UNIVERSIDAD AUTÓNOMA DE CHIAPAS

FACULTAD DE MEDICINA HUMANA

DR. MANUEL VELASCO SUÁREZ

Módulo II

“EL HOMBRE SANO Y SU ENTORNO II”

BIOQUÍMICA MÉDICA

Dra. Teresa Dávila Esquivel

NEUROTRANSMISORES EN LA ENFERMEDAD DE PARKINSON y ALZHEIMER

DAVID OCTAVIO LÓPEZ MUÑOZ E191082

FERNANDO JÍMENEZ LÓPEZ E191108
KEVIN LÓPEZ DAMIÁN E191013
JUAN CARLOS LÓPEZ RAMÍREZ E191003
ALEJANDRA MONTSERRAT CONTRERAS ROLÓN E191012
LISSETH CAROLINA LÓPEZ NIÑO E191140
RUBEN CASTELLANOS VERDUGO E191124

2° “B”

TUXTLA GUTIERREZ, CHIAPAS A 12 DE NOVIEMBRE DE 2019

ALZHEIMER'S DISEASE
ABSTRACT: The objective of this article
is to review the current state of the art in
neurotransmission in Alzheimer's disease
(AD) and its participation in the
pathophysiology of the disease since it is
a neurodegenerative disorder that is
estimated to affect 15 million of people
around the world. Since the EA
cholinergic hypothesis was presented 20
years ago, numerous studies have been
conducted made in an attempt to
determine the role that neurotransmitters
play in AD. Among other things, this has
made posible to develop medications
based on the inhibition of
acetylcholinesterase.
Monoaminergic neurotransmission
systems are examined, with special
attention to the cholinergic system and its
anatomical distribution, function,
receptors, activity and degradation
systems are also described. Peptidergic
neurotransmission systems are only
briefly analyzed, since they are not the
main objective of this report. We also
review the cholinergic hypothesis and the
possible interrelationships between
cholinergic neurotransmission and β-
amyloid metabolism, as well as the
possible involvement of
acetylcholinesterase inhibitory drugs in
more fundamental pathophysiological
mechanisms, which act with a and serotonergic activity in AD.
neuroprotective component.
INPUT: Alzheimer's disease (AD) is a
progressive neurodegenerative disorder.
The brain regions that are associated
with superior mental functions,
particularly the neocortex and the
hippocampus are the most affected by
the pathological characteristics of AD.
This includes extracellular deposits of
βamiloid (derived from the amyloid
precursor protein) in senile plaques,
intracellular formation of neurofibrillar
clews (containing an abnormally
phosphorylated form of a microtubule
associated with the tau protein) and loss
of neuronal synapses and pyramidal
neurons. Although the cause, there have
been great advances during the last
years that have improved our
understanding of the factors Genetic and
environmental of this disease.
Neuropathological and biochemical
changes of AD can be divided into two
general groups: structural changes and
alterations in neurotransmitter systems In
this article we are going to refer to the
latter.
COLLINERICAL SYSTEM: Acetylcholine
(Ach) was the first neurotransmitter
identified in 1914 for Nobel laureate
Henry Dale. The investigation
Biochemistry of the brains of patients with
AD began in the late 1960s and early
1970s. In 1974, David Drachman found
that using scopolamine, an Ach
antagonist, caused a clear memory deficit
in subjects healthy, very similar to that
observed in patients with AD. In those
years it was discovered that there is a
marked reduction, of up to a 95%
according to series, of cholinergic activity,
and to a lesser extent of noradrenergic
Subcortical corticopetal systems:
From an anatomical point of view, the
anterior cerebrobasal system is
constituted by the nuclei of the basal
forebrain (Ach), rafe nuclei –serotonin–,
locus coeruleus –noradrenaline (NA),
adrenaline (A) - and black substance –
dopamine (DA) -, which in turn constitute
the so-called inn unnamed substance,
located caudal to the pale globe. These
nuclei receive dopaminergic, serotonergic
and noradrenergic projections of other
brain structures (midbrain,
peripeduncular nucleus, tonsil and
hypothalamus). The neurons responsible
for the cholinergic transmission project
their axons to innervate the
hippocampus, the amygdala and the
frontal, parietal cortex, Temporary and
occipital. These neurons and, especially,
those of the nucleus of Meynert, contain
CAT (cholinecethyltransferase) and ACE
(acetylcholinesterase), enzymes
responsible for synthesis and hydrolysis,
