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Mode and age of onset

Mode of onset

The mode of onset of PD-D is insidious; it is often difficult for the patient and family members to remember when the first signs of mental dysfunction became apparent. It is not uncommon for mental dysfunction to emerge or be visible following a minor trauma, surgery, infection, or dehydration; the symptoms may then not be fully reversible although the triggering insult has vanished. This in fact represents an incipient dementia becoming overt; such constellations may mislead caregivers to conclude that the onset of mental dysfunction was acute. Conversely, acute confusion (delirium) due to systemic diseases or adverse effects of drugs may be mistaken for dementia. Therefore, an acute onset or acute worsening of mental dysfunction should always be suspicious for exogenous factors and necessitates a careful history, detailed clinical examination, and appropriate laboratory investigations.

Age at onset of dementia and time from disease onset to dementia

Although marked cognitive dysfunction can be found in de novo populations or at the time of diagnosis [8% of newly diagnosed patients were found to have marked cognitive impairment defined as a Mini-Mental State Examination (MMSE) score <24] [7], dementia at the time of diagnosis of PD is rare. By current definitions, such cases would qualify for a diagnosis of DLB. A diagnosis of PD-D requires the preceding diagnosis of PD, followed by dementia developing on the background of established PD.

In the majority of patients cognitive dysfunctions are usually subtle at the time of disease onset and develop during the later stages. In a cohort of patients with newly diagnosed PD, 10% developed dementia at a mean of 3.5 years from diagnosis; the annual incidence of dementia was calculated to be 30 per 1000 person-years [8] (see Chapter 2). In the prospectively followed Sydney cohort the prevalence of dementia was 16% at baseline [9], whereas 84% of patients developed cognitive dysfunction, 48% severe enough to justify the diagnosis of dementia 15 years after the diagnosis of PD [10]. In the same cohort, dementia was present in 83% of all surviving patients 20 years after the diagnosis [11]. In another prospective study, old age and longer disease duration were found to be strong determinants of dementia [12]. The reason for the delay to the onset of dementia may be the relatively late involvement of brain structures subserving mental functions in typical PD patients. This is suggested by the staging of disease pathology described by Braak et al. [13]. According to this hypothesis, LB pathology in PD has its onset in certain susceptible nuclei of the brainstem, subsequently ascending to the upper brainstem, limbic structures, and finally to the cerebral cortex, heteromodal association cortices succumbing first, followed by homomodal association and primary sensory-motor cortices. However, there also seem to be patients with a greater burden of cortical pathology who have a more malignant disease course and a shorter time before the emergence of dementia [14].

The average time to the onset of PD-D was found to be about 9 years in one cohort [15]. An important determinant of time to occurrence of dementia is current age; the older the patient the more likely is a shorter time to the onset of dementia. Estimates of age-specific incidence of cognitive impairment suggest that it is 2.7% per year at ages 55-64 increasing to 13.7% at 70-79 years [16-18]. Similar effects of age were observed in the Sydney cohort: the prevalence of dementia at baseline was 5% in those aged <60, 14% at 60-69, and 35% in patients aged >70 years [9]. The effect of age at disease onset is, however, debated: whereas several studies have reported that a younger age of onset is associated with a lower risk of dementia, a recent analysis suggested that it is age per se rather than age of onset which determines the risk [19].

 
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