Abstract
The aim of the study was to determine the feasibility of screening older adults attending general medical practice for features suggesting prodromal Parkinson’s disease (PD). Four general practitioners recruited 392 subjects aged ≥60 years, attending their primary clinics. A self-administered questionnaire collected information on history of probable rapid eye movements sleep behavior disorder (pRBD), constipation, risk markers for PD, and on subjective cognitive function. Olfactory function was tested. Constipation (27.8%), and hyposmia (19.9%), but not pRBD (4.3%), were more prevalent with age. Further supporting the feasibility of a longitudinal study, 299 subjects agreed to be followed.
INTRODUCTION
Parkinson’s disease (PD) develops insidiously over many years, and by the time patients are diagnosed extensive and irreversible neurodegeneration has already occurred [1]. An enormous advantage could be achieved by recognizing PD in the prodromal or premotor phase [1, 2], when early interventions could slow the disease process before the onset of debilitating symptoms. Several attempts to develop and validate criteria for the identification of prodromal PD (pPD) are ongoing [1–4], but it remains unclear what is the best approach for its identification in the general population. Considering that the overall prevalence of pPD symptoms ranges between 2% at age 60 to 4% at age 80 and above [1, 2], several thousand people would have to be examined, for example, to identify 100 individuals with pPD possibly eligible for hypothetical trials of novel drugs or interventions aiming at slowing neurodegeneration. A more practical approach is to implement a two-stage strategy: a low cost rapid screening followed by more specific diagnostic tests for those who tested positive [1]. We have recently demonstrated that the odds of PD among individuals with self-reported intestinal constipation, probable rapid eye movements sleep behavior disorder (pRBD), and reduced olfactory discrimination ability are 160 times higher than among individuals without any of these features [5]. Purpose of the present study was to determine the feasibility of screening healthy older adults attending general medical practice in Italy for these features, and to determine their prevalence in different age groups. Further, we assessed the prevalence of selected determinants of PD risk, and calculated for each individual the probability of prodromal PD, using the updated criteria proposed by the Movement Disorders Society (MDS) [4].
METHODS
Study population
Each of four general practitioners (GP) (total covered population ∼ 4,500 individuals) was asked to recruit consecutively 100 subjects aged ≥60 years, attending their primary health care clinics for reasons other than neurologic disorders during the 3-month study period. The total cost per subject was 13 euros, including an incentive (5 euros per recruited patient) for the GPs.
This study was approved by the Bologna Health Trust Ethics Committee and by Harvard University IRB.
Recruitment and assessment of prodromal features
In each clinic, patients aged ≥60 years and without diagnosed neurodegenerative diseases were given an informed consent, a self-administered one-page questionnaire, and an adapted and translated version of the University of Pennsylvania Brief Smell Identification Test (B-SIT–see below) [6]. The questionnaire inquired about history of probable RBD (pRBD) and constipation, and included questions on selected factors associated with PD (smoking history, coffee consumption, and physical activity), and on subjective cognitive function (SCF).
Constipation was defined as a bowel movement frequency of every other day or less, and/or laxative use at least twice a week [7]. Probable RBD was assessed using an RBD screening question from the validated Mayo Sleep Questionnaire [8]. Because this question (“Has your spouse [or sleep partner] told you that you appear to “act out your dreams” while sleeping [punched or flailed arms in the air, shouted or screamed], which has occurred at least three times?”) relies on a sleeping partner, participants without a sleeping partner or with missing information (15.3% of those eligible) were excluded. This question, but without the specification of dream enactment having occurred at least three times, has been reported to have 100% sensitivity and 95% specificity for the diagnosis of polysomnography (PSG)-confirmed RBD in a community-based sample [9]. Olfactory function was assessed using a custom-made B-SIT, a standardized, four-alternative, forced choice test consisting of a booklet containing 12 odorants with one odorant per page; we used the results of Piccillo et al. [10] to select 12 odors that appear to differentiate individuals with PD from healthy control in the Italian population. An olfactory score (B-SIT score) was calculated for each participant by summing the number of correctly identified odors. For the purposes of this study, we defined hyposmia as a B-SIT score ≤7, based on previously used cutoff [5].