respectively, of Ach. There are also
neurons in the brainstem, rostral part,
which constitutes the pedunculopontin-
thalamus-cortic-reticulum-nigral system.
The third intraneuronal cholinergic
system is found in the striatum, and
through the Base nodes are directed to
the frontal cortex.
The cerebrobasal system is responsible
for keeping the cerebral cortex operative,
and plays a decisive role in the memory
processes and selective attention. The
corticostriatal loop controls the processes
of perception, learning, knowledge,
affectivity, judgment and REM sleep.
Cholinergic axons exert their effects
through two types of cholinergic
receptors: muscarinic receptors (M) and
nicotinic receptors (N). The M receiver is
a pentamer formed by four different
subunit types α2βγδ. These Subunits
have considerable sequence homology
(40-65%) and tertiary structure. Each
subunit has four helix segments through
the membrane (M1 to M4) arranged
around the central axis of the pore
(formed by the propellers M2 of each). It
has a central pore with a maximum
diameter of 2.5 mm which is the cationic
channel, which opens when The receptor
binds two Ach molecules cooperatively.
Currently, five different subtypes of M
receptors are known, and the highest
density of them is found in the striatum
and in the hypothalamus The density is
intermediate grade in the amygdala, the
hippocampus and cerebral cortex, and
minimal in the cerebellum.
N receivers belong to a channel
superfamily ionic ligands associated. It is
a pentameric unit, and although the
combination of several subunits can
produce several subtypes of N receptors
(nAChR), the family of N receptors can
be separated into three functional
classes: nAChR muscle (α1, β1, δ, ε, γ),
heteromeric neuronal receptor nAChR
(α2-α6 and β2-β6) and homomeric
nAChR (α7). Presynaptic and pretermal
receptors increase the release of
neurotransmitter, and postsynaptic N
receptors mediate a small minority of
rapid excitatory transmission N7
receptors are presynaptic, activate
calcium input currents, influence the
release of glutamate, 5HT, γ-
aminobutyric acid (GABA) and ACh.
N4β2 N receptors are postsynaptic and
exert an excitatory postsynaptic activity.
Further, some subtypes of N receptors
play a role in the synaptic and developing
plasticity.
Ach is the most important modulating
neurotransmitter in the brain, and its
distribution is complex and extensive if
compared with that of NA, DA and
serotonin. The cholinergic presynaptic
neuron is responsible, through CAT, for
synthesizing Ach a starting from choline
by the action of acetylcoenzyme A. After
being released into the synaptic cleft,
through an action potential, It binds to the
pre and postsynaptic M and N receptors.
At the postsynaptic level the stimulus is
transmitted through diacylglycerol, the
inositol and calcium dependent protein
kinase. The enzyme responsible for the
metabolism of Ach, is together with ACE,
butyrylcholinesterase that is synthesized
in the glia and participates in the
degradation of Ach in choline and
acetate. Bliss enzyme abounds in the
medial temporal cortex, in the amygdala
and in the hippocampus Unlike the rest of
the brain where the Primary form of
cholinesterase is ACE, in the amygdala
and in the hippocampus is
butyrylcholinesterase. CAT is found only
in presynaptic cholinergic neurons, while
the ACE is found in presynaptic and
postsynaptic cholinergic pathways.
A decrease in central acetylcholinergic
activity was observed in the first studies
conducted in the 1980s on AD. The
figures that were handled in relation ith
this reduction in activity they range
between 50-95% according to the series,
up to 90% for hippocampus and temporal
cortex and 80% for the frontal cortex of
convexity and orbital.
Such cholinergic depletion, which occurs
mostly in the layers superficial II and III, it
is bilateral and symmetrical, mainly
affecting areas 20, 21, 22 and 28 of
Brodmann. From a quantitative point of
view, it has been shown that in EA the
number of postsynaptic Ach receptors is
normal or moderately diminished and that
there is a selective reduction of
presynaptic receptors. In different
studies, has appreciated a marked
reduction in CAT activity in the amygdala,
hippocampus and cortex equivalent to
ACE reduction. In others it was also
