Orexins as biomarkers for Alzheimer dementia and their relationship with neuropsychiatric symptoms.

ABSTRACT

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The most studied biomarkers in Alzheimer’s dementia (AD) are elevated levels of A?42 and Tau protein in cerebrospinal fluid. Given the complexity of the cognitive symptomatology and neuropsychiatric symptoms (NPS) of this pathology, some recent studies propose substances such as orexins as a therapeutic target for AD and NPS. The present work aims to review recent scientific publications that have analyzed the association between orexins, PNS and AD in humans. There are some animal models that have evaluated orexins as possible biomarkers both for research and in the clinical area. This review also describes studies that suggest orexins as possible biomarkers in AD, given their relationship with A?42 and Tau protein, and other studies that associate them with the presence of SNPs, especially sleep disturbance. It is hypothesized that the presence of SNPs in AD is associated with orexins, because this system influences hypothalamic functioning and indirectly in brain areas that regulate behavior. However, further research is still lacking, mainly longitudinal studies to clearly know the influence of orexins on SNPs.

Key words: Alzheimer’s disease, orexins, neuropsychiatric symptoms, sleep disturbances, dementia biomarkers.

INTRODUCTION

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Alzheimer’s disease (AD) is the most prevalent dementia worldwide(1),. Some of its main characteristics    are    progressive    deterioration in cognitive functions and the presence of neuropsychiatric symptoms (NPS)(2-4). On a histopathological  level,  this  disease  is  known to have neurofibrillary tangles (intraneuronal formations  secondary  to  hyperphosphorylation of the Tau protein) and hippocampal-neocortical neuritic or amyloid plaques (its main component is amyloid beta peptide, A?.(5)

Neuropsychiatric symptoms, present from the early  stages  of  AD(5,6),  have  been  associated with greater cognitive impairment and institutionalization of patients, as well as with caregiver overload(7,8). They have also been widely described in literature, reporting their multifactorial etiology(7,9,10). Their neurobiology has been attributed to alterations in the neurotransmitter system, involving serotonin, dopamine(11),    ?-aminobutyric    acid    (GABA) (12)  and   the epsilon genotype (?)   allele of apolipoprotein E ( APOE -?4 ), mainly(13,14). None of the neurobiological approaches have been sufficient to explain SPCD, therefore the search markers related   to these symptoms continues. It has been proposed that the alteration of the orexin system in humans could be related to SNPs in AD.(15-18)

Orexins     are     neuropeptides     involved     in the regulation of metabolism, especially compromising  the  sleep-wake  cycle,  and feeding,  as  well  as  homeostasis  processes  of the organism(18,19). This system is altered in old age and in neurodegenerative pathologies such as AD. Additionally, a correlation between the presence of SNPs and changes in  orexin levels measured in cerebrospinal fluid (CSF) in patients with AD(16)  has been observed.

The orexin system becomes important in AD, since its alteration has been related to an increase in the levels of amyloid beta 42 (A?42), of total and phosphorylated Tau protein (tau-p)(18-21); and with  alterations  in  the  circadian  cycle,  which is a SNP characteristic in AD(22-24). However, a clear  and  direct  relationship  between  orexins and AD has not yet been established, so more research on this matter is required, especially if it is considered as a possible biomarker related to SNP in AD.(18)

In medicine, a biomarker is a measurable indicator of the severity or presence of a certain disease state(25). Biomarkers in AD have been used mainly for diagnosis, prognosis, and susceptibility since it has been established that the accumulation of A?42 and Tau begins approximately 10 to 20 years prior to clinical symptoms. However, the presence of these    biomarkers becomes necessary but not sufficient  to  explain  the  clinical  symptoms  of AD, since there are symptoms, such as delusions, that have not been exclusively associated with increased A?42 and Tau.(26)

Considering the recent research contributions on orexins, possible biomarkers in DA and SNP, this groundwork aims to review studies that report a relationship between these topics, and to review proposals about orexins as a possible biomarker of AD or as a pharmacological target to control of SNPs in AD. A brief description of the biology of orexins is provided, followed by a review on how orexins are related to AD and biomarkers in AD. Subsequently, a description of  studies that have taken place in the last five years, related to the proposal of orexins as a biomarker in AD and SNP, are included.

The search for references was carried out in the PubMed,   ScienceDirect   databases,   using   the terms: orexins, hypocretins, “biomarkers in Alzheimer’s disease”, Alzheimer’s disease and neuropsychiatric symptoms.

