Neurocognitive Psychiatric and Neuropsychological Alterations in Parkinson's Disease: A Basic and Clinical Approach

Abstract

The main histopathological hallmarks of Parkinson's disease (PD) are the degeneration of the dopaminergic neurons of the substantia nigra pars compacta and the loss of neuromelanin as a consequence of decreased dopamine synthesis. The destruction of the striatal dopaminergic pathway and blocking of striatal dopamine receptors cause motor deficits in humans and experimental animal models induced by some environmental agents. In addition, neuropsychiatric symptoms such as mood and anxiety disorders, hallucinations, psychosis, cognitive impairment, and dementia are common in PD. These alterations may precede the appearance of motor symptoms and are correlated with neurochemical and structural changes in the brain. This paper reviews the most crucial pathophysiology of neuropsychiatric alterations in PD. It is worth noting that PD patients have global task learning deficits, and cognitive functions are compromised in a way is associated with hypoactivation within the striatum, anterior cingulate cortex, and inferior frontal sulcus regions. An appropriate and extensive neuropsychological screening battery in PD must accurately assess at least five cognitive domains with some tests for each cognitive domain. This neuropsychological screening should consider the pathophysiological and clinical heterogeneity of cognitive dysfunction in PD.

Keywords: Parkinson’s disease; cognitive dysfunction; genetics; neuropsychological tests; pathophysiology; psychiatric illness.

Figure 1

Death of dopaminergic neurons. Schematic representation of dopaminergic neuronal death associated with the generation of ROS in an uncontrolled way. 1. The pigment that gives color to dopaminergic cells is due to the oxidation of cysteinyl-DA products (dopamine that is not adequately removed works as ROS-generating molecules), products that interact with Fe+ forming a complex that activates the microglia and thereby generates the production of pro-inflammatory cytokines and the production of ROS, which induce the formation of alpha-synuclein fibrils. 2. Activation of microglia by the release of neuromelanin from pars compacta causes an increase in the sensitivity of dopaminergic neurons to oxidative stress; the dopaminergic neurons of the compact substantia nigra are more susceptible to ROS, which is why they more easily cause the death of this neuronal subpopulation in areas such as nuclei A9. 3. Decreased midbrain compact substantia nigra.

Figure 2

Mapranosis. Schematic representation of Friedland and Trudler’s proposal to explain neurodegeneration. Amyloid is secreted by bacteria resident in the nasal and intestinal epithelium, which causes neuroinflammation in two ways: 1. Misfolded Protein 1.1. Bacterial amyloid can cross seed with host beta-amyloid and alpha-synuclein. 1.2. This cross seeding induces the wrong folding of the alpha-synuclein due to prionic behavior; therefore, it extends through the vagus and olfactory nerve. 1.3. The new poorly folded endogenous proteins it disseminates reaches the CNS, causing neuronal death. 2. Induction of oxidative stress and neuroinflammation. 2.1. Bacterial amyloid is capable of inducing inflammation and oxidative stress. 2.2. Subsequently, there is cross sensitization against endogenous amyloid, which causes the immune system’s abnormal recognition of its epitopes, mounting a response directed against beta-amyloid and alpha-synuclein in the host’s CNS. 2.3. The sensitized immune cells reach the CNS through the hematogenous pathway, crossing the BBB, and activating the microglia, causing neuronal death.

Figure 3

Representation of the basal ganglia focused on cognitive functions. Ventrolateral circuit. 1. It begins in the ventrolateral frontal cortex, which is the first node of interaction with the posterior regions. It’s in charge of low-level control processes and involved in stimulus-driven recall and information retrieval from long-term memory. Lateral mediodorsal circuit. 2. It begins in the mediolateral cortex of the frontal cortex. It’s in charge of high-level executive processes and involved in the manipulation and monitoring of care and is in charge of creating organizational strategies. Abbreviations: GPe, globus pallidus pars externa; Gpi-ldm, lateral dorsomedial globus pallidus pars interna; GPi-mdm, medial dorsomedial globus pallidus pars interna; VApc, ventroanterior thalamic nucleus parvocellular part; VAmc, medialventroanterior thalamic nucleus magnocellular part.

Figure 4

Dopamine synthesis. Schematic representation of the synthesis of the neurotransmitter dopamine. 1. Produced from the amino acid tyrosine, which passes through tyrosine hydroxylase, which generates L-DOPA. This enzyme is the one that limits the production of dopamine (which is inhibited by high concentrations of its substrate tyrosine). 2. Transformation of L-DOPA into dopamine by the aromatic amino acid decarboxylase enzyme, which is found in a cytosolic way and is not active for the release with the action potentials. 3. Transport of cytosolic dopamine to vesicles via the vesicular monoamine transporter enzyme. 4. The potential action releases dopamine to the synaptic cleft, so it reaches its receptor and generates its function. These nerve terminals will be found in the circuits already mentioned in the text; however, we can find a tonic release at a frequency of 5 Hz, and another 10–15 Hz interburst release. 5. Extracellular dopamine will be metabolized by catecholamine O-methyl transferase and mono-amino oxidase towards homovalinic acid. 6. Presynaptic receptors will recapture unmetabolized dopamine for reuse. 7. Unmetabolized dopamine may bind to presynaptic receptors to block tyrosine hydroxylase. Abbreviations: Tyr, tyrosine; TH, tyrosine hydroxylase; AADC, aromatic acid decarboxylase; MAT, monoamine transporter; DAT, dopamine transporter; MAO, monoamine oxidase; COMT, catecholamine O-methyl transferase.

Figure 5

Summary of characteristic neuropsychiatric alterations in Parkinson’s disease.

Figure 6

Summary of the characteristic cognitive alterations in Parkinson’s disease.