Assessment of subjective cognitive function
Assessment of SCF was based on 6 yes/no questions, adapted and translated from a previous study [11–13], on recent change in general memory, executive function, attention and visuo-spatial skills: “Do you have more trouble than usual remembering recent events?”, “Do you have more trouble than usual remembering a short list of items, such as a shopping list?”, “Do you have trouble remembering things from one second to the next?”, “Do you have any difficulty in understanding things or following spoken instructions?”, “Do you have more trouble than usual following a group conversation or a plot in a TV program due to your memory?”, “Do you have trouble finding your way around familiar streets?”. We then assigned equal value to each question, giving 1 point for every “yes”. Based on the distribution of scores in the study population, scores have been categorized as “good” (0 points), “moderate” (1–2 points), and “poor” (3–6 points). SCF can serve as a preclinical indicator of dementia, and is associated with the brain pathology of dementia in clinically normal older individuals [11].
Statistical analysis
Continuous variables were presented as mean and standard deviation (SD), while categorical variables as absolute (N) and relative frequency (%). Chi-square test was used to evaluate the association between factors.
Exploratory analyses on risk factors for SCF using a Poisson regression model, adjusted for age and gender were conducted. Other variables were assessed as covariates (smoking, coffee use, walking, other physical activity, constipation, pRBD and hyposmia). The probability of prodromal PD was calculated using the MDS updated criteria [4].
Statistical analysis was performed using Stata SE 14.2.
RESULTS
During the period of the study (October 1st 2017 to December 28th 2017), a total of 392 individuals completed the questionnaire and the B-SIT. The question on willingness to be contacted for a follow-up was answered by 343 participants; of these, 299 (87.2%) were willing to be contacted, either by phone (n = 227, 78.5%), and/or mail (n = 100, 34.6%), or home visit (n = 20, 6.9%). Demographic and lifestyle of the 392 participants as well as the distribution of pRBD, constipation, hyposmia, and combinations of these features, are summarized in Table 1. No major differences were found comparing GPs’ patients.
Demographics, clinical features and lifestyle habits of the 392 participants
Constipation was more common in women, whereas no significant differences by gender were observed for pRBD and hyposmia (data not shown). The frequency of poor cognitive function increased with age (Table 2).
Associations of age with prodromal features and subjective cognitive function
pRBD, probable rapid eye movements sleep behavior disorder.
The multivariate Poisson regression model, adjusted for age and gender, showed an association between moderate physical activity (90–360 minutes/week vs. no activity) and good cognitive function (IRR = 0.70, 95% CI = 0.51–0.97). According to the MDS updated research criteria, none of the participants in our study qualified as probable prodromal PD. However, the probability of prodromal PD was over 60% in four (1%) participants, and between 40 and 60% in 20 (5%) participants.
DISCUSSION
In this investigation among individuals aged ≥60 years attending primary health care clinics in Bologna, Italy, we demonstrated the feasibility of screening this population at low cost for the presence of prodromal features suggestive of PD. This screening could be routinely applied to identify individuals at high risk of PD, who could then be further evaluated with more specific diagnostic tools and eventually invited to participate in intervention studies on lifestyle changes, such as increase in physical activity and dietary improvements, likely to delay the onset of clinical disease.
Overall, the prevalence of constipation and pRBD in our population was similar to that reported in previous population-based studies that used similar methods and definitions. The prevalence of hyposmia was comparable to other studies [5, 14]. Constipation and hyposmia as isolated features are common among otherwise healthy elderly, but their occurrence with pRBD is distinctly rare in individuals without PD, as would be expected in the absence of a common pathogenic mechanism. This is confirmed by our findings. In contrast, these three features are simultaneously present in a large proportion of individuals with PD [5], probably reflecting the consequence of alpha-synuclein aggregation at different anatomical locations.
Although none of the participants qualified as probable prodromal PD according to the MDS criteria, five individuals had a probability of prodromal PD greater than 40%. These individuals could undergo a second stage screening, including a more thorough assessment of prodromal features and polysomnography. Further, if the purpose of the screening is to identify individuals eligible for clinical trials of novel neuroprotective interventions, more definitive evidence of dopaminergic deficit could be obtained by single-photon emission computerized tomography (SPECT) [15]. Our results are complementary to those of several other studies that used different strategies in order to identify pPD. The strengths and limitations of these studies have been discussed in several recent reviews [16].
A major strength of our study is its low cost and the possibility to scale-up the proposed strategy to all primary care settings.
CONFLICT OF INTEREST
A. Ascherio has received research grants from the National Institutes of Health and the US Department of Defense. S. Bauleo has received speaker honoraria from SIMG (Società Italiana di Medicina Generale). E.Baldin, C. Zenesini, P. Cortelli, R. D’Alessandro, M. Spampinato, F. Montanari, and S. Santi have nothing to disclose.
Footnotes
ACKNOWLEDGMENTS
This study was supported by a private donation for neuroepidemiology research to the Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.