Is Parkinson’s Disease a Very Rare Pathology in Centenarians? A Clinical Study in a Cohort of Subjects

INTRODUCTION

With the progressive increase in life expectancy, due to improvements in social and health measures in nutrition, education, sanitation, and medicine [1], many older populations have recorded impressive expansion, particularly centenarians that are among the fastest growing groups in developed and developing countries [2].

However, living longer does not necessarily mean staying healthy: aging is a complex time-dependent process in which individual genetic and epigenetic traits associated with environmental differences and lifestyle heterogeneity have a great impact on the onset of the age-related disorders. Cardiovascular and cerebrovascular disorders, neurodegenerative diseases, diabetes mellitus, and cancer are among the most frequent pathological conditions of the elderly [3].

In the field of neurodegenerative diseases, after Alzheimer’s disease (AD), Parkinson’s disease (PD) is the most common disorder in developed societies. As a movement disorder, PD is clinically characterized by rigidity, resting tremor, bradykinesia, and postural imbalance. PD neuropathology shows a selective loss of dopaminergic neurons in the substantia nigra pars compacta and presence of Lewy body inclusions, that are alpha-synuclein intracellular aggregates, neuropathological hallmark of PD.

As in other age-related neurodegenerative disorders, brain aging is the main risk factor of PD, but different risk factors, such as use of postmenopausal hormones, exposure to pesticides or environmental chemicals, brain microtrauma, focal cerebrovascular damage, and genomic defects, may play a potentially pathogenetic role in the onset of the disease [4]. On the other hand, different habits and lifestyle have been associated with a lower PD risk: smoking [5, 6], coffee and caffeine [7, 8], and physical activity [9, 10] have been described as protective factors.

PD is more prevalent in males than in females, although some studies found no significant difference in PD prevalence between men and women. Epidemiological studies show that PD is uncommon before 50 years of age, with a progressive increase of prevalence at later ages [3]. Importantly data on prevalence of PD in people over 100 years old are very rare.

In 2014, we started the population-based study “CaT: Centenari a Trieste” with the purpose to enroll all centenarians living in Trieste city and province, a small coastal area in the North-East of Italy. This area has wide genetic heterogeneity, different languages, religions, and habits. According to the protocol, all centenarians enrolled in the study underwent neurological and neuropsychological examination [11]. Here we discuss the neurological findings in 93 centenarians from the CaT Study, focusing on PD clinical signs, demographic data, and lifestyle. To our knowledge, this is the first study on PD and subjects in the 11th decade of life.

METHODS

The CaT Study is a population-based study on the centenarians living in Trieste, aimed at studying their health status and health service use, with specific focus on cognitive status. Centenarians are visited at their place of residence after obtaining informed consent. The aims of the CaT project, the protocol, and the preliminary data have been published [11]. The study is currently ongoing.

To assess the presence of PD, we performed: 1) medical history collection from interview with the centenarian plus the caregiver or the family members, recording all demographic data, family history, habits and lifestyle, eating habits dating back, if possible, to 50 years ago, and past and present pathologies and neuropsychiatric disorders, particularly agitation, depression, and psychosis. We also reviewed present and past therapeutic plans; 2) neurological examination for PD diagnosis took into account rigidity, bradykinesia, hypokinesia, resting tremor, and postural imbalance. Atypical parkinsonism signs were excluded during the neurological examination. Evaluation of non-motor disturbances included neuropsychiatric and autonomic disorders; 3) neuropsychological evaluation for cognitive impairment was performed using the Consortium to Establish a Registry on Alzheimer’s Dementia (CERAD) battery [12]. The diagnosis of dementia was made applying the criteria of DSM-IV [13].

Trieste LHA Ethics Committee approved the first wave of this study, while the Friuli-Venezia Giulia Regional Ethics Committee approved the ongoing wave.

RESULTS

Neurological evaluation was possible in 90 (97%) of the 93 centenarians included in the project until December 2018. Their general characteristics are presented in Table 1. The sex ratio (9 women for each man) is in line with usual demographics at this age. The high percentage of coffee consumers (particularly compared to tea drinkers) is specific to the Italian population. One in three centenarians still takes a walk every day to keep fit, with a wide variety of mean daily walking times (between 10 minutes and more than an hour). None of the centenarians presented orthostatic hypotension and drooling, while some of them presented constipation or incontinence.