found that there was a greater loss of
CAT in the temporal cortex and in the
hippocampus and, at the subcortical
level, in the tonsil and in the unnamed
substance. Unlike the previous one,
different works have shown that
butyrylcholinesterase is increased in AD.
SEROTONERGIC SYSTEM:
Approximately only 1-2% of serotonin is
found in the brain. The rest is located in
platelets, mast cells and chromaffin cells.
Cerebral serotonin is synthesized by
hydroxylation of tryptophan and
subsequent decarboxylation of it. The
neurons that contain this neurotransmitter
are located near the midline (regions of
the raphe) of the brainstem, mainly in the
bulge. Cortical serotonergic maps have
poorly defined patterns, and the main one
Serotonin effect is inhibition. The
reduction of serotonergic activity in AD
has been observed, but also that in the
previous hypothesis it is possible that
said alterations of postsynaptic 5-HT
receptors are due to cholinergic
denervation itself.
NORADRENERGIC SYSTEM: 2,3-
norepinephrine is synthesized in the
brain, in cells chromaffin and in the
sympathetic ganglia and nerves from a
precursor called tyrosine by the action of
the enzyme tyrosinehydroxylase (TH),
forming 3,4-dihydroxyphenylalanine
(DOPA). DOPA-decarboxylase leads to
the formation of DA that at through
dopamine-β-hydroxylase (DBH) and
phenylethanolamine-N-methyl
transferase produces NA. Neuronal
bodies Noradrenergics are located in the
locus coeruleus and in the lateral
tegment. From here three tracts are
formed that innervate the cerebral cortex
and whose main effect is the inhibitor.
The noradrenergic neurons of the lateral
tegmental system innervate the entire
NEUROPEPTIDES: The
septum and the amygdala. Although
somatostatinergic neuron receives direct
since 1996 it is known that there is an
interference from the cholinergic neuron,
alteration of the noradrenergic system in
which synapses on it in the cortex
the EA, subsequent work has been
cerebral. The action of the cholinergic
controversial. There is a neuronal loss in
system on the release of growth hormone
both the locus coeruleus as in the nuclei
(HC), action is well known which is
of the raphe, in which pathological
augmented by cholinergic agonists such
abnormalities such as neurofibrillary
as pyrdostigmine. Regarding the
tangles are observed. A comparative
eurotransmitters that influence the
study conducted in patients with AD and
release of HC, it is known that DA favors,
subjects healthy about the activity of DBH
by an indirect mechanism, the release of
and the neurons of the locus coeruleus,
this hormone. The stimulus of Adrenergic
found that the activity of this enzyme,
receptors decrease their levels, Ach
involved in the synthesis of NA, did not
inhibits its secretion and serotonin
correlate significantly with the number of
increases it.
neurons of the locus coeruleus, although
there was a tendency to decrease the
activity of said enzyme with respect to the
increase in the number of senile plaques. PHYSIOPATHOLOGY: At the end of the
Others authors have shown a reduction seventies, the interest aroused discovery
of almost 40% of the DBH activity. Given that patients with AD presented a
this, it is thought that the noradrenergic significant reduction of CAT and Ach in
alteration could be a late change in the the hippocampus and in the neocortex.
EA. This reduction in the ability to synthesize
Ach was attributed to the loss of neurons
in the basal nuclei from Meynert. These
studies, along with the emerging role of
DOPAMINERGICAL SYSTEM: DA is
the Ach in learning and memory, led to
involved in motor activity, emotion and
generate the hypothesis cholinergic AD.
motivation. Participate in the long tracks
During the last years since the origin of
(nigroestrial system, mesocortical
this hypothesis, data from different
system, mesolimbic system and
studies have gone changing it as an
diencephalospinal system), in addition to
explanation of the EA.
intermediate or short and ultra-short.
Dopaminergic alterations are not as First, we must bear in mind that there is
constant nor consistent as in the other controversy over the chronology of
monoaminergic systems. The neurochemical changes, since that some
