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Study of an old Man's Profile - Galleria degli Uffizi - Firenze
Parkinson's Disease in the elderly: an example of Geriatric Syndrome? Torna agli editoriali

di
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 (2).

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: 982-4).

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 (11).

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 condition (12).

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 nutritional reserve.

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).

REFERENCES

1. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease. Neurology 2009; 72:S1-136.

2. de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol 2006; 5:525-35.

3. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24:197-211.

4. Lauretani F, Maggio M, Silvestrini C, Nardelli A, Saccavini M, Ceda GP. Parkinson's disease in older adults: a new scenario for this old actor? J Am Geriatr Soc. 2010; 58:982-4.

5. Calabresi P, Picconi B, Parnetti L, Di Filippo M. A convergent model for cognitive dysfunctions in Parkinson's disease: the critical dopamine-acetylcholine synaptic balance. Lancet Neurol 2006; 5:974-83.

6. Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, Jacobs AH, Herholz K, Heiss WD. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 2005; 65:1716-22.

7. Gaig C, Tolosa E. When does Parkinson's disease begin? Mov Disord 2009; 24:S656-64.

8. Jankovic J .Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79:368-76.

9. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999; 56:33-9.

10. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci. 2010; 289:18-22.

11. Lauretani F, et al. The capturing side-effects of medications for identifying persons at risk of delirium. Aging Clin Exp Res 2011 (in press).

12. Paganelli R, Di Iorio A, Cherubini A, Lauretani F, Mussi C, Volpato S, Abate M, Abate G, Ferrucci L. Frailty of older age: the role of the endocrine--immune interaction. Curr Pharm Des 2006; 12:3147-59.

13. Bandinelli S, Lauretani F, Boscherini V, Gandi F, Pozzi M, Corsi AM, Bartali B, Lova RM, Guralnik JM, Ferrucci L. A randomized, controlled trial of disability prevention in frail older patients screened in primary care: the FRASI study. Design and baseline evaluation. Aging Clin Exp Res 2006; 18:359-66.

14. Lauretani F, Maggio M, Saccavini M, Ceda GP. Should the "Preventive Geriatric Section" be implemented in our hospital? Aging Clin Exp Res 2008; 20:384.

Corresponding author:
Fulvio Lauretani, MD
Geriatric Unit and
Laboratory of Movement Analysis,
Geriatric and Rehabilitation Department
University Hospital of Parma, Parma, Italy
Via Gramsci 14, 43100
Tel. 39-0521-703315
Fax. 39-0521-703330
E-Mail: flauretani@ao.pr.it

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