Orexin biology

Orexins (also called hypocretins, HCRT) are neurotransmitters secreted by the hypothalamus in its peripheral and lateral areas and are involved in the regulation of several homeostatic processes, such as feeding, sleeping, endocrine and cardiovascular function, thermogenesis, as well as arousal, reward, and mood(27). HCRT functions in the brain are pleiotropic, including regulation of the human biological clock(28), activation of the organism, and cognition.(18,21,29)

The orexin system is mediated by two ligands called orexin A and orexin B (also called hypocretin 1 and hypocretin 2,). These ligands are produced by the peptide prepro-orexin and are regulated by the action of the G protein- coupled receptors (as second messengers), orexin 1 (HCRTR1/OX1R) and orexin 2 (HCRTR2/ OX2R).(19)

Neuronal receptors have affinities for both types of orexins: orexin A binds preferentially to the OX1R receptor, while orexin A and orexin B have similar affinities for the OX2R. Orexin receptors are  found  in  different  brain  regions  including the hypothalamus, paraventricular nucleus, hippocampal formation, dorsal raphe, and locus coeruleus(19,30,31). Additionally, the OX2R receptor is expressed in the cerebral cortex, nucleus accumbens, subthalamic and paraventricular nucleus, and anterior pretectal nucleus. Orexin receptors project from the anterior hypothalamus to different areas of the brain including the stem, cerebral cortex, and limbic system mediating several activities such as cell excitation and death.(30)

The orexin system is also responsible for sending excitatory signals to the ventral tegmental dopaminergic area, substantia nigra, limbic structures, amygdala, and frontal and prefrontal regions that are important for emotional regulation, stress, and depression(32). This system has found to be altered in patients with panic attacks and suicide attempts with subsequent chronic stress, and with diseases such as delirium(33), narcolepsy, obesity, and drug addiction.(4,8,28)

Orexin levels in the brain are under complex regulation. It has been established that this system is under the influence of environmental variations of light and darkness, so its deregulation is related to alterations in the circadian cycle(34). OXR receptor deficiency has been involved in pathologies such as narcolepsy and neurodegenerative diseases such as AD(30,25), Huntington’s disease  and Parkinson’s disease.(36)

Orexins and alzheimer’s disease

Sleep disturbance has been related to variations in  the  orexin  system  and  to  an  increase  in DA precursors such as increased A? and phosphorylated Tau.    In  the  study  by  Liguori et al.(15), carried out in patients with a clinical diagnosis of Mild Cognitive Impairment (MCI) and  using  biomarkers  for  AD,  an  alteration in REM sleep with prolonged latencies, and presence of nocturnal sleep fragmentation were evidenced. This was also related to an increase in orexin levels in CSF, showing that the alteration of this system can be identified even in preclinical stages of AD. In stages of MCI, it has been found that the complaint of daytime sleepiness  is  a  risk  factor  for  its  progression to AD.(37,38)

It is not yet clear whether presymptomatic AD leads to circadian disturbances or if circadian rhythm malfunctions influence the development of AD. Results from a murine model for AD stated that the circadian oscillator in the hippocampus might be regulated by orexins. In this model, orexin activity regulates the hippocampal clock and the circadian oscillator of AD risk genes such as APOE and beta-secretase-2, BACE2 (whose protein product is necessary for the production of A?).(21)

Sleep deprivation is associated with accumulation of A?, plays an important role in clearing toxins in the brain, including A?. In this way a sleepless night or alteration in the sleep-wake cycle, due to changes in the orexin system would be related to an increase in A? levels(39). On the other hand, elevated A? levels in the hippocampus and cerebral cortex have been associated with increased orexin levels and insomnia in animal models(30). Recent research has also shown that altered levels/concentrations of orexins and an elevated presence of Tau protein are related.(17)

Orexins, like all neurotransmitters, are subject to long-term modulation. This suggests that age may influence the hypothalamic neurons receptors’ density over the years, and that approximately 23 to 25% of these neurons decrease the number of orexin receptors in adulthood(40,41). Consequently, a greater loss of these receptors is observed during aging patients and in those with AD who present sleep disturbances.(15,18)

It    has    been    reported    that    patients    with NPS, evaluated through the Cummings Neuropsychiatric Inventory (NPI), have lower scores  in  the  mental  state  screening  test  or the Mini Mental State Examination (MMSE), together with elevated orexin and Tau levels in CSF. Some authors have also found a relationship between high NPI scores and a greater probability of night awakening. However, future longitudinal studies should confirm and explain in a biological context, if the involvement of this system in sleep disturbances, is either a cause or a consequence of AD(16-18), as well as the bidirectional relationship between AD and sleep disturbances.(42-46)