modifications described are scarce and authors suggest that these are more
appear mainly in patients with marked in the early onset EA forms, while
extrapyramidal symptoms associated and others propose that it is unlikely that
not clearly related to symptomatology cholinergic markers could be early
cognitive. indicators of AD, since the reduction in
the activity of this enzyme occurs
gradually throughout of the illness. nicotine isomers to visualize the
Although it has been commented that the receptors, and the reduction in AD has
findings in the initial works they could be been confirmed, unlike M receptors,
interfered by the pharmacological which have not been reduced using this
treatments used in the symptomatic technique.
therapy of patients with AD, subsequent
The brain has a mechanism to accelerate
studies carried out post mortem having
the clearance of the accumulation of β-
healthy subjects as controls did not show
amyloid, and it seems that one of the
substantial changes.
physiological mechanisms to maintain
constant levels of β-amyloid is through
muscarinic stimulation. A Work on
Patients with severe AD have ACE and
transgenic mice, while being tested for
CAT levels 85-90% lower than normal,
immunization therapies, has shown a
while the enzyme butyrylcholinesterase is
similar effect, that is, a marked reduction
increased, possibly due to the increase of
in amyloid loading using a type of
synthesis or gliosis. It is known that in
cholinesterase inhibitors. In the
certain neurons, the enzyme that is most
hypothesis of the amyloid cascade of AD,
deficient is not ACE, but the
it is proposed that the wrong metabolism
butyrylcholinesterase, although the
of the amyloid precursor protein and
function of these neurons is not e knows
increased production of β-amyloid is the
still well. It has been found in several
critical initial event in AD. The cholinergic
laboratorios that both ACE and
neurotransmission can be a specific
butylrylcholinesterase are added in senile
target for β-amyloid, as demonstrated by
plaques, along with β-amyloid, and it has
a reduction in vitro of choline load and
also seen the existence of both enzymes
release of Ach. Studies in cell lines and
in the balls.
primary neuronal cultures have observed
that the activation of M receptors,
glutamate metabotropic receptors and
With respect to cholinergic receptors, a other phospholipase C linked receptors
study showed that there is a clear favor the non-amyloidogenic processing
decrease in the activity of CAT related to of the precursor protein of amyloid. On
AD and a subtle increase in binding to M the other hand, there are works in which
receptors, which may represent a the neurotoxicity of β-amyloid could be
compensatory mechanism. In AD, there attenuated by activation of M receptors.
is a significant reduction in density of N
receptors, unlike the overall density of M
receptors that remain relatively stable.
It has been observed that
However, the density of the M2 receptor
phosphorylation of the tau protein, step
seems to be diminished, while that of the
important in the formation of neurofibrillar
M1 remains stable, although its function
clews, can be influenced by a second
could be altered and the density of the
messenger system of phospholipase C.
M3 is normal or increased. It seems that
After stimulation of the M receptors,
the M2 are mainly in the presynaptic
activates a protein kinase C, which leads
button and can have a self-regulating
to the inactivation of the GSK-3 protein
function and the M1 are fundamentally on
kinase, which phosphorylates the tau
the postsynaptic side. The nicotinic
protein. Culture neuronal cells
system has been studied by PET, using
transfected with M1 receptors show a
reduction in tau phosphorylation after
treatment with cholinergic agonists. The
central role of amyloid in the onset and
progression of the EA is still not fully
understood, and the validity of the
Amyloid cascade hypothesis is still
discussed.
acetylcholinesterase inhibitors. Taking
into account the interactions that exist
between neurotransmitters, the amyloid
precursor protein and the
neuropathological characteristics of the
EA, it is not uncommon to consider
whether procolinergic drugs could have a
neuroprotective effect on the evolution of
disease.

