Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2817_Библиотеки_им_академика_М_И_Перельмана.pdf
10
Oxidative stress in Parkinson’s disease
2
(
(
(
(
earlier onset than the sporadic form of the disease and
represents a minority of PD cases (∼15%). This research
has led to the identification of several genes associated
with inherited forms of PD—both autosomal dominant
and recessive forms. Missense mutations in the SNCA
gene encoding α- synuclein, and also copy number variations (duplication or triplication) in this gene, are associated with autosomal dominant forms of PD. Another
gene associated with autosomal dominant inheritance
is LRRK2, which encodes the protein leucine- rich repeat
protein kinase 2 (also named dardarin). Mutations in the
PRKN (encoding a ubiquitin ligase) and PINK1 (encoding a mitochondrial serine/threonine- protein kinase)
genes are examples of mutations associated with autosomal recessive forms of juvenile- onset PD. It is important to note that there are still many cases of familial
and early- onset disease with no known genetic cause.
The majority of cases of PD, which are the sporadic and
late- onset form of the disease, are not associated with a
clearly defined unique genetic determinant. Genomewide association studies (GWAS) have identified more
than 90 independent risk- associated variants, mostly
in patients of European ancestry, and much remains to
be understood about genetic risk for PD in other populations. GWAS and meta- analyses have shown that
sporadic disease- linked common variability exists at
loci, such as SNCA, LRRK2 and GBA1 (encoding glucocerebrosidase), all of which harbour disease- causing
mutations associated with Mendelian forms of PD. This
suggests a clear link between familial and sporadic forms
of the disease, especially in terms of commonality of
pathophysiological mechanisms. Although the loci identified through GWAS may confer a small risk in isolation,
summation of the impact of several loci makes it possible
to calculate a polygenic risk score for an individual, thus
creating future opportunities for genetics- informed personalized therapy in PD.
Progress in the genetics of PD has contributed to
advances in the characterisation of key processes
involved in the pathophysiology of the disease.
Dopaminergic cell loss in the SN occurs naturally with
increasing age, but is accelerated in PD. This may be
due to increased oxidative stress or selective neurotoxins, which may preferentially target dopaminergic cells
that are rich in neuromelanin. The oxidation of endogenous dopamine leads to the formation of H2O2 and
highly reactive free radicals (Fig. 10.6). Neuromelanin,
which gives nigral dopaminergic cells their characteristic
colour, is an oxidation product of dopamine. Postmortem
studies show evidence of oxidative damage and
decreased activity of complex I of the mitochondrial electron transport chain in the SN in PD. Patients also have
increased iron levels in the SNpc and a reduced concentration of the iron- binding protein transferrin, which
makes iron more available for oxidation reactions. There
is also evidence of increased lipid peroxidation in PD.
The reported development of severe parkinsonian
symptoms in young drug addicts following accidental
exposure to the toxin 1- methyl- 4- phenyl- 1,2,3,6-tetrahydro-
pyridine (MPTP) not only lends strength to a neurotoxic
MOTOR SYSTEMS II: THE BASAL GANGLIA
link in PD, through exposure to environmental neurotoxins, but has also highlighted the role of mitochondria
in PD pathophysiology. MPTP can be produced during
the synthesis of the opiate pethidine. MPTP is very lipophilic and crosses the blood–brain barrier (BBB) without difficulty. It is converted into a toxic metabolite, the
1- methyl- 4- phenylpyridinium ion (MPP+), through the
action of the enzyme monoamine oxidase type B (MAOB).
MPP+ is taken up by the plasma membrane dopamine
transporter into nigral dopaminergic neurons, and selectively destroys them by inhibiting complex I of the respiratory chain in mitochondria (Fig. 10.7). The administration
of MPTP in primates replicates all the clinical signs of PD
including tremor, rigidity, akinesia and postural instability.
The aggregation of α- synuclein in PD tissue indicates
a defect in proteostasis, that is, the cellular pathways that
control the formation, maintenance, trafficking and degradation of proteins. The function of this protein is not
well understood, but there are indications that it has a
role in synaptic vesicle dynamics, mitochondrial function and protein folding processes. α- Synuclein acquires
neurotoxic properties during the process of transition
from soluble monomeric forms, to oligomers and protofibrils, and ultimately insoluble mature fibrillary deposits.
The triggers for aggregation may be the overproduction
of protein or mutations that leads to protein misfolding. The cellular mechanisms that ensure degradation of
proteins, such as lysosomal- mediated autophagy or the
ubiquitin- proteasome system, may be deficient, especially in ageing, and this leads to impaired clearance of the
aggregates. Furthermore, there is evidence that aggregated
α- synuclein can be released by neurons and ultimately
propagated along axonal pathways, thus leading to a
widespread dissemination of pathology across the neuraxis. There is also evidence that α- synuclein aggregation
and mitochondrial dysfunction may exacerbate each other.
Neuroinflammation, and, in particular, microglial activation, is another element of the pathophysiology seen in PD.
There is evidence that neuroinflammation can exacerbate
protein misfolding. Interestingly, several genes associated
MAO
+ H2O 3,4-DHPA + NH3 + H2O
DA + O
a)
b)
c)
d)
Fig. 10.6 Oxidation processes in the basal ganglia. Examples of
reactions involving dopamine, leading to the formation of free
radicals, and oxidation of protective substances such as glutathione.
DA, Dopamine; H2O2, hydrogen peroxide; 3,4- DHPA, 3,4- dihydroxy
phenylacetaldehyde; OH−, hydroxyl ion; OH•, hydroxyl radical; GSH,
reduced glutathione; GSSG, oxidized glutathione; Fe2+, ferrous iron;
Fe3+, ferric ion; •O
SQ•, quinones.