Biomarkers in alzheimer - type dementia

The  most  accepted  molecular  biomarkers  in AD are ?-amyloid peptide, 42 total Tau protein and hyperphosphorylated Tau (Tau-p). These biomarkers reflect the pathophysiology of this disease, which is why they have been proposed as   diagnosis   criteria,   in   addition   to   being used in research as prognosis variable and are susceptible to greater cognitive impairment(47-49). The heterogeneity of AD symptoms, especially related to the presence of SNPs, suggests the need to broaden the study of biomarkers and not only limit them to determinations of ?-amyloid and Tau levels(47). Currently the study of other substances  such  as  orexins,  which  have  been associated with AD and SNP, as possible biomarkers, considering them as therapeutic targets are not excluded.(48)

Possible biomarkers for some SNPs in AD have also  been  described,  however,  low  specificity is  reported.  For  example,  agitation/aggression as a SNP in AD has been associated with neuropathological markers, neuroimaging markers, neurotransmitters, APOE genotype, and markers of neuroinflammation, but none have been totally specific, probably due to a lack of understanding of its neurobiology and the inconsistencies in the scientific evidence.(50)

The above is supported by the work of Skogseth et al. 51), who found a relationship between the presence of apathy and neurofibrillary tangles (another  AD  biomarker)  without  an  increase in levels of ?-amyloid or Tau. Recently, the multicenter study on the association between biomarkers and SNP in AD, carried out in more than 1000 patients with subjective memory complaint,  MCI  and  AD,  analyzed  the  result of INP and A?42 levels in CSF and were only related to the symptom of apathy(52). Both studies conclude that the presence of SNPs in AD is influenced by other factors such as biological, social,  or  psychological  ones,  suggesting  the need to study new molecular markers for a better understanding of SNPs in AD.

Clinical studies related to alzheimer- type dementia and orexins as possible biomarkers

Several studies have tried to establish an association   between   DA   and   orexins,   but the results are not conclusive in humans. A review  of  the  scientific  articles  in  the  last five years, in which cognitively healthy older adults and older adults with AD participated, highlights the constant research of this system as a possible biomarker and therapeutic target in AD, suggesting sleep disturbance as a predominant  symptom  and  a  clinical  marker for AD, and establishing an association with well-defined markers for AD such as increased levels  of A?42  and  hyperphosphorylated  Tau(Table 1).

Research papers on orexins and DA describe the relationship between increased   levels of orexins in  CSF and the presence of sleep disturbances, such as: poor performance in REM sleep, impaired sleep structure and efficiency from the patients. In addition, these alterations are related to increased levels of DA precursors such as A?42 and Tau, even in early stages such as MCI or preclinical stages in patients with cognitive complaints.(43,53)

The studies reviewed reflect a greater alteration in orexin-A in patients with AD compared to frontotemporal dementia, dementia with Lewy bodies or neurological pathologies such as basal cortical degeneration, reporting elevated levels of orexin that correlate with the presence of A?42 and Tau(54-56). Orexin-A levels have also been compared in cognitively healthy older adults and patients with AD, finding a positive correlation between elevated levels of A?42, total Tau and phosphorylated Tau(26,30). Other studies have found high levels of orexin in AD have no relation to a pathological increase in A?42 or Tau(57,58), but they do identify sleep disturbance and increased orexin levels as risk factors in AD.(43)

Neuropathological research has also confirmed that orexins and AD biomarkers are related. The study of 13 brains of patients with: Early-onset familial AD (n=7) and late-onset AD (n=6) showed a decrease in orexin receptors in the hippocampus, in the horn of ammonis (“ram horn”) (CA1) and the GPR103 receptor, which has a similar function to orexins in patients with AD and was related to the accumulation of amyloid plaques and the presence of hyperphosphorylated tau. This study confirms, on a pathological level, the importance of orexin alteration  and  proposes  them  as  a  therapeutic target for patients with AD(59)  and thus to know the dynamics of A? for future clinical trials.(18)

Another explanatory proposal for the bidirectional relationship between orexins and DA precursors establishes that both sleep disturbance and increased orexin levels are risk factors for AD; the presence of pathological levels of A? and Tau, proteins  associated  with  neurodegeneration  in AD, affects the process of clearing brain residues (glymphatic system) and alters the orexin system, which leads to characteristic sleep disturbances in AD.(45,60,61)

DISCUSSION

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The present research focused on the literature review, of the last five years, which addresses orexins as possible biomarkers in AD and their relationship with SNP from a brief theoretical exploration, and the review of clinical studies in cognitively healthy older adults and patients with DA. In first place, an indirect relationship between DA biomarkers, orexins and SNPs(16,17,54,55,58)   was found. It has advanced in the neurobiological description but is persistent in divergent findings. The most studied SNP are sleep disturbance and the disruption of the circadian cycle(41,45), although anxiety, depressive symptoms, stress response(18), appetite disturbance and addictive behaviors(74) have also been reported.