The secretases that are responsible for

the proteolytic processing of the amyloid
precursor protein are α, β and γ-
secretase. Α-secretase has been
identified as disintegration and
metalloprotease ADAM 10 and ADAM17
or TACE; β-secretase, such as BACE1
and BACE 2, and γ-secretase, such as
PS1 and PS2. Α-secretase acts as a
zinc-dependent metalloproteinase, which
cuts the amyloid precursor protein in non-
amyloidogenic fragments, thus
preventing its deposition and therefore
the formation of amyloid plaques
Although the cells contain a certain basal
level of α-secretase activity, proteolysis
by this enzyme can be enhanced by
activators of protein kinase C. In addition,
the activation of receptors that work
through protein kinase C can increase
the activity of the α-pathway. -secretase,
of the amyloid precursor protein, with the
concomitant reduction in the processing
of β-secretase.

The agonists of metabotropic glutamate

receptors may increase the α-secretase
pathway. The muscarinic agonists (M1
and M3) they can decrease the
production of β-amyloid and this has
been seen in both in vitro and in vivo
studies. Many experimental research
studies have been conducted since the
cholinergic hypothesis was developed as
an explanation for AD, as well as
pharmacological studies with

PARKINSON'S DISEASE
ABSTRACT: Parkinson's disease is a
neurodegenerative pathology affecting
the mobility of patients, whose main
alterations are: tremor at rest,
bradykinesia, rigidity and postural
alteration. However, they are not the only
alterations that allow recognizing the
appearance of the disease, as there are
non-motor symptoms that have been
found related to this pathology, such as
hallucinations, mania and pain. The
antiparkinsonian treatment, focused on
improving the patient's motor condition
can leave non-motor damage that is often
ignored. Therefore, in this review we will
talk briefly about the non-motor
alterations that have been related to
Parkinson's disease.
INPUT: Parkinson's disease (PD) is
characterized by resting tremor, stiffness,
bradykinesia and loss of postural
reflexes, so James Parkinson described it
in 1817 as agitating paralysis. PD is
neurodegenerative and although its
etiology is still unknown, it is known that
the pathophysiological processes
triggered cause the loss of dopaminergic
neurons in the black substance (SN)
.Despite being considered a motor
disorder, this may be accompanied by
various clinical manifestations of non-
motor type, which accompany incipient
way to the development of the disease.
Therefore, EP is considered to include
motor and non-motor alterations. The
initial manifestations can be so mild, slow
and almost imperceptible that the patient
usually does not remember the exact
moment they began. The first motor
symptoms are a slight feeling of
weakness and tremor of some part of the
body, however it has reported that non-
motor type symptoms appear before the
motor and is the first to reduce the quality
of life of patients suffering from
Parkinson's disease. Therefore, it is
important to recognize the non-motor
manifestations associated with PD and
those caused by the drugs used in its
treatment, this in order to improve the
quality of life of both the sick and their
caregivers.
So far the treatments for PD have been
divided into two types: surgical and
pharmacological. He surgical treatment
consists of stimulation deep brain of the
internal pale globe (GPi) or of the
subthalamic nucleus (NST), resulting in
the decrease in motor alterations its
inconvenient is that only 5 to 10% of the
Idiopathic PD patients have a good
response to This surgery.6 Therapeutic
drugs to treat EP are divided into
symptomatic therapeutic drugs and
targeted therapeutics; therapeutic drugs
Symptomatic mainly include Levodopa
(L-dopa), DA receptor agonists
(ropinirole, pramipexole, rotigotine,
apomorphine, sumanirol, pyribedil and
bromocriptine), inhibitors of type B
monoamine oxidase (rasagiline,
selegiline) and catechol-O-
methyltransferase (entacapone)
inhibitors. L-dopa is the drug most
effective oral treatment for PD and may
reduce tremor and improve slowness and
stiffness.
However, despite the great benefit that
has been observed with the use of drugs
in the reduction of motor alterations of the the maintenance of the state of physical
disease, too there is evidence of physical integrity and mental illness, causing the
complications, mental and behavioral that loss of these capacities and the
arise as effects adverse for the same consequent deterioration to the quality of
drug treatment, as the appearance of life of the sufferer, as well as the people
dyskinesias reported even in 60% of who live with them.
patients treated with L-dopa, among
other adverse effects associated with
drugs that we will see later. The purpose
of this review is to describe the