2
–
DA + O
2
DA + •O
2
+ 2GSH GSSG + 2H2O
H
2O2
−
, superoxide radical; MAO, monoamine oxidase;
2
–
+ 2H
+2
SQ• + •O
+
OH• + OH– + Fe
+
+ H
2
SQ• + H2O
2
+3
H2O2 + Fe
209THE NERVOUS SYSTEM
10
Dopaminergic
neuron
Blood Brain
MAO
MPTP
Fig. 10.7 The fate of MPTP after systemic administration and mechanisms underlying its toxicity for dopaminergic neurons. DA, dopamine;
MAOB, monoamine oxidase B; MPP+, 1- methyl- 4- phenylpyridinium ion; MPTP, 1- methyl- 4- phenyl- 1,2,3,6- tetrahydropyridine.
MPTP
B
MAO
inhibitors
B
MPP
extraneuronal
MOTOR SYSTEMS II: THE BASAL GANGLIA
Mitochondrion
Inhibition of oxidative
phosphorylation
+
Inhibitors
of DA
uptake
+
MPP
intraneuronal
+
MPP
intramitochondrial
and/or
Induction of lipid
peroxidation
and/or
Disturbance of
calcium homeostasis
Fig. 10.8 Biosynthesis and metabolism of dopamine. L- DOPA, L- dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; COMT, catechol- O-
methyl- transferase; SAM, S- adenosylmethionine; MAO, monoamine oxidase.
with PD risk encode proteins involved in immune regulation, such as LRRK2. However, neuroinflammation can
play a complex role; microglia could phagocytose extracellular aggregates and clear complexes of antibody- bound
α- synuclein aggregates, which is the intended result of
immunotherapeutic interventions currently being explored
for this disease, as discussed below.
peutically useful. L- DOPA (levodopa), a precursor in
the biosynthetic pathway of dopamine (Fig. 10.8), can
be used to increase dopamine concentrations in the
deficient areas. After oral administration, L- DOPA is
absorbed into the systemic circulation through the
energy- dependent saturable activity of a neutral amino
acid transporter in the duodenum. The same transporter also facilitates the passage of L- DOPA across the
Treatment of Parkinson’s disease
BBB. In the brain, L- DOPA is taken up into dopaminer-
gic neurons and can be converted into dopamine in the
Pharmacological treatment of PD attempts to compensate for the loss of nigral dopaminergic cells and
the imbalance in input thus created in the striatum.
Dopamine replacement therapy has been the major principle of treatment for PD for more than five decades (Box
10.3). This therapy and other therapeutic approaches are
reviewed below.
remaining cells in the SN. It is important to note that
uptake of L- DOPA will also occur in other dopaminergic
cells, such as the cells of origin of the mesolimbic and
mesocortical dopaminergic pathways (see Fig. 10.9).
Conversion of L- DOPA into dopamine is catalysed
by an aromatic amino acid decarboxylase (also called
DOPA decarboxylase). This conversion occurs not only
in the brain but also at the periphery. The conversion
Dopaminergic medication
L- DOPA
Dopamine does not cross the BBB; therefore direct systemic supplementation with dopamine is not thera-
at the periphery can be blocked by co-administration
of a DOPA decarboxylase inhibitor such as benserazide
or carbidopa. L- DOPA can also be metabolized at the
periphery by catechol- O- methyltransferase (COMT).
The administration of L- DOPA with COMT inhibitors,
210 SYSTEMS OF THE BODY
Nucleus accumbens
Caudate–putamen
Amygdala
entral tegmental area
10
MOTOR SYSTEMS II: THE BASAL GANGLIA
Cingulate cortex
Prefrontal cortex
Olfactory tubercle
Arcuate nucleus
Fig. 10.9 Dopaminergic projections in the central nervous system.
A
B
Substantia nigra
V
Median eminence
Table 10.3 Complications of L- DOPA therapy
Motor fluctuations (end- of- dose deterioration, ‘on- off’
phenomenon, delayed or no ‘on’ responses)
Dyskinesias (‘on’- period dyskinesia, biphasic dyskinesias, ‘off’-
period dystonia)
Non-motor complications (tingling, pain, akathisia, autonomic
dysfunction)
Neuropsychiatric complications (hallucinations, delirium, mood
changes, hypersexuality, sleep fragmentation, nightmares)
Fig. 10.10 PET studies on [18F]6- L- fluorodopa accumulation in a
subject with Parkinson’s disease (Hoehn and Yahr stage 3). (A) A
scan after administration of L- DOPA without entacapone, (B) a scan
at the same level after administration of L- DOPA with entacapone.
Note that striatal uptake of fluorodopa is enhanced in the presence
of entacapone. (From Olanow C.W. et al. (2000). ‘Continuous
dopamine-receptor stimulation in early Parkinson’s disease.-’ Trends in
Neurosciences, 23(10 Suppl):S117-26.)
such as entacapone, opicapone or tolcapone, significantly
improves the central bioavailability of the precursor
(Fig. 10.10) and leads to fewer variations in plasma concentration. As other amino acids compete with L- DOPA
for intestinal absorption through the same transporter,
dietary protein intake can change the bioavailability of
L- DOPA.
life expectancy following diagnosis was approximately
10 years. L- DOPA has increased the quality of life, particularly in the early years of treatment, and improved
survival. L- DOPA remains the most efficacious antiparkinsonian drug. However, the use of L- DOPA is
associated with a wide range of unwanted effects and
Prior to the introduction of L- DOPA into clinical use,
long- term additional drug- induced problems: nausea,
vomiting, postural hypotension, hallucinations and paranoid delusions, and complex acute and delayed motor
complications, such as dyskinesias (abnormal involuntary movements) and the ‘on- off’ effect (Table 10.3).
