This large community-based prospective study has permitted the observation of the emergence of EPS in incident AD cases.
We found EPS to be present even in very early stages of AD, even before confirmation of the diagnosis, with their prevalence increasing over time. Compared to other forms of EPS, resting tremor was less frequent and did not increase over time. This observation has also been made by previous studies.1, 2, 8, 11, 19
EPS symptoms other than resting tremor were seen to progress rapidly over time as previously noted, 1, 2, 10, 11, 19
with an annual increase in EPS scores of between 0.85 to 2%, with only 0.15 for tremor. These calculated rates are smaller or quite close to previously reported ones.10, 11
However, differences with regard to population sampling and baseline levels of EPS limit direct comparisons.
EPS and AD may share similar pathogenesis. The presence of one increases the probability of having the other.3, 20
Whether EPS represent the presence of AD pathology, Lewy body disease or vascular pathology is still uncertain. Explanations other than Lewy bodies for the existence of EPS in AD include the presence of senile plaques in the putamen, caudate and substantia nigra, the presence of neurofibrillary tangles in the substantia nigra and a neuronal loss.21, 22
A main limitation of our study is that the findings are based on a clinical diagnosis of probable AD, without neuropathological examination.
It is important to note that EPS may pre-date the clinical diagnosis of dementia as observed in previous studies. Mild parkinsonian symptoms have been described in subjects with Mild cognitive Impairment.20, 23
In a French general population study 24
, where 30% of an elderly cohort free of dementia were seen to have at least one EPS. Their clinical significance remains unclear. Decline in nigro-striatal dopaminergic regulation with advancing age is probably implicated 25
, however the observed relationship between EPS and disability appears to be independent of age, which suggests that EPS are not a benign feature of a normal aging process. 24
They could be associated to early cognitive symptoms in the course of probable AD and have also been linked to depression possibly through common effects of underlying dopaminergic changes.
In our study, EPS occured in AD in the absence of psychotropic medications, particularly neuroleptics. Wilson and McLehnnan 26
found no difference between idiopathic and iatrogenic EPS except for higher number of gait EPS. Regarding the difficulties in separating relative contribution of neuroleptic use and AD-related sensitivity to neuroleptics, we analyzed non drug induced EPS in order to increase our confidence that the occurrence of EPS is strictly related to underlying disease process.
Baseline EPS symptoms were associated with lower baseline cognitive performance suggesting either early impact of the underlying neurological changes related to EPS on cognition or that persons with higher performance have increased resistance to EPS due to a greater number of synaptic connections permitting longer resistance to clinical manifestations of dopaminergic or serotoninergic loss.
Moreover, studies concerning the cognitive reserve hypothesis suggest that there are individual differences in the ability to compensate AD lesions.27, 28, 29, 30
Subjects with more cognitive reserve may have AD pathology longer before or without clinical expression.30,31
When AD pathology is clinically expressed, AD pathology is already quite advanced and the disease is more severe. Our study is consistent with this hypothesis, regarding the results of EPS and the level of education. Subjects with a higher educational attainment have a higher cognitive reserve.27, 29, 30
In this study, subjects with higher level of education are most likely to develop EPS, which may be a hallmark of a more severe disease.
Furthermore, our study is in accordance with the previous studies, it enables us to validate a link between the risk of cognitive decline and a more advanced age at time at inclusion, a lower socio-cultural level and the presence of EPS at time at inclusion.
This study is one of the largest prospective studies on a multiethnic cohort allowing a detailed and longitudinal analysis of the correlation between EPS and cognitive decline in AD. The number of incident cases led to analyses with good statistical power and allowed us to examine many covariates. The AD diagnosis is based on a complete analysis of the clinical and neuropsychological data and the final validation of AD cases is conducted by a multidisciplinary expert team. The EPS evaluation could be limited since it is a subjective assessment of the various symptoms but it was based on a short assessment scale validated in other cohort studies. Finally, the present study confirms the association between EPS and early AD.