aging: Changes in brain function over time that affect cognition.
• Psychiatric disorders: Conditions like schizophrenia, which are frequently accompanied by cognitive impairments.

A cognitive disorder refers to an impairment in one or more cognitive functions.

Measurement Approaches

Cognitive functions are typically assessed using standardized test batteries, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) ^[7]. These batteries are designed to measure various cognitive phenotypes, including specific abilities like spatial and verbal recognition memory ^[7]. Researchers have utilized such comprehensive testing approaches to investigate numerous cognitive phenotypes, with studies examining as many as 11 distinct cognitive measures ^[7].

Variability

Cognitive function is known to be highly heritable^[8]. Studies have estimated the heritability of cognitive abilities by comparing correlations in cognitive performance between monozygotic (identical) and dizygotic (fraternal) twin pairs ^[7]. Research indicates that both the variability and stability of cognitive abilities, particularly later in life, are substantially influenced by genetic factors ^[8].

Cognitive function is significantly influenced by genetic factors, with studies showing high heritability for cognitive abilities^[7]. Cognitive impairments associated with neuropsychiatric disorders are also present in unaffected relatives at a higher rate than in the general population, suggesting that cognitive measures can serve as endophenotypes for these conditions ^[9].

Genetic Factors

• Common Genetic Variation: Initial genome-wide association studies (GWAS) on memory, specifically using a word recall task, identified genes such as KIBRA and CAMTA1 ^[10]. However, the KIBRA association has not been consistently replicated in subsequent research ^[11], and the CAMTA1 association awaits independent replication. Although hundreds of papers have reported associations between particular genetic polymorphisms and memory, there remains a lack of good candidate polymorphisms that consistently replicate across different datasets. Recent studies suggest that common genetic variation may not strongly influence cognition in healthy subjects ^[11].
• Rare Genetic Variation: The genetic variation underlying neurocognitive traits is likely often too rare to be detectable with current genotyping platforms. There is strong evidence from other neurocognitive traits, such as schizophrenia, autism, and epilepsy, that large, rare copy number variants (CNVs) are associated with disorders that have not shown obvious associations with common variation in genome-wide screens. A surprising finding is that the same rare variants can be associated with multiple neuropsychiatric conditions (including autism, mental retardation, and schizophrenia) and are also present in apparently unaffected individuals. These rare genetic variants might indirectly contribute to these disorders by causing cognitive changes. The gene NRXN1 has shown evidence of significant association with cognition when investigating single nucleotide polymorphisms (SNPs) in genomic loci known to harbor rare variants linked to neuropsychiatric disorders^[11].
• Epigenetic Modifications: It is possible that epigenetic modifications affect cognition in healthy subjects. However, this type of genetic contribution is currently undetectable with existing methods.

Environmental Factors

Differences in the ultimate cognitive phenotype or disease state may depend on the interaction between genetic influences, such as rare genetic variants, and other environmental factors.

Cognitive disorders involve a range of impairments that significantly affect daily life. These impairments are a core feature of several neuropsychiatric conditions, such as schizophrenia and bipolar disorder, and are often resistant to current treatments. The degree of cognitive dysfunction can strongly predict the overall progression and outcome of these diseases. Alzheimer’s disease, for example, is primarily characterized by severe memory loss and cognitive decline, with no effective treatment currently available. Developing therapies to improve cognitive symptoms is a critical area of research for both patients and society.

Genetic Underpinnings

Cognitive function is known to be a highly heritable trait, suggesting a substantial genetic influence on cognitive abilities.^{[12][13][8][7]}. Cognitive impairments observed in individuals with neuropsychiatric disorders are also found more frequently in their unaffected relatives and can persist in patients even when the illness is not active. These characteristics align with the definition of “endophenotypes,” which are measurable biological or behavioral traits that are heritable, associated with a disease, and present in unaffected relatives at a higher rate than the general population. Consequently, cognitive measures are considered suitable endophenotypes for neuropsychiatric conditions.^[9][14]. Studying these cognitive phenotypes in healthy individuals is therefore a promising method to identify connections between cognitive traits and common genetic variations.

Molecular and Cellular Pathways

Research into the molecular and cellular mechanisms underlying cognitive function and impairment has identified several genes and pathways of interest:

• Neurotrophic Factors:Variations in the brain-derived neurotrophic factor (BDNF) gene have been associated with performance on cognitive prefrontal tests, particularly in individuals with bipolar disorder. ^[15].
• Neurotransmitter Receptors:
  • Polymorphisms in the HTR2Agene, which codes for a serotonin receptor, have been linked to longitudinal memory performance.^[16].
  • The cholinergic muscarinic 2 receptor (CHRM2) gene plays a role in cognition and has shown an association with intelligence quotient (IQ).^[17][18].
• Proteases:A specific polymorphism in exon 2 of the Cathepsin D gene has been associated with general intelligence in a healthy older population.^[19].