Nausea and vomiting are due to conversion of L- DOPA
into dopamine at the periphery and activation of dopamine receptors in the chemoreceptor trigger zone (in the
area postrema in the medulla), which is outside the BBB.
This can be largely prevented by co-administration of
L- DOPA with DOPA decarboxylase inhibitors such as carbidopa or benserazide (in the case scenario, L- DOPA is
given to the patient with carbidopa). Nausea can also be
treated with domperidone, which is a dopamine receptor antagonist that does not cross the BBB. Hallucinations
are due to the increased production of dopamine in mesolimbic dopaminergic neurons. The motor complications
of long- term L- DOPA therapy are particularly disabling
(Box 10.4). The pathogenesis of late complications is only
partly understood. They occur in 75%–80% of patients taking L- DOPA for more than 4–5 years but can also occur
in patients taking it for less time than this. They do not
appear immediately after the initiation of L- DOPA therapy
211THE NERVOUS SYSTEM
10
but require chronic exposure to L- DOPA with intermittent dosing. Dyskinesias are subdivided into chorea- like
movements (hyperkinetic, purposeless dance- like movements) and dystonias (intense and sustained muscle
contractions). Peak- dose dyskinesia and wearing- off dystonias are due to fluctuations in the level of dopamine
produced intracerebrally after each dose of L- DOPA. The
‘on- off’ effect refers to dramatic fluctuations in motor performance, which are not always related to the intake of
L- DOPA. Patients experience normal mobility (‘on’) followed suddenly by total ‘freezing’ (‘off’). This has been
likened to switching a light on and off. The majority of
patients treated with L- DOPA for several years also experience an increasingly rapid wearing- off of the clinical
benefit after each dose of precursor, termed ‘end- of- dose
deterioration’. This may be due to the altered pharmacokinetics of L- DOPA, with exacerbations of peaks and
troughs in the concentration of dopamine produced and
changes in the sensitivity of dopaminergic receptors. In
MOTOR SYSTEMS II: THE BASAL GANGLIA
patients with marked motor fluctuations, benefit may
be derived from controlled- release forms of L- DOPA/
carbidopa or L- DOPA/benserazide, which compensate
for the short half- life of the standard formulation (Table
10.4). Their bioavailability is 70%–80% that of normal
L- DOPA/carbidopa or L- DOPA/benserazide combinations. To avoid fluctuations in its level, L- DOPA can be
administered continuously by intravenous or intraduodenal routes (using surgical percutaneous tube placement). Surgical intervention may also be attempted to
relieve L- DOPA- induced dyskinesia and dystonia (see
below). Furthermore, drugs acting at a variety of targets
have been explored to specifically treat L- DOPA- induced
dyskinesias. These include α2 receptor antagonists, glutamate receptor antagonists (acting at 4- amino- 3- hydroxy5- methyl- 4- isoxazole propionic acid [AMPA], N- methylD- aspartate [NMDA] and metabotropic glutamate receptors), 5- HT1A receptor antagonists, D4 receptor antagonists
and adenosine A2 receptor antagonists. An example of
such a drug is amantadine (a low- affinity NMDA receptor
antagonist).
Dopaminergic agonists
Dopamine receptor agonists represent another therapeutic option and compensate for the failure in dopaminergic
transmission by directly stimulating dopamine receptors. Agonists are ergot (a fungus that grows on grasses
Table 10.4 Half- life of dopaminergic drugs
L- DOPA/carbidopa 1–1.5 h
Bromocriptine 12–15 h
Cabergoline >24 h
Pramipexole 8–12 h
Ropinirole 6–8 h
Rotigotine 5–7 h
such as rye and wheat)- derived (e.g. bromocriptine, cabergoline) or non-ergot- derived (pramipexole, ropinirole,
rotigotine); the prescription preference is for the latter
group because of the risk of fibrotic heart valve disease
associated with ergot compounds. They have varied halflives (Table 10.4) and have a higher affinity for the D2
subtype of dopamine receptors (Box 10.5). They can be
used when adequate control of the symptoms can no longer be achieved with L- DOPA/carbidopa, or significant
unwanted effects of this combination (dystonia and dyskinesia) have developed. A significant number of patients
may improve on dopaminergic agonists alone, especially
at the beginning of the disease. The early introduction
of dopaminergic agonists might be beneficial, especially
in younger patients, in delaying the introduction of
L- DOPA and the subsequent onset of the dyskinesia and
‘on- off’ effects seen with L- DOPA. The decision whether
to initiate treatment in a patient with L- DOPA or with
dopaminergic agonists is based on clinical judgement.
The agonists do not have the same efficacy as L- DOPA;
thus, ultimately, L- DOPA must be prescribed. Agonists
are more likely to induce sleepiness, hallucinations and
impulse- control disorders (e.g. binge eating, hypersexuality, gambling) compared to L- DOPA. The latter are likely
due to the increased dopaminergic tone in the mesolimbic reward- associated pathway. Dopamine agonists can
induce nausea and vomiting, which can be treated with
domperidone. They can also induce hallucinations, cardiac arrhythmias and postural hypotension. Their potential for causing dyskinesia and dystonia is much less than
that of L- DOPA/carbidopa (Fig. 10.11). Agonists with
longer half- lives avoid the peaks and troughs in plasma
concentration seen with short- acting compounds such as
L- DOPA and other agonists. A pulsatile profile of receptor stimulation is considered to be at least partly responsible for the onset of dyskinesias after the administration
of short- acting compounds. Apomorphine is an agonist
that can be used subcutaneously (intermittent injection
or continuous infusion) in patients who experience major
loss of L- DOPA efficacy. Pramipexol and ropinirole are
available as extended- release formulations, and rotigotine
can be used transdermally as a patch, thus providing continuous drug delivery and added pharmacokinetic benefit compared to agents that need to be taken orally several
times a day.