characteristics and forms of presentation NEUROPHYSIOLOGY OF PD: The
of non-motor alterations in presented by basal ganglia are considered as a
Parkinson's disease patients, same which modulating center that regulates the flow
are not usually associated directly with of information from the cerebral cortex to
the disease considered alterations with the motor neurons of the spinal cord, but
less relevant or secondary to motor the information that travels through them
alterations not only covers the motor circuit. There
are four other attached circuits such as
the oculomotor, the dorsal prefrontal, the
lateral orbitofrontal and the limbic. In
PARKINSON'S DISEASE: Is a condition
general, one could say that the remaining
chronic and neurodegenerative slow
circuits also tend to function abnormally
evolution which affects the central
in the presence of PD. It should be said
nervous system, it has related to
that the circuit oculomotor has the
neuroinflammation9 and degeneration
function of orienting and directing the
premature, progressive and irreversible
view; the dorsolateral prefrontal and
of dopaminergic neurons of the black
lateral orbitofrontal are responsible for
substance, what which leads to the
processes cognitive and the limbic circuit
presence of motor disorders; this disease
of emotional aspects, which when altered
has a higher incidence among the 45 and
modify the functional homeostasis of the
70 years and turns out to be the second
patients.
most common neurodegenerative
disease after Alzheimer's disease. 90%
of cases usually occur sporadically and
the remaining 10% is usually of genetic Dopaminergic alteration in the striatum,
origin. as well as the appearance of Lewy
bodies in the locus coeruleus, the Rafe
nuclei, the thalamus and the tonsil can
affect the emotional dimension and the
As for the symptomatology, it usually
subjective perception of pain in the case
present 5 to 10 years before the
of visual hallucinations. Appearance of
appearance of the first obvious clinical
Lewy bodies in the occipital lobe has an
signs. To the whole of alterations present
important role; while the combination of
have been classified succinctly as motor
low levels of DA and norepinephrine in
alterations and non-motor alterations, all
the basal ganglia have been related to
of the manifestations of the disease, are
anxiety and alteration in the limbic
the expression of the deterioration of
system and cortical areas have been
different neurocircuits in the that
linked to depression.
necessary executive functions reside in
 pharmacological treatment is not saved
from being seen involved as a cause of
Dopaminergic disturbances that cause
alterations since generating excessive
motor disturbances in PD have been
stimulation of the D3 and D4 dopamine
studied for a long time. However, for non-
receptors of the mesolimbic system is
motor symptomatology (SNM),
attributed to the appearance of
homeostasis of some neurotransmitters
hallucinations.
has also been disturbed; as is the case
with glutamate, which has been related to
the appearance of psychosis, apathy,
Excessive stimulation of dopaminergic
hallucinations and other cognitive
receptors in limbic centers, such as the
modifications; The cholinergic system
nucleus accumbens and the medial
has also been linked to cognitive
prefrontal cortex have been linked to the
dysfunctions such as dementia and
appearance of visual hallucinations, this
amnesia; while dopaminergic neurons in
coupled with psychiatric processes that
the tegmental area have been associated
can be caused by the lack of
with sleep disturbances as well as
dopaminergic regulation, cholinergic
serotonin, which is also related to mood
deficits and Lewy body formation. In the
control; Another example is the
case of dysarthria, hypophony and
GABAergic system and that of
sialorrhea commonly presented by these
adenosine, which indirectly are
patients are usually attributed to
responsible for DA modulation and pain
bradykinesia and stiffness of the
control. On the other hand, neuronal
oropharyngeal muscles, as well as to the
receptors have been associated with
condition of the anterior ventral thalamus
some alterations, since due to the drugs
(VA) which does not send signals
consumed their function is modified, an
properly to the premotor cortex, which
example is the D3 dopamine receptors of
hinders the articulation and speech of
the limbic region in which it is believed
words. In the case of olfaction it has been
that the drugs that have them as White
found that the loss of mitral cells in
can give rise to manias presented by
conjunction with a decrease in substance
patients, as well as to addiction
P in the olfactory bulb could be part of the
behaviors. Not all causes are directly
reason for hyposmia or anosmia
related to brain chemistry; for example
presented in patients with PD.
some

