Fulvio Lauretani, MD, Anna Nardelli, MD
Parkinson disease (PD) is an age-related neurodegenerative
disorder that affects as many as 1-2% of persons aged 60 years
and older (1). With the aging of the population, the prevalence
of PD is expected to increase dramatically in the coming decades.
PD is clearly an age-related disease, rare before 50 years
of age and up to 4% in the highest age groups. Some studies
report a higher prevalence of PD in men than in women, although
other studies found no significant differences in PD prevalence
between sexes (2). Reported standardized incidence rates of
PD are 8-18 per 100 000 person-years. Onset of PD is rare
before age 50 years and sharply increase after age 60 years
In the latest decade, the approach to Parkinson's Disease
was dramatically changed. In fact, although for many years
Parkinson's Disease has been considered only a "disease
that affects walking", with a key role of the neurotransmitter
dopamine, recently the neurological approach has been modified.
The approach for this disease is not only a neurological issue.
Given the complexity of its symptomatology, such as depression,
anxiety, dementia, sleep disorder, pneumonia dysfagia-related
and malnutrition, a multidisciplinary and not just a neurological
evaluation is needed. Recently, Braak et al. (3) proposed
a neuroanatomical stages, that could explain all symptoms
observed in each phase of this disease. Briefly, the neurophatological
stages of the disease identified by Braak's could be associated
with its clinical aspects (Braak's stages 1 and 2 associated
with the pre-clinical phase; Braak's stages 3-4 associated
with the motor symptoms and Braak's stages 5-6 associated
with cognitive impairment).
We suggest, a new multidisciplinary approach for this old
actor, underlying a subtle link between neurophatological
stages of the disease (braak's classification (3)) and clinical
aspects (braak's stages 1 and 2 associated with the pre-clinical
phase; braak's stages 3-4 associated with the motor symptoms
and braak's stages 5-6 associated with cognitive impairment).In
addition we emphasize the usefulness of geriatric evaluation
for the identification of pre-frail, frail, and disable status
for improving care and treatment in this multifaceted disease
(4) (Figure 1, adapted from Lauretani et al. JAGS 2010; 58:
It is now evident that this disease needs of a multidisciplinary
approach for curing and treating each aspect of its complexity.
Parkinson's disease is now well characterized on the basis
of the neuro-anatomical changes. Braak et al. (3) have elegantly
described the course of the pathology in incidental and symptomatic
Parkinson cases proposing a staging procedure based upon the
readily recognizable topographical extent of the lesions.
Essential for neuropathological diagnosis are alpha-synuclein-immunopositive,
Lewy neuritis and Lewy bodies. The pathological process targets
specific induction sites: lesions initially occur in the dorsal
motor nucleus of the glosso-pharyngeal and vagal nerves and
anterior olfactory nucleus (Stage 1-2). Thereafter, the disease
process involve the brain stem pursues with an ascending course
and with little inter individual variation (Stage 3-4). Finally,
cortical involvement occurred, beginning with the anteromedial
temporal mesocortex (Stage 5-6). From there, the neocortex
succumbs, involving with high order sensory association and
prefrontal areas. First order sensory association/premotor
areas and primary sensory/motor fields then follow suit.
Recently, Parkinson's disease has also been well characterized
on the bases of the neurotransmitters changed occurring during
the course of the disease. In fact, while in the early phase
of the disease, reduction on the levels of dopamine, serotonin
and noradrenalin have been well described from many authors
(5). Then, cholinergic reduction was observed in the advanced
stages of disease, even using neuro-imaging techniques (6).
This complex modification of neurotransmitters that occurs
during the progression of the disease, which is probably closely
associated with the neuro-anatomical modification described
by Braak, could ultimately explain the jeopardized symptoms
found in the Parkinson's disease. In fact, many authors schematically
proposed a role for each neurotransmitters (5), suggesting
for example a role for the dopamine in the development of
the motor symptoms and also for the dysecutive syndrome, a
role for the noradrenalin in the attentive deficit, a role
for the serotonin for the depressive symptoms and a role for
the acetylcholine for the memory impairment, and all these
information could be used for generating an holistic view
of the disease, producing a neuroanatomical-neurotrasmettitorial-
and-clinical phases of the disease which permit a better care
and treatment of this disease (5).
Clinically, the disease is characterized by non-specific
symptoms in a early phase, such as hyposmia, constipation,
depression and skeletal-muscle pain, which are probably associated
with earlier neuroanatomical changed described by Braak (stage
1 and 2) (7). Post-mortem studies based on nigral cell counts
and evaluating dopamine levels in the striata, and imaging
studies assessing the nigrostriatal pathway in vivo, have
estimated that this time period could last 3 to 6 years. Studies
on ''premotor'' symptoms, such as hyposmia or depression,
suggest that these symptoms may be present or develop 7 years
or longer before motor symptoms of PD, while REM sleep behavior
disorder (RBD) may antedate motor signs by an average interval
of 11-12 years, and constipation may present 12-18 years or
for even longer time before parkinsonism develops. Overall,
information from these studies suggests that the first symptoms
of PD are non-motor and that the onset of PD may take place
10 to 20 years before the onset of motor symptoms (8). During
this ''subclinical'' period, a progressive loss of dopaminergic
neurons takes place and striatal dopamine content is reduced,
but function can be offset by several compensatory mechanisms.