Monoamine oxidase B inhibitors
MAOB is the isoform of monoamine oxidase (MAO) that
is involved in dopamine metabolism (see Fig. 10.8). The
inhibition of MAOB by selegiline (also called deprenyl),
rasagiline or safinamide, can increase the levels of dopamine and may also protect against xenobiotics that may
be converted into neurotoxic species in a manner similar to MPTP (see above). MAOB inhibitors are used as
adjunctive therapy. Used in conjunction with L- DOPA,
selegiline allows a dose reduction and prolongs the duration of L- DOPA action. It can be used as monotherapy
only at a very early stage of the disease.
212 SYSTEMS OF THE BODY
Box
Dyskinesia score
28
Day
10.5
10
MOTOR SYSTEMS II: THE BASAL GANGLIA
Dopaminergic systems and receptors
Dopamine is a catecholamine neurotransmitter associated
with numerous physiological and pathological processes,
including motor activity, emotion, cognition, addiction,
endocrine regulation, and cardiovascular and renal function.
Because of the variety of effects induced by dopamine, one
of the major challenges is to develop dopaminergic drugs
that selectively affect these processes.
In the central nervous system, dopamine- containing neu-
rons form three main pathways (Fig. 10.9).
1. The nigrostriatal pathway: cell bodies lie in the
substantia nigra, and the axons innervate the caudate
nucleus and the putamen. This system is mainly
involved in the integration of sensory information and
the control of movement.
2. The mesolimbic/mesocortical pathway: cell bodies are
situated mainly in the ventral tegmental area (which is
medial to the substantia nigra), and the axons innervate
the nucleus accumbens (considered by some authors to be
the most ventral part of the striatum), olfactory tubercle,
amygdala and cortex (in particular, the prefrontal and
cingulate cortices). This system is associated with reward
and reinforcement mechanisms (involved in addiction),
emotional behaviour and cognition.
3. The tuberoinfundibular pathway: cell bodies are
located in the arcuate nucleus in the hypothalamus,
and the axons project to the median eminence. In
this system, dopamine acts as a modulator of the
hypothalamic–pituitary axis (e.g. it inhibits prolactin
secretion).
Dopamine exerts its effects through five receptor subtypes: D1, D2, D3, D4 and D5. These can be grouped into
two classes: D1- like receptors (this includes the D1 and
D5 receptors) and D2- like receptors (this includes the
D2, D3 and D4 receptors). Additional complexity is conferred by the existence of multiple receptor isoforms
within a receptor subtype. All dopamine receptors are
G- protein- coupled receptors. They are associated with
several signal transduction systems. The two main classes
of receptor may exert opposite effects on the same signalling mechanism. For example, D1- like receptors activate adenylate cyclase, whereas D2- like receptors inhibit
this enzyme. D1 and D2 receptors are the predominant
dopamine receptor subtypes in the central nervous system. They are present at moderate- to- high densities
in the projection areas of the dopaminergic pathways.
Dopamine receptors can be located postsynaptically or
presynaptically. In the latter case, they may act as autoreceptors, which regulate dopaminergic signalling, but
also as heteroreceptors, through their location on nondopaminergic terminals.
Fig. 10.11 Dyskinesia in 1- methyl- 4- phenyl- 1,2,3,6- tetrahydropyridine
(MPTP)- treated monkeys. Frequency of dyskinesia in MPTP- treated
marmosets treated with L- DOPA, ropinirole or L- DOPA with ropinirole.
Note the significantly higher dyskinesia score in L- DOPA- treated
animals. (Redrawn from Olanow C.W. et al. (2000) Continuous
dopamine-receptor stimulation in early Parkinson’s disease. Trends in
Neurosciences, 23(10 Suppl):S117-26.)
Non-dopaminergic medication
Anticholinergic agents
Anticholinergic medication is used in order to redress the
potential dopamine–acetylcholine imbalance that may
L-DOPA
4
L-DOPA + ropinirole
3.5
2.5
1.5
0.5
Ropinirole
3
2
1
0
02 46810 12 14 16 18 20 22 24 26
develop in the parkinsonian striatum. Dopamine exerts an
inhibitory effect on striatal cholinergic cells. Therefore, cholinergic hyperactivity may be due, at least in part, to this
loss of inhibitory control. Antimuscarinic agents, such as
benzhexol, benztropine and procyclidine, are particularly
effective in reducing tremor. They produce only a minor
improvement in bradykinesia. Their side effects include
dry mouth, difficult micturition, constipation and confusion. Their use is very problematic in the elderly, as they
increase the risk of confusion and cognitive impairment.
Amantadine
Amantadine was initially developed as an antiviral compound, and its antiparkinsonian effects were discovered
serendipitously. It appears to increase dopamine release,
and it can inhibit dopamine uptake and block NMDA
glutamate receptors. It is well absorbed and has a halflife of approximately 24 hours. Its efficacy is moderate.
Its side effects include confusion, hallucinations, nightmares, ankle oedema and livedo reticularis (an erythematous rash of the lower extremities).