NON-MOTOR SYMPTOMATOLOGY:
Patients present with neuro-ophthalmic
Non-motor symptomatology (NMS) even
alterations, such as conjunctival irritation
when it has a high prevalence in PD is
caused by decreased flickering reflection
only reported by 30 to 40% of patients,
and an altered tear film. Taking into
because these symptoms are not usually
account the above, it has been said that
recognized promptly by themselves.
the SN is also the cause of these
During the evolutionary course of PD the
alterations since it sends connections to
patient can present any of the two
the upper colliculus, which has the
existing stages in response to the
function of controlling saccadic eye
pharmacological treatment administered
movements, concluding that this circuit is
for the control of motor alterations, an
also altered in the EP. In these cases the
“on” period where motor alterations are
adequately controlled and a period "Off"
where there is no immediate response to
treatment. However, there is another
symp tomatology involved in PD that is
not of motor origin, for practical purposes
some authors have considered that the
manifestation of non-motor alterations is
also present with stages, considering as
periods "off" those in which the patient
presents anxiety, panic and low status in
the mood, while in the “on” stage he is in
a better mood and even has a mania, a
lower need for sleep and risk behaviors,
as well as increased interest and sexual
potency, pedophilia, paraphilias,
voyeurism, sadomasochism and
exhibitionism.
The SNM in PD is capable of impacting
the progression of the disease, since
these are manifested in the vast majority
of patients throughout the evolutionary
course of the disease, and often
represent the main complaints and
discomforts, so that these They play a
leading role in their quality of life. Among
the SNM that commonly occurs are
drooling, loss of taste and smell, difficulty
swallowing, vomiting and / or nausea,
constipation, fecal incontinence,
incomplete bowel emptying, urinary
urgency, nocturia, unexplained muscle
pain, change in unexplained weight,
memory impairments, apathy,
hallucinations, concentration problems,
sadness, anxiety, change in libido,
difficulties in sexual activity, dizziness,
falls, daytime sleepiness, insomnia, vivid
dreams, MOR sleep disorders (rapid eye
movements), restless legs syndrome,
edema, excessive sweating and
delusions, as well as behaviors addictive,
among others.
DEPRESSION: Studies have suggested
that depression is highly related to the
onset of PD and this is usually mild or
moderate with a rate of low suicide.
Some predisposing factors for presenting
depression are the onset of Parkinson's
disease at an early age, as well as being
in the most advanced stages of it, the
presence of stiffness in much of the body
and even belonging to the female sex. It
is considered that depression could occur
in response to the development of motor
symptoms, others report that It is due to
the dysfunction of circuits such as the
orbitofrontal and dorsolateral, or to a
hypometabolism of the caudate nucleus
and the frontal dorsolateral tract. What is
left without doubt is that its
symptomatology is common with the EP
itself.
ANXIETY: Anxiety disorders are a
condition hardly recognized by the patient
in stages prior to the diagnosis of
disease, and although more than 40%
experience clinically anxiety not always
the presence of one will determine the
mandatory appearance of the other.
Anxiety could be the earliest non-motor
manifestation of the disease, other than
being the most common disorder
developed after the onset of motor
symptoms. Anxiety in conjunction with
PD is most often found in women and
usually brings other alterations. It can
occur with agitation or chronic anxiety,
panic attacks and even as obsessive
compulsive behaviors.
HALLUCINATIONS: Hallucinations are
common complications of chronic
pharmacological treatment of diopatic
PD, which makes it more complicated to
select these to control motor disorders. It
is believed that hallucinations may be
due to dopaminergic and serotonergic
changes involving the black substance
and the Raphe dorsal nucleus, as well as
the loss Neural and Lewy body formation
in the temporo-ventral region of the brain
associated with cognitive disorders.
Other studies presume that visual
hallucinations could be due to an inability
to process visual stimuli in the visual
associative cortex. Currently, treatment
for hallucinations in patients with PD is
very limited since commonly used drugs
(antipsychotics) tend to increase motor
alterations derived from parkinsonism.
Hence the importance of seeking new
treatments that control these alterations
without affecting the rest of the systems
However, there are studies that have
described that it could not only be due to
the use of drugs, but also to the
progression of the same disease, since it
has been seen that high doses of
intravenous L-dopa do not precipitate the
appearance of hallucinations.
It has been found that visual
hallucinations are related to cognitive
impairment and other disorders such as
macular degeneration. It can also be
associated with altered states of
consciousness, attention deficit, memory
problems, sleep disturbances and
episodic agitation. As in other non-motor
alterations, hallucinations are poorly
reported by patients because the majority
are tolerable, or because patients are
afraid of being considered mentally ill,
making it more difficult to know the real
prevalence of this condition in PD.
APATHY: The presence of apathy,
characterized by indifference, lack of
motivational interest, is continually
expressed in patients with Parkinson's
disease, which makes it difficult to
manage and care. Three subtypes of
apathy are known: cognitive, emotional
and behavioral; according to the phase
that is altered in the decision making
process, which They depend on the
sphere they affect. In each of these
subtypes, there are affected neurological
pathways and to be addressed effectively
it is important that they be properly
diagnosed.
No evidence has been found that
treatment with L-dopa promotes the
symptoms of apathy; its origin has
associated with alterations in the
dopaminergic (nigroestriatal and
mesocortical), serotonergic,
noradrenergic and cholinergic, as well as
damage to the basal ganglia, infarcts in
the caudate body and in the anterior
cingulate. Because various drugs, such
as cholinesterase and amphetamine
inhibitors, are able to improve the
symptoms of apathy, it is believed that
there is no single mechanism causing it,
so it is important to identify the type of
apathy and its mechanism for Administer
the most effective treatments. Apathy,
anhedonia, anxiety and depression can
be so related that it is often difficult to
differentiate them, even though they can
be completely independent of each other.
MANIA: Lack of self-control and
impulsivity are non-motor symptoms that
have been observed in patients with PD.
Lack of self control and impulsivity, the
lack of inhibition of some behaviors can
be considered an antisocial behavior with
which not only patients are affected their
lifestyle, but also that of the rest of their
family. Alterations in hedonic
homeostasis which usually occur in PD
include disturbances in the control of
impulses by playing, buying, eating and From these results, it is inferred that
sexual appetite. these differences could be due to the
difficulty that patients present to inhibit
 
