Altered mental status pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo, M.D., Pratik Bahekar, MBBS [2]
Overview
Altered mental status is a state of a variety of diseases, hence, there is no single pathophysiology mechanism. Although, the neural science behind alertness, wakefulness, and arousal are not fully understood, it is known that the reticular formation plays an important role in these.
Pathogenesis
Altered mental status is a state of a variety of diseases, hence, there is no single pathophysiology mechanism. It is known that the reticular formation plays an important role in the state of alertness. We explain the most important subtypes of altered mental status:
Dementia
Alzheimer's disease
While the pathogenesis of AD remains unclear, It is thought that dementia is the result of:
- Neuronal loss.[1][2][3]
- Overproduction and/or decreased clearance of amyloid beta peptides.[4][5][6]
- Accumulation of neurofibrillary tangles (tau proteins).[7][8]
- Production of oxygen radicals and nitric oxide, and inflammatory processes.[9]
- Decreased levels of cholinergic neurotransmission.
- Over-excitation of the glutamate neurotransmitter system via N-methyl-D-aspartate.
Parkinson's disease
The pathogenesis of Parkinson's disease is a depletion of dopamine due to the following mechanisms:
- Protein misfolding with decreased function and plasticity.[10][11][12]
- Defective proteolysis with aggregation of this protein and neuronal death.[13][14][15]
- Mitochondrial dysfunction with the following cell damage.[16][17][18]
- Oxidative stress with the following neuronal damage.[19][20]
- Iron metabolism with following increase of storage in the substantia nigra.[21][22][23]
- Immunologic and inflammatory mechanisms due to infiltration of CD4+ T cells.[24][25]
Delirium
Delirium is caused by a broad spectrum of diseases and clinical problems. Among the hypothesis of delirium developement are:
- Neurotransmitter hypothesis. A decreased oxidative metabolism in the brain may cause a reduced cholinergic function, excess release of dopamine, norepinephrine, and glutamate, and both decreased and increased serotonergic and γ-aminobutyric acid activity may underlie the different symptoms and clinical presentations of delirium.[26][27][28]
- Inflammatory hypothesis. Stress causes the release of cytokines which may directly damage the brain or affect neurotransmitter synthesis.[29][30][31]
Genetics
Dementia
Alzheimer's disease
Early onset (Alzheimer's dementia-AD 1, 3 and 4)
30-50 percent of early-onset Alzheimer's dementia (AD) is associated with an autosomal dominant inheritance and consists of mutations in the following genes:[32][33]
- Presenilin1 (PS1) gene, also called PSEN1 gene on chromosome 14 (20-30% cases)
- Presenilin 2 (PS2) gene, also called PSEN2 gene on chromosome 1 ( rare)
- Point mutations in amyloid beta A4 protein gene, also called amyloid precursor protein (APP) gene on chromosome 21 are associated in some cases of early onset (< 65 yr) familial AD cases
Late onset (Alzheimer's dementia -AD2)
- Apolipoprotein 4 gene (APOE4) mutation is associated with late onset (>60 years) Alzheimer's dementia (AD)[34]
- p.Arg47His allelic variant in TREM2 gene[35]
Parkinson's disease
Some of specific genes involving in PD are:
- Glucocerebrosidase gene [36]
- SNCA-associated PD [37]
- LRRK2-associated PD [38]
- Parkin-associated PD [39]
- PINK1-associated PD [40]
- DJ-1-associated PD [41]
Delirium
The genes that may be used as risk biomarkers for the developement of delirium are the following:
- Polymorphisms in the receptor DRD2 and dopamine transporter genes (rs6276, rs6277, and rs2734839)[42]
- Homozygous AA genotype of rs393795 in the SLC6A3 gene[43]
- APOE4 polymorphism[44]
- Reduced expression of miRNA-124 which results in decreased Ku70[45]
Associated Conditions
The most important conditions/diseases associated with altered mental status include:
- Stroke
- Metabolic imbalances
- Traumatic brain injury
- Fever
- Infections
- Lung diseases (e.g. cancer)
- Chronic or terminal illnesses
- Miocardial infarction
Gross Pathology
Dementia
Alzheimer's disease
The most important characteristics of Alzheimer's disease on gross pathology are:
- Temporal atrophy (especially in the hippocampus)
- Dilation of ventricles
Parkinson's disease
The most important characteristics of Parkinson's disease on gross pathology are:
Delirium
There are no characteristic gross pathology findings in dementia.
Microscopic Pathology
Dementia
Alzheimer's disease
The most important histopathological characteristics of Alzheimer's disease are:
- Neurofibrillary tangles: Consists of tau, location in the hippocampus, cerebral cortex, hypothalamus. Dementia severity correlates better with neurofibrillary tangles number rather than senile plaque number
- Senile plaques or the neuritic plaques consists of two components which are A-beta amyloid which radiate from the center and the neurites with swollen axons. Senile plaques are considered to be more specific for alzheimer's than neurofibrillary tangles
- Loss of neurons
- With or without cerebral amyloid angiopathy
Parkinson's disease
The most important histopathological characteristics of Parkinson's disease are:
- The pathologic hallmark of PD is the presence of lewy bodies, which are round cytoplasmic eosinophilic inclusions. The content of these bodies are mostly alpha synuclein and ubiquitin, but we can also find complement proteins, microflament subunits, and parkin substrate protein.[46]
- The pathologic manifestations of apoptosis include condensation of chromatin and cytoplasm, fragmentation of cell and lysosome-mediated phagocytosis.[47] Neuronal apoptosis occurs in normal individuals (0.5 percent of substantia nigra neurons) but in PD patients this can be as high as 2 percent.[48][49]
Delirium
There are no characteristic histopathological findings in delirium.
References
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- ↑ van Munster, Barbara C.; Aronica, Eleonora; Zwinderman, Aeilko H.; Eikelenboom, Piet; Cunningham, Colm; de Rooij, Sophia E.J.A (2011). "Neuroinflammation in Delirium: A Postmortem Case-Control Study". Rejuvenation Research. 14 (6): 615–622. doi:10.1089/rej.2011.1185. ISSN 1549-1684.
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- ↑ Ely, Wesley E; Girard, Timothy D.; Shintani, Ayumi K.; Jackson, James C.; Gordon, Sharon M.; Thomason, Jason W. W.; Pun, Brenda T.; Canonico, Angelo E.; Light, Richard W.; Pandharipande, Pratik; Laskowitz, Daniel T. (2007). "Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients*". Critical Care Medicine. 35 (1): 112–117. doi:10.1097/01.CCM.0000251925.18961.CA. ISSN 0090-3493.
- ↑ Zhu, Fei; Liu, Jing-Li; Li, Jing-Pin; Xiao, Fang; Zhang, Zhao-Xia; Zhang, Lei (2013). "MicroRNA-124 (miR-124) Regulates Ku70 Expression and is Correlated with Neuronal Death Induced by Ischemia/Reperfusion". Journal of Molecular Neuroscience. 52 (1): 148–155. doi:10.1007/s12031-013-0155-9. ISSN 0895-8696.
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