Other strategies
Surgical intervention
Surgical procedures were first attempted in PD in
the early 20th century (Box 10.6). The introduction of
213THE NERVOUS SYSTEM
10
200 ms
Box
10.6
Surgery and neurostimulation in
Parkinson’s disease (or finding the
right answers through trial and
error)
Surgical intervention was relatively common in the management of Parkinson’s disease before the introduction of
L- DOPA. In 1930, L.J. Polack and L. Davis performed posterior rhizotomies (cutting of sensory nerve roots), which
led to some improvement in rigidity but no improvement
in tremor. Later on, Paul Bucy excised Brodmann’s cortical
area 4, which led to decreased tremor but was accompanied by contralateral hemiparesis. In the 1950s, lesions to
the caudate, ansa lenticularis and pallidum led to a reduction in tremor and rigidity in 40%–70% of patients but with
high mortality rates. In 1952, while attempting a peduncu-
MOTOR SYSTEMS II: THE BASAL GANGLIA
lotomy in a parkinsonian patient, Irving Cooper damaged
and then ligated the anterior choroidal artery. This led to a
reduction in tremor and rigidity, which was attributed to an
ischaemic lesion in the medial pallidum, ansa and fasciculus
lenticularis, and the ventrolateral nucleus of the thalamus.
This focused attention on two important targets for lesioning or stimulation: the thalamus and the medial pallidum.
Alim-Louis Benabid in the mid- 1990s showed that stimulation of the subthalamic nucleus was an equally interesting
approach. In recent years, continuing advances in stereotaxic procedures, brain imaging and electrophysiological
recording have gradually made surgery much more precise
and accurate. Deep brain stimulation (DBS) is now an established technique and, since the 1990s, more than 160,000
patients have undergone the procedure. DBS is based on
the implantation of electrodes linked to an implantable
pulse generator (similar to a pacemaker) to provide longterm, continuous stimulation. The immediate effects of DBS
involve an alteration of firing patterns in neural circuits,
but it is likely that there are also other longer- term effects
involving alterations in neurotransmitter dynamics and
gene expression, and possibly neurotrophic aspects. DBS
is used in Parkinson’s disease, essential tremor and dystonia. Other indications include treatment- resistant epilepsy,
depression and obsessive- compulsive disorder.
L- DOPA therapy led to a relative loss of interest in surgical intervention. However, more recently, this approach
has been playing an increasingly important role in the
management of advanced PD, especially in patients with
motor complications due to pharmacological treatment.
The rationale for surgical treatment is based on the
alterations in neuronal firing in the basal ganglia that
accompany the degeneration of nigrostriatal neurons.
The loss of nigral cells, combined with intermittent
stimulation of dopamine receptors, may lead to abnormal firing patterns in striatal output pathways. There
may be reduced activity of neurons in the GPe, in parallel with a significant increase in the activity of neurons
in the SNpc, GPi and STN. For example, after nigral
lesion, neurons in the STN change their activity from a
200 ms
Fig. 10.12 Changes in neuronal activity after experimental
nigrostriatal lesion: firing of neurons in control rats (top) and rats
whose nigrostriatal projections are lesioned unilaterally using
6- hydroxydopamine (bottom). Note that the lesion changes the
spiking activity from a regular pattern of discharge to bursting activity.
From Hirsch E.C., et al. (2000) ‘Metabolic effects of nigrostriatal
denervation in basal ganglia’. Trends in Neurosciences, 23(10
Suppl):S78-85.
spiking pattern to a bursting pattern (Fig. 10.12). PD is
associated with increased rhythmicity and synchrony of
neural activity and oscillations. These abnormalities may
underlie parkinsonian symptoms, and the dyskinesia/
dystonia induced by long- term L- DOPA replacement
therapy. Stereotactic lesions can be performed in the thalamus or GPi. Targeting the thalamus may prove particularly useful in patients with intractable tremor, whereas
pallidotomy may alleviate rigidity and L- DOPA- induced
dyskinesia/dystonia. Furthermore, the wearing- off and
‘on- off’ phenomena may also be significantly reduced.
These lesion procedures were often performed before
the advent of L- DOPA. However, it became apparent
that chronic electrical stimulation instead of lesions at
various sites in the basal ganglia could be performed. For
example, stimulation of the STN, now a well- established
procedure in PD, can induce a depolarizing block of
the neurons and alleviate rigidity, akinesia and druginduced dyskinesia. The surgical procedure involves the
implantation of an electrode with an exposed tip into
the target. The electrode is connected to a wire running
beneath the skin to a stimulator placed in the chest. The
stimulator can be adjusted externally using a programmer. If a side effect occurs due to electrical stimulation,
the stimulation can be reduced. Fig. 10.13 illustrates
these techniques and the clinical improvement associated with their successful use. The improvement can
last for years and may allow a very significant reduction in the doses of drugs taken by the patient. Bilateral
deep brain stimulation (DBS) of the STN can lead to an
approximately 50% improvement in activities of daily
living and the motor score, compared with the preoperative state; drug dosage and dyskinesia are reduced by
more than 60%. Therefore, although this neurostimulation treatment is not used routinely in a large number of
patients, it offers a valuable option in the management of
advanced disease.
214 SYSTEMS OF THE BODY
B
A
C
Fig. 10.13 Surgical intervention in Parkinson’s disease. (A) Bilateral
implantation of electrodes for stimulation of the subthalamic nucleus.
(B) Bilateral pallidotomy (arrows indicate the lesions). (A and B,
Courtesy of Dr S. Karanth.) (C) Improvement in handwriting in a
patient who received a unilateral thalamic lesion. (After Narabayashi
C. (1990). Surgical treatment in the levodopa era. In Stern G, ed.
Parkinson’s Disease. The Johns Hopkins University Press, 609.)