While a genome-wide association study (GWAS) previously implicated the KIBRA and CAMTA1genes in memory, these findings have not yet been consistently replicated in independent studies. Other investigations have explored candidate genes associated with conditions such as stroke, Alzheimer’s disease, brain aging, and vascular dementia, often leveraging established databases like NCBI Gene, PubMed, OMIM, Alzforum Alzgene, and the Science of Aging Knowledge Environment.

Rare Genetic Variants

Recent findings indicate that rare genetic variants, particularly Copy Number Variants (CNVs), are associated with multiple neuropsychiatric conditions, including autism, mental retardation, and schizophrenia. These variants are not restricted to a single diagnostic category and can even be present in individuals who do not display apparent symptoms of these disorders. Since these neuropsychiatric conditions are all linked to some form of cognitive impairment, it is hypothesized that these rare genetic variants may contribute to the disorders by causing cognitive changes. The specific manifestation of a disease phenotype may then depend on interactions with other genetic factors or environmental influences. Detailed cognitive assessments of individuals carrying these rare variants, including unaffected relatives, could help identify specific cognitive deficits associated with them.

Pathways and Mechanisms

Cognitive disorders involve complex molecular and physiological mechanisms that affect various aspects of brain function and memory. Research indicates that both genetic factors and cellular processes contribute to these conditions.

Molecular MechanismsGenetic variations play a significant role in influencing cognitive function. For example, theAKT1 gene has been associated with verbal learning, verbal memory, and the density of regional cortical gray matter ^[20]. Polymorphisms within the catechol-O-methyltransferase(COMT) gene, particularly the Val158Met variant, have been linked to executive function and working memory performance^[2]. Other genes, such as G72, are also implicated in cognitive processes ^[21].

Variations in dopamine receptor genes have been studied in relation to cognitive performance, including tasks that assess executive function, such as the Wisconsin Card Sort Test^[15]. Similarly, the HTR2Apolymorphism has been associated with changes in memory performance over time^[16]. Specific alleles of the Kibragene are linked to human memory performance^[10], and alleles of calmodulin-binding transcription activator 1 (CAMTA1)are associated with episodic memory performance^[22].

Beyond specific genes, broader molecular pathways contribute to cognitive function. The monoamine system, involving various neurotransmitters, is influenced by functional gene variants, which affect monoamine metabolite concentrations in the cerebrospinal fluid^[23]. Transcriptional control of superoxide dismutase-2, particularly involving the kappaB element in neurons and astrocytes, represents another molecular pathway ^[24]. Glutamate receptor activation can lead to the calpain-mediated degradation of Sp3 and Sp4, which are important transcription factors in neurons^[24]. Metabotropic glutamate receptors (mGluRs) are known to regulate mood disorders, which often present with cognitive impairments^[25]. Furthermore, microRNAs and their effectors have been identified as long-term targets in the regulation of mood ^[26].

Physiological MechanismsCognitive disorders can manifest as impairments in specific cognitive domains. Executive function and working memory, for instance, are affected by genetic factors such as the COMT Val158Met polymorphism^[2]. Memory performance, encompassing verbal learning, verbal memory, and episodic memory, is influenced by genes likeAKT1, HTR2A, Kibra, and CAMTA1 ^[20]. Regional cortical gray matter density is a physiological marker linked to genes such as AKT1 ^[20]. Hormones like cortisol have been investigated in the context of psychiatric conditions, suggesting a potential role in broader neurocognitive regulation^[27]. The process of brain aging, observable through MRI and cognitive tests, also demonstrates genetic correlates^[1].

Clinical Relevance

Cognitive disorders are a significant concern due to their impact on patient outcomes and the lack of effective treatments. In psychiatric conditions such as schizophrenia and bipolar disorder, cognitive impairments are often unresponsive to current therapeutic approaches^[28]. The degree of cognitive function serves as a strong indicator for the eventual prognosis of these diseases^[28]. Similarly, Alzheimer’s disease is characterized by severe declines in memory and overall cognitive abilities, for which no effective treatments are currently available. This highlights an essential need, both for affected individuals and for society, to develop interventions that can improve cognitive symptoms in these disorders^[28].

Key Variants

RS ID	Gene	Related Traits
rs429358	APOE	cerebral amyloid deposition measurement Lewy body dementia, Lewy body dementia measurement high density lipoprotein cholesterol measurement platelet count neuroimaging measurement

Frequently Asked Questions About Cognitive Disorder

These questions address the most important and specific aspects of cognitive disorder based on current genetic research.