This phase could be considered from a geriatric point of view
as a pre-frail condition.
After this first phase, it should appear the four cardinal
motor symptoms of the disease, corresponding to the Braak's
stage 3 and 4. This and other neuropathological studies have
demonstrated that the classical Parkinsonian motor symptoms
do not appear until a significant reduction in striatal dopamine
content and massive neuronal loss in the Substantia Nigra
(SN) were observed. A reduction of 80% in the striatal dopamine
content and a loss of about 60% of dopaminergic neurons in
the SN pars compacta are necessary for developing the classical
motor parkinsonian syndrome. Indeed, from the geriatric point
of view, this could be defined as a frail phase, given the
high risk of subsequent disability.
Finally, when the reduction of the neurotransmitter acetylcholine
is significant, the Parkinson disease-dementia (PDD) appears,
with again a close association with the Stage 5 and 6 proposed
by Braak and where the cortex is involved on the course of
the disease. In fact, the UK Parkinson's Disease Society Brain
Bank Clinical Diagnostic criteria state that "early severe
dementia with disturbances of memory, language and praxis"
is an exclusion criteria (8) and more recently, "Dementia
preceding motor symptoms or in the first year" is suggestive
of alternative diagnoses (10). Similarly, the recently revised
consensus criteria for a clinical diagnosis of DLB state that
if dementia onset is before or within 1 year after onset of
PD, (the "one-year rule") a diagnosis of DLB should
be made (9). In an early review of 27 studies representing
4336 patients with PD, Cummings found a mean prevalence of
40% for PDD (10). Although the studies were critically considered,
most studies were based on patients referred to neurology
clinics and may therefore not be representative of unselected
PD populations. In addition, at that time, studies did not
include the identification and exclusion of patients with
DLB. In a systematic review employing strict methodological
inclusion and exclusion criteria, 13 studies with a total
of 1767 patients were included. Of these 554 were diagnosed
with dementia, yielding a prevalence of 31.3%. The majority
of studies report that the mean duration from onset of PD
to development of dementia is approximately 10 years (9).
There are, however, wide variations, and some patients develop
cognitive impairment and subsequent dementia within few years
after onset of PD, whereas others remain free from dementia
for 20 or more years before developing dementia.
In this phase of the disease, even acute delirium is common,
where probably an unbalanced dopamine/acetylcholine ratio
is the "core" for the development of the delirium.
We recently proposed that a hypo-reactive delirium may be
caused by an absolute deficiency of acetylcholine in contrast
to monoamines levels (such as dopamine, norepinephrine and
serotonin), while a hyper-reactive delirium may be caused
by a relative deficiency of acetylcholine respect to dopamine,
with an unbalanced ratio between these two neurotransmitters
and an excess of dopamine level respect to the acetylcholine
This latest clinical phase is often a condition where the
patient became disable for the activity of daily living, and
where the multidisciplinary approach should be maximal.
Geriatric point of view of the Parkinson's disease
The "frail elderly" syndrome is a complex clinical
entity and since now an agreement about a standardized definition
or based on an empirical basis is still lacking.
Many possible definitions of frailty have been proposed in
the literature, a large number of different and often conflicting
criteria were used ranging from: non-disabled older persons
to old-old, bedridden subjects with multiple end stage medical
Frailty was commonly erroneously often used interchangeably
with disability, co-morbidity or advanced old age, recently
a clear characterization of these four concepts was presented
and discussed, elucidating also their interrelationship (12).
Clinically the frailty syndrome is characterized by wasting
(muscle, strength and unintentional weight loss), reduction
in endurance, balance and mobility, but also decreases in
cognitive performance should be included in that phenotype.
In general subjects at risk of becoming frail, that are in
a state of instable homeostasis, use compensatory strategies,
and could be unmasked by stressor events, or in clinical/epidemiological
setting using objective performance tests such as the Short
Physical Performance Battery (SPPB) (13).
In that way a vicious loop develops from sarcopenia to disability,
to neuromuscular impairment, to loss of mobility skill, falls,
hospitalization, immobilization and sarcopenia again. Another
component of the frail loop syndrome is the decline of the
The clinical definition of frailty rarely is encompassed
by a single altered system but multiple systems must be involved,
and we proposed that the model of the Parkinson's disease
with its complexity on clinical manifestations could be considered
as prototype of this condition, providing new insight and
new perspective to understand the complex biological pathways
underlying the pathogenesis of frailty and physical disability
in older persons (14).
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Fulvio Lauretani, MD
Geriatric Unit and
Laboratory of Movement Analysis,
Geriatric and Rehabilitation Department
University Hospital of Parma, Parma, Italy
Via Gramsci 14, 43100
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