Cell replacement therapies
It has been hypothesised that the neurodegenerative
processes in PD could be counteracted by the provision of neurotrophic factors that could support the failing neurons (Box 10.7). However, in spite of promising
experimental results with factors such as GDNF and
neurturin (a factor related to GDNF), translation to
the clinic has not been successful. Considering the significant localized neurodegeneration in the midbrain
in PD, use of neural grafts would appear to be a particularly well- suited strategy for the replacement of lost
dopaminergic cells. Cell replacement therapies for PD
began more than 50 years ago and have evolved significantly over the last three decades of the 20th century,
as summarized in Table 10.5, providing a solid base for
present cell replacement research. In experimental animals, autologous foetal dopaminergic cells transplanted
into the striatum survive and adopt a morphology and
neurochemical phenotype consistent with dopaminergic reinnervation. Initial attempts in patients involved
the use of homografts of adrenal medulla, which contains catecholamine- secreting cells. However, follow up studies showed poor survival of the grafts, modest
clinical improvement accompanied by numerous
side effects and a high level of morbidity and mortality. Human embryonic nigral grafts were subsequently
attempted, and the accumulated observations so far
show that they can lead to significant and long- lasting
clinical improvement. Furthermore, positron emission
tomography (PET) studies have provided evidence of
regulated dopamine release from such grafts. As illus-
Box
10.7
Neurotrophic factors are endogenous substances that control cell proliferation and differentiation in the nervous
system. Trophic effects are essential during development,
but also at the adult stage, in the immediate aftermath
of injury and during regeneration. Many neurotrophic
and growth factors are present in the substantia nigra
and/or the striatum. Experimental evidence shows that
several of these neurotrophic factors support the survival and differentiation of mesencephalic dopaminergic
neurons. These factors include epidermal growth factor
(EGF), basic fibroblast growth factor (bFGF), brain- derived
neurotrophic factor (BDNF), glial cell line- derived neurotrophic factor (GDNF) and neurturin, which is related to
GDNF. Neurotrophic factors reverse dopaminergic deficits
in animal models. However, neurotrophic factors are large
molecules that do not cross the BBB after systemic administration. Direct injection of these factors into the cerebral
ventricles or parenchyma is unlikely to become a routine
clinical procedure. An alternative is the cerebral implantation of encapsulated cells engineered to produce and
secrete neurotrophic factors, or the use of viral vectors (e.g.
adeno- associated virus or lentivirus). Encapsulation would
protect against a host immune response and counter the
danger of abnormal growth. Studies carried out so far with
neurotrophic factors have not led to any significant clinical
benefits in PD.
Table 10.5 Cell- based therapies in Parkinson’s disease
1970–72 Experimental adrenal medulla and foetal nigral cell
1979 Experimental grafts of foetal nigral cells in animals with
1985 Adrenal medulla grafts in patients with Parkinson’s disease
1988 Foetal nigral grafts in patients with Parkinson’s disease
1997 Foetal pig nigral grafts in patients with Parkinson’s
1998 Experimental grafts of embryonic stem cells in animals
Neurotrophic factors
grafts in the anterior eye chamber
nigrostriatal lesions
disease
with nigrostriatal lesions
trated in Fig. 10.14, in the case of a patient who unilaterally received ventral mesencephalic tissue from four
human embryos in the anterior, posterior and middle
putamen, clinical improvement was paralleled by
improvement in dopamine storage capacity, as reflected
in the accumulation of DOPA. Furthermore, PET analysis with the use of [11C]raclopride, an in vivo marker of
D2 receptors, showed that the endogenous dopamine
produced by the graft can be released by agents such as
methamphetamine and thus displace the marker from
the receptors, which further confirms the functionality
10
MOTOR SYSTEMS II: THE BASAL GANGLIA
215THE NERVOUS SYSTEM
10
UPDRS motor score
Time after transplantation (years)
A
and can differentiate into a variety of cell types, includ-
70
60
50
40
30
Daily time in ‘off’' (%)
20
10
0
Preop.
B
MOTOR SYSTEMS II: THE BASAL GANGLIA
0.012
)
O
1
0.008
0.004
F]-DOPA uptake (K
18
[
0.000
Preop.
Transplantation
50
40
UPDRS motor score
30
20
10
Daily time in ‘off’
0
123 45678910
Time after transplantation (years)
Transplantation
Normal mean
+ 2 SD
Grafted putamen
Non-grafted putamen
123 45678910
ing dopaminergic neurons. After transplantation, stem
cells can integrate into the host tissue and differentiate
into neurons and glia. Their high plasticity offers enormous potential, but their unrestrained and uncontrolled
growth could lead to tumour formation. This can be
obviated by transforming the cells into more differentiated cells before transplantation. It is now possible to collect non-neuronal, somatic cells from a patient (e.g. skin
fibroblasts) and re- programme them using a combination
of transcription factors, to achieve stem- cell characteristics, that is, induced pluripotent stem cells (iPSCs), and
neurons can then be derived from these pluripotent cells.
It has recently become possible to convert somatic cells
directly into neurons, without the intermediate stem cell
step. This approach has all the advantages of cell therapy
without the risk of allogeneic approaches based on the
use of cells from other donors, which require immunosuppression. Furthermore, the cells can also be edited
for specific deleterious genetic mutations; exploratory
studies are focused at present on editing mutations in
the GBA gene. Therefore autologous neuron replacement
therapy is providing new hopes in the field of grafting.