Secondly, the approach of orexins as possible biomarkers in AD is recent and the main discovery is their relationship with increased levels of total A?42 Tau and phosphorylated Tau. Clinical studies are still insufficient to determine the diagnosis and prognosis value of measuring orexins in patients with AD, and their association with the presence of SNPs.

In order to analyze the first finding of this review, the involvement of brain areas such as the hypothalamus and hippocampus in the presence of SNPs and the alteration of orexins in AD should be discussed. The hypothalamus is crucial in maintaining the body’s homeostasis, in actions such as the regulation of food intake, weight, body composition, metabolic activities, and behavior regulation.(28,62)

The presence of A? and Tau in the hypothalamus has been described in postmortem studies of brain tissue from patients with AD, as well as hypometabolism in patients with sleep disturbances, posing it as being  responsible  for  non-cognitive  symptoms of AD, due to the disconnection with the limbic system in these patients(29). Although this proposal does not directly associate the presence of SNPs with orexins and AD, the involvement of the limbic system in neuropsychiatric pathologies is known and it is a brain area involved in the neurobiology of SNPs in AD (53); furthermore, this system is a candidate for the treatment of SNPs.(63)

Among the functions of the hypothalamus and the orexin system, there are also projections of excitatory signals to dopaminergic areas of the ventral tegmental area, substantia nigra, amygdala, frontal, and prefrontal cortex(18,64). Therefore, it is suggested that these systems are related to the presence of other SNPs related to mood, such as apathy, depression, impulsivity, appetite regulation and behavioral alteration. However, it does not explain the presence of all SNPs, such as psychosis or agitation. This might be due to the fact that SNPs in AD have a multifactorial etiology and these symptoms are associated with alterations in other systems such as cholinergic, serotonergic or glutamatergic.(65)

Orexin activity also facilitates synaptic plasticity in the hippocampus and improves cognitive function, although its function is not well understood(62). It is proposedthattherhythmicactivityofthehippocampus may be altered with orexin dysregulation, especially in patients with AD(66). In murine models, orexin receptor blockage has been associated with anxiety symptoms and memory failures.(18)

The functions of the hypothalamus and hippocampus do not unidirectionally affect the orexin system or the A? and Tau biomarkers, but instead,   an   interaction   between   these   systems is proposed. AD is related to the presence of neurodegeneration  and  elevated A?  and  Tau,  as well as a decrease in orexin OXR receptors,  which consequently alters this system. Additionally, we can find hypometabolism in the hypothalamus and damage in the hippocampus, which are main features of AD. However, the action pathways between these brain areas are still unclear in terms of which of

them initiates the neurodegeneration process. The presence of SNPs may be due to an alteration in the rhythm of hippocampus and the hypometabolism of the hypothalamus due to the neuropathology of AD, likewise the alteration in these brain areas initiates the accumulation cascade of A? and Tau in the neocortex, in addition to the alteration of the orexin system generating the presence of SNPs (Figure 1). A hypothalamus-hippocampus axis could even be considered given their relationship(29), although this approach needs further research.

Figure 1. Interaction diagram between Alzheimer type dementia levels  of orexins and presence of neuropsychiatric symptoms. NPS: Neuropsychiatric symptoms

 

CONCLUSION

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The alteration of the orexin system is present in cognitively healthy older adults and those with dementia(67), especially AD(18,43,45,60), suggesting that it is a system involved in aging and neurodegeneration(17,18,64). The association between the orexin system and pathological levels of A? and hyperphosphorylated Tau(18,29,43), state that this system is susceptible to evaluation and monitoring, and consequently, a plausible candidate as a biomarker in AD.

At the same time, orexins are useful to be able to understand biological mechanisms of regulation of A? and Tau, through brain areas such as the hippocampus and hypothalamus(17,18,67) and offer a great opportunity for their study as target therapies for AD, SNP and cognitive impairment in AD(18), in other psychiatric pathologies(68-70) or anxious symptoms.(31)

More clinical studies are necessary to understand the mechanisms that bidirectionally affect orexins, neuropathology in DA and SNP, since evidence suggests that there are multiple components involved, including sleep disturbance, circadian cycle, glymphatic system, orexins and inflammatory processes(60). The study of the relationship between orexins and dementia is recent and is mainly focused on sleep disturbance as a risk factor related to aging and the development of neurodegenerative pathologies, including AD(71). This line of research is gaining great interest in the areas of genetics(72) neuroimaging and metabolic studies(73) that report alterations in orexinergic neurons in specific areas of the brain.

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