irrelevant stimuli, which function as
Impulse in impulses is usually a major interference when trying to evoke
problem in a small percentage of memories.  As for the structures involved
patients, in addition, it is believed that the in the memory impairment of patients
appearance of obsessive symptoms with PD, the caudate nucleus (a nucleus
occur in advanced stages of PD where of the basal ganglia involved) has been
no longer only the nigrostriatal pathways found in cognitive functions), as well as
are altered, but also striatocortical the prefrontal cortex which has shown a
projections.  Compulsive buyers usually decrease in dopamine, resulting in
receive higher doses of L-dopa to decreased memory for patients.
counteract the symptoms. Few patients
receive impulse control disorders when
receiving treatment from dopamine
agonists, so it should not be neglected to
PAIN: Pain is a symptom that has been
consider individual vulnerability factors
reported in approximately 50% of patients
such as patient impulsivity, age, gender
with Parkinson's disease, which has been
and serotonergic levels. However, in
categorized depending on the
treatments that involve Surgical
dopaminergic phase in which it occurs
intervention such as the stimulation of the
(maximum dose peak and the final dose
subthalamic nucleus that has been used
phase, or, according to its origin:
to reduce symptoms motor of PE, has
musculoskeletal, radicular or neuropathic,
been related to the appearance of
dystonic-postural and of central origin.
compulsions and obsessions.
Musculoskeletal pain can involve
alterations such as osteoarthritis, frozen
shoulder, postural alterations, scoliosis
MEMORY: One of the altered cognitive
and physical trauma.
functions in PD is memory, which can be
directly affected with the evolution of the
disease, profoundly changing the quality
This pain is a symptom that is usually
of life of those who suffer from it. In
worsened by the characteristic stiffness
memory tests against the clock, the
of PD, for which a pain loop is formed
patients obtained poor results with
that includes muscle stiffness, lack of
respect to the subjects controls, however,
movement and which is known to be
in the efficiency for solving problems,
related to involuntary muscle contraction
their memory is not altered, the same
and central pathways of pain processing
happens with prospective memory, which
consequently greater muscle stiffness
seems to remain intact. These tests
and can also be associated with other
suggest that patients with PD may have
symptoms such as dystonia.
difficulty evoking memories
spontaneously, and Your cognitive
flexibility may be diminished.
Another type of pain presented by
patients with PD is radiculopathy, which
consists of pain or stiffness directed at
some limb that comes from some spinal
root. In this alteration the pain is usually
distributed by legs and arms and it has
been seen to be related to the altered
dopaminergic transmission of the spinal
cord.  As for central pain, it usually
begins spontaneously with burning
sensations, burning and tingling, which
are usually more exacerbated on the
affected side. It has not been shown that
treatment with L-dopa reduces this type
of pain. However, there is pain of central
origin, as is the case of trigeminal
neuralgia, which usually disappears once
the corresponding dose of Ldopa is
consumed.
Other less common forms of pain
occurrence are "unspecified pain," in
which patients cannot accurately locate
which part of the body hurts, or if it has
muscular origin or due to some particular
movement.
SLEEPY: Research has revealed that
approximately 62% of Parkinson's
patients have sleep disturbances which
can be classified as primary if they are
due to alterations central anatomical, or
secondary if they are the result of the
pharmacological treatment itself. These
alterations can range from insomnia,
fragmented sleep disturbances during
sleep with rapid eye movements or MOR
sleep (reduction in stages III and IV and
eye movement with phasic tonic muscle
disorder during sleep), sleep apnea and
restless legs syndrome.
Pharmacological treatments can also
directly affect the quantity and quality of
sleep of patients, giving origin of daytime
sleepiness, sleep attacks, MOR sleep
disorder, vivid reveries and leg síndrome
restless.
Some authors have linked sleep
disorders with the appearance of
hallucinations in patients with PD.
BODY MASS: The most common causes
for weight loss in Parkinson's patients are
usually due to decreased appetite, either
as a result of depressive symptoms or
changes in the perception of flavors and
odors, also influencing the increase in
eating time and type of medication.
However, it has been reported that some
patients despite having a first period of
weight loss after being diagnosed, they
tend to regain their initial weight and even
increase it once they are
pharmacologically stabilize.
Another study notes that weight loss
begins earlier of the diagnosis of the
disease and that despite increasing
intake, energy expenditure begins early,
which can be intuit a metabolic defect in
these patients since the modification of
body weight correlates with the evolution
of the disease.
One of the alterations that entails the
decrease in body weight, is the loss of
bone mineral density and a lower body
mass index, resulted in the increased risk
of fractures. These characteristics have
been associated with a poor prognosis of
the disease.
SEXUALITY: Whether dysfunction or
hypersexuality, the alteration in sexual
behavior is something that has been
studied in PD, however, it remains
without Be explained at all. Studies have
shown that the disease is not related to
neurological damage that directly affects
the sexual response, however, a
decrease in the incentive value for sexual
behavior has been found with increasing
age, as well as after the onset of motor
symptoms.
Both motor and non-motor alterations
characteristic of PD can be the cause of
multiple behavioral alterations. Sexually
presented by patients. Excessive
increase in libido or hypersexuality has
been related to drug treatment, overdose pramipexole, which have been
of dopaminergic therapies, such as the associated with excessive atypical sexual
combination of L-dopa-carbidopa or thoughts or
behaviors, fantasies aberrant sexual, pedophilia, exhibitionism, development of
erectile dysfunction, premature genital mutilation, sexual promiscuity
ejaculation, difficulty getting orgasms,
and paraphilias, between others.

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