The experimental and clinical observations of intracerebral cell grafts suggest that the cells used for transplantation should have the capacity to: (1) grow neurites,
(2) establish connections with the appropriate neurons in
the host tissue (e.g. in PD, the grafts are placed ectopically in the striatum), (3) differentiate successfully into
dopamine- releasing cells and (4) resist destruction by
any neurotoxic latent process.
General management strategy and long- term
prognosis in Parkinson’s disease
Fig. 10.14 Effect of nigral transplants in PD. (A) Percentage of the
day spent in the ‘off’ phase and motor examination score on the
Unified Parkinson’s Disease Rating Scale (UPDRS), preoperatively and
after intrastriatal grafting. (B) [18F]DOPA uptake before and after
transplantation. Note the concomitant increase in [18F]DOPA uptake
and clinical improvement after grafting. (From Piccini P. et al. (1999).
‘Dopamine release from nigral transplants visualized in vivo in a
Parkinson’s patient.’ Nature Neuroscience, 2(12):1138.)
of the graft. Retrospective studies on postmortem tissue
from patients who survived for more than 10 years after
receiving their grafts in the 1990s clearly showed that
most of the transplanted neurons remained healthy and
functional, but there was, in some cases, evidence of
Lewy body pathology in the graft, suggesting that hostto- graft transmission of PD pathology is possible.
Other grafting attempts have involved the use of
dopaminergic xenografts from porcine donors and
non-neuronal cells engineered to secrete dopaminesynthesizing enzymes (thus acting as a pump that provides the deficient amine). However, more recently,
efforts have been focused on the use of stem cells derived
from the blastocyst stage of the embryo, before implantation in the uterus. They are capable of multiple divisions
216 SYSTEMS OF THE BODY
There is currently no cure for PD, as progression of the
neurodegenerative process is irreversible. The evolution
of the disease is highly variable between individuals.
Some patients maintain reasonable function 12–15 years
into the disease, while others experience rapid worsening of symptoms very early on. Current approaches to
classification into subtypes are not optimum, and consensus on patient stratification is lacking. Current treatments are only symptomatic but have improved the
patients’ overall quality of life, especially in the early
years of treatment, and have increased average life
expectancy. Patients usually experience improvement
in symptoms when L- DOPA therapy is first introduced.
The response is relatively stable throughout the day, and
this is probably due to the ability of remaining nigrostriatal neurons to produce dopamine from L- DOPA, and
store it and release it in a relatively physiological manner. It is particularly important to stress the need to take
the medication ‘on time and every time’ in this disease,
thus minimising fluctuations in drug levels. However, in
spite of the medication, degeneration continues and disability becomes more severe. This leads to a tendency to
increase the dose of dopaminergic drugs. However, the
number of nigral residual cells is very small, and the
10
levels of dopamine produced from L- DOPA supplementation will start to fluctuate widely. Patients first notice
a much shorter duration of improvement after taking a
dose of medication and also develop peak- dose dyskinesias. At this point, further increasing the doses of drugs
leads to more severe dyskinetic episodes, which are not
necessarily accompanied by significant improvement in
the dyskinesia- free intervals. The importance and complexity of successfully managing a patient who presents
with a combination of akinesia and dyskinesia cannot be
overstated, and the strategies chosen depend on the preference and experience of the specialist in charge of the
case (see example in Table 10.6). In parallel with pharma-
Table 10.6 Treatment recommendations for motor fluctuations and dyskinesias in Parkinson’s disease including akinetic crisis
1. End- of- dose deterioration (wearing- off)
Take L- DOPA well before meals (30–60 min)
Add dopamine agonist
Add selegiline
Change to, or add, L- DOPA administration and reduce size of individual doses to avoid overdosage
Take the first L- DOPA dose immediately on rising
Eat a low- protein diet during the day
Take L- DOPA as a dispersible or liquid formulation for early- morning or afternoon akinesia
2. Paroxysmal ‘on- off’
See the preceding recommendations on wearing- off
Fewer, higher doses of L- DOPA, however, may be preferable in some patients
Administer apomorphine by subcutaneous intermittent injections or continuous infusion (mini- pump)
3. Peak- dose mobile dyskinesias
Discuss with the patient whether the dyskinesias are an acceptable price to pay for mobility (mild to intermediate dyskinesias often bother
the carer more than the patient)
Discuss whether the patient prefers more time ‘on’ with dyskinesia or less time ‘on’ with less dyskinesia
Suggest intake of drug with meals (may help peak- dose dyskinesias)
Adding a long- acting dopamine agonist should help reduce ‘troughs’ of dopaminergic stimulation; it may also permit lower doses of L- DOPA
to be used and hence often reduce the severity of dyskinesias
Try controlled- release L- DOPA preparations (peak- dose dyskinesias can increase)
Administer subcutaneous apomorphine by injection or infusion pump
Add amantadine
4. Biphasic dyskinesia
Overlapping doses of L- DOPA and use of controlled- release preparations often result in permanent dyskinetic chaos
May be worsened by protein meals
Take higher doses less often, going through complete cycle to ‘off’ again before taking next dose
5. Off- period dystonia
Dispersible L- DOPA preparation or apomorphine injection, especially as a first dose, eliminate early- morning dystonia
Controlled- release L- DOPA during day or at bedtime
Add agonist during day or at bedtime
Add anticholinergic
Local administration of botulinum toxin in selected cases
6. Akinetic crisis
Intensive care facilities should be available
Ancillary measures: parenteral fluids with electrolyte and caloric substitution, anti-thrombotic prophylaxis, physiotherapy, skin care
Restart L- DOPA at a slightly lower dose than before and increase gradually to the previous dose over 1–2 days if akinetic crisis is the result of
L- DOPA withdrawal
Increase L- DOPA dose by 100–200 mg/daily until response is observed if akinetic crisis is due to underdosing
Administer single injection of apomorphine by subcutaneous continuous infusion (initially 1–2 mg/h; increase by 0.5–1 mg every 12 h with
an 8–12 h break at night; maximal daily dose 170–240 mg). If domperidone cover is required, give 20 mg three times daily before staring
apomorphine; in emergencies, give 50–60 mg domperidone 30–60 min before apomorphine, if necessary via nasogastric tube
cological adjustments, the surgical options are important
additional options in such cases.