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1. My parent has memory issues; will I get them too?

Cognitive function is highly heritable, meaning it often runs in families. If your parent has memory issues, you might have a higher predisposition. Studies show that cognitive impairments linked to neuropsychiatric disorders can appear in unaffected relatives more often than in the general population, suggesting a genetic link.

2. Why do I struggle with new tasks at work sometimes?

Challenges with learning new information and problem-solving are hallmarks of cognitive difficulties. Your ability to learn and perform daily tasks is influenced by a complex interplay of genetic factors and your environment. Genes like KIBRA or CAMTA1 have been explored for their role in memory, though research is ongoing.

3. Can a DNA test tell me my risk for memory problems?

Yes, genetic research aims to develop tools for early identification of risk. DNA tests can identify certain genetic variations linked to cognitive function or disorders like Alzheimer’s (e.g., genes like SORL1 or BACE1). However, these tests usually indicate risk factors, not a definitive diagnosis, as many genes with small effects contribute.

4. My friend’s memory medicine helps, but mine doesn’t. Why?

Cognitive deficits, especially those linked to psychiatric disorders like schizophrenia or bipolar disorder, often respond differently to treatments. Your genetic makeup can influence how your body processes medications and how your brain responds. Understanding these genetic “endophenotypes” is key to developing more targeted and effective interventions.

5. I had learning issues as a kid; does that mean future problems?

Not necessarily, but cognitive function is a trait influenced by strong genetic components from birth. Learning challenges can be part of this broader cognitive profile. Research continues to explore the genetic pathways that contribute to cognitive abilities throughout life, and early difficulties might indicate a predisposition that warrants attention.

6. I feel “foggy” even when my mood is good. Is that normal?

Yes, it can be. Cognitive impairments associated with neuropsychiatric disorders can persist even when the primary illness is not active. This “brain fog” isn’t just about mood; it points to underlying biological mechanisms that affect your memory, attention, and executive function, even during periods of remission.

7. Does my family’s background affect my cognitive risk?

Yes, your ancestral background can influence your genetic risk for cognitive problems. Different ancestral groups may have unique genetic variations that affect cognitive function. This is why researchers need to consider potential genetic differences between populations when studying these complex traits.

8. Can healthy habits overcome my family’s memory genes?

While cognitive function has a strong genetic component and is highly heritable, it’s also influenced by environmental factors. Healthy habits can play a role in supporting overall brain health and potentially mitigating some genetic risks. Research into genetic underpinnings aims to develop targeted interventions, suggesting that lifestyle modifications could be part of a comprehensive approach.

9. My sibling is sharp, but I forget things often. Why the difference?

Even within families, there can be significant differences in cognitive abilities due to the complex nature of genetics. While cognitive function is highly heritable, it’s influenced by many genes, each with small effects, plus unique environmental exposures. This “missing heritability” means individual variations are common, even among close relatives.

10. Is my memory just aging, or could it be a disorder?

It’s a valid concern, as cognitive decline is a feature of conditions like Alzheimer’s, dementia, and Parkinson’s, which are often age-related. These disorders have specific genetic associations, such as BACE1 or VLDLR for Alzheimer’s and dementia. If you’re concerned, it’s best to consult a healthcare professional to distinguish normal aging from a potential disorder.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[9] Braff, D.L., et al. “Deconstructing Schizophrenia: An Overview of the Use of Endophenotypes in Order to Understand a Complex Disorder.”Schizophr. Bull., vol. 33, 2007, pp. 21-32.

[10] Papassotiropoulos, A. et al. (2006) “Common Kibra alleles are associated with human memory performance.”Science, 314, 475–478.

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[12] Benyamin, B., et al. “Large, Consistent Estimates of the Heritability of Cognitive Ability.” Twin Res. Hum. Genet., vol. 8, no. 2, Apr. 2005, pp. 124-30.

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[16] Reynolds, C.A. et al. (2006) “Longitudinal change in memory performance associated with HTR2A polymorphism.”Neurobiol. Aging, 27, 150–154.

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[18] Dick, DM, et al. “Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence.”Behav Genet, vol. 37, 2007, pp. 265–272.

[19] Payton, A, et al. “Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population.”Mol Psychiatry, vol. 8, 2003.

[20] Pietilainen, O.P. et al. (2008) “Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins.” Am. J. Med. Genet. B Neuropsychiatr. Genet.

[21] Jansen, A. et al. (2009) “A putative high risk diplotype of the G72 gene is in healthy individuals.” Human Molecular Genetics, 18(23).

[22] Huentelman, M.J. et al. (2007) “Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance.”Hum Mol Genet, 16, 1469–1477.

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