A significant number of patients develop dementia
and also experience major postural problems. Postural
imbalance is not improved significantly by drugs, is
a cause of morbidity and mortality and increases the
strain on the carers. Dopamine agonists often offer
only transient improvement of motor symptoms. In the
early phases of the disease, the stigma of tremor may
be restrictive and a serious threat to employment. Thus
each aspect of the disease requires careful consideration
and specific rehabilitative management. A view that has
emerged recently is that the optimum management of
MOTOR SYSTEMS II: THE BASAL GANGLIA
From Möller J.C., Bandmann O. and Oertel W.H. (1999). ‘The therapy of the parkinsonian syndrome.’ Deutsch Med Wochenschr, 124(8), 219-222.
217THE NERVOUS SYSTEM
10
Treatment?
Clinical
YesNo
None or
moderate symptoms: amantadine?
mild symptoms: selegiline
<55 years
55–70 years
>70 years
reassessment
re correct
diagnosis
Monotherapy with
dopamine agonists
Not satisfactory,
side effects
Not satisfactory
L-DOPA
monotherapy
MOTOR SYSTEMS II: THE BASAL GANGLIA
Fig. 10.15 Algorithm for treating akinetic rigid Parkinson’s disease patient. COMT, catechol- O- methyltransferase; DA, dopamine agonist.
(Adapted from Braune HJ, Moeler JC, Oertel WH. (1999) In LeWitt PA, Oertel WH, eds., Parkinson’s Disease: The Treatment Options. London:
Martin Dunitz, 251.)
young (i.e. 50–60- year- old) patients and elderly patients
may differ. Fig. 10.15 offers a possible algorithm of differential treatment to illustrate this point. In particular,
the introduction of L- DOPA is delayed as much as possible in younger patients, because L- DOPA- induced
dyskinesias and dystonias seem to be more marked in
young patients. Therefore, for younger patients, symptomatic therapy may be better initiated using a dopamine agonist. In the case presented here, it may have
been wiser to delay the introduction of L- DOPA therapy. The complications could be initially treated with a
controlled- release L- DOPA preparation, with or without
a dopaminergic agonist.
Dopamine agonists may adequately control symptoms for several years, after which L- DOPA introduction
becomes inevitable. Finally, it is important to stress that
the successful management of parkinsonian patients,
particularly in the middle and late stages of the disease,
involves a multidisciplinary approach combining medical treatment with physiotherapy, speech therapy and
occupational therapy (Table 10.7), and also the provision
of specialist nursing care. For example, it has been shown
that boxing exercises (e.g. jabbing and hook punches) can
lead to improvement in balance, gait, walking speed,
stride length, step width, ‘get- up- and- go’ time and ability to reach forward, after only 3 months of practice. It
has been suggested that sustained multidisciplinary therapy may support neuroplasticity.
One of the most promising areas of research is focused
on the development and validation of biomarkers that
would allow diagnosis of the disease at an early, prodromal stage. It is likely that PD pathology is present at least
10–15 years before motor symptoms become apparent.
At this early stage, many patients may present with nonmotor symptoms, such as hyposmia, constipation and
Individualised dose adjustment
Progression
or further
complications
Early combination therapy
with L-DOPA and
dopamine agonist
L-DOPA + DA + COMT-inhibitor
L-DOPA + COMT-inhibitor
Fluctuations
and/or dyskinesias
or
+ amantadine in case
of dyskinesias
Side effects not
satisfactory
Adjustment
of L-DOPA and
dopamine agonist
rapid eye- movement sleep behaviour disorder (a form of
sleep disturbance during which individuals may act- out
dreams). Research diagnostic criteria that can be used
for prodromal stage interventions will have significant
value for the exploration of compounds with neuroprotective and preventive potential. Other biomarkers could
be used to assess disease risk; for example, it has been
found that increased levels of serum or plasma uric acid
are associated with a decreased risk of developing PD.
Furthermore, aggregates of α- synuclein can be detected
in the skin of patients with PD, raising the possibility of
the future diagnostic use of skin biopsies.
As the aggregation of α- synuclein is a key pathological event in PD, there is intense research focus on new
immunological therapeutic approaches based on passive
or active immunization against α- synuclein; antibodies
against α- synuclein aggregates could become the first
disease- modifying therapies in PD.
Huntington’s disease
Huntington’s disease (HD) is a hereditary neurodegenerative disease that affects the striatum and the cortex
and is characterized by motor, cognitive and psychiatric
symptoms. HD is associated with prominent atrophy of
the cortex, which mostly affects the motor and premotor areas, and a loss of (enkephalinergic) striatal spiny
GABAergic neurons, which are the origin of the striatal efferent pathways. MRI and CT scanning show that
in advanced HD there is atrophy of the caudate, putamen and cerebral cortex. In some cases, brain weight
may be reduced by one- third (Fig. 10.16). There is early
massive loss of striatopallidal neurons, followed by
loss of striatonigral neurons. Striatal interneurons are
218 SYSTEMS OF THE BODY