In subjects with a past history of depression, the diagnosis was a reactive form resolved with antidepressants. Few centenarians showed slight depressive mood disorder, especially those living in nursing home. When asked about their professional history, we did not elicit any exposure to toxic agents. Furthermore, we have no notice of specific environmental toxic presence in the Province of Trieste and neighborhoods. None of the centenarians presented a clinical picture compatible with a classic form of PD (prevalence 0%, 95% score confidence interval: 0% to 4.1%). Surprisingly, even the subjects with vascular encephalopathy documented by CT scan, presented pyramidal syndrome but not hypotonic-akinetic syndrome. Consistently with the diagnosis, no subject took any anti-parkinsonian drug (ATC code N04).

In our study, 57% of the subjects met criteria for diagnosis of dementia. Very few centenarians performed cerebral CT scan. Subjects affected by dementia presented clinical pictures compatible with degenerative forms characterized by predominant memory impairment, but not all of them presented typical picture superimposable to AD. Other cases presented mixed form of degenerative and vascular dementia. Sporadic episodes of psychomotor agitation, mainly at nightfall or overnight, were observed in few centenarians affected by dementia.

DISCUSSION

In our study we studied PD prevalence in a cohort of Italian centenarians: the diagnosis of PD was made by medical history, neurological examination, and review of past medical records and treatment plans. To our knowledge, there are no systematic clinical data from studies focused on people over 100 years of age, of which only sporadic data have been published.

Despite the concomitant high prevalence of dementia in our centenarians, no one was affected by PD. The rarity of the presence of PD in centenarians is peculiar, considering that this neurodegenerative disorder is second for prevalence only to AD in subjects under 85 years and PD prevalence increases with age from 425 cases/100.000 at 65–74 years to 1903/100,000 at over age 80 [3]. Other studies reported a decline in prevalence of PD in the oldest population [14], but data differences probably could depend on methodological heterogeneity of the studies.

In recent studies on centenarians, PD prevalence was one out of 23 in one study [15] and one out of 40 in another [16], both roughly compatible with our estimate.

The strength of our study is the large number of ultra-centenarians (100–108 years) of different origins, habits, and lifestyle.

A limitation of our study is that postural instability, one of the classical symptoms of PD, was difficult to evaluate because some centenarians were not cooperating or were bedridden or affected by medical comorbidities. Furthermore, we could not gather enough information on presence of neurodegenerative disorders in relatives of the centenarians.

In the centenarians affected by dementia, the clinical picture was predominantly characterized by loss of memory, similar but not always really superimposable to AD. In these cases, we could speculate that some centenarians suffer from LATE dementia [17]. Mixed forms of degenerative and vascular dementia were also observed. The criteria for the diagnosis of dementia have intrinsic difficulties when used in centenarians: indeed, a decline from previous levels of cognition is often regarded as “normal” in this population. Moreover, sensory limitations, such as deafness and blindness, can give false positive results to neuropsychological evaluation. In addition, acknowledged normative data are not available for this age group as already reported [18].

When clinical history was collected interviewing the family or caregivers of centenarians, we had a confirmation that in the past none of the subjects of the study presented symptoms or had a diagnosis of PD. In line with this, none of them took, at enrollment or before, any anti-Parkinson drugs.

Taking into account our results, some preliminary considerations can be made on the low prevalence of PD in centenarians.

The first one is the gender effect: the majority of the studies show that PD is more frequent in men than women and, since centenarians males are only 10% of the population, we can assume that male subjects with PD have already died before reaching 100 years. Following this line of thought, data on survival of subjects who had PD before 100 years of age would be important in shedding light on the real prevalence of PD in centenarians.

Second, recent neuropathological studies in centenarian and supercentenarian brains have reported the scarcity or absence of alpha-synuclein pathology, despite the high presence of amyloid-β, tau and TDP-43 pathology [19, 20]. We could speculate that alpha-synuclein aggregates when present in substantia nigra are not sufficient to cause a significant neuronal loss leading to PD signs. Other explanations may be attributed to the complex regulation by the metabolic pathways important in the aging process, such as REST or Sirtuins [21] or the genetic influence by genes associated to longevity. It has recently been reported that FOXO3A, whose gene variations correlate with longevity [22], controls autophagic and mitophagic flux in neurons, pointing to the gene as an important factor in substantia nigra neuron survival [23].

In conclusion, PD prevalence is very low in the centenarians and this could depend on the specific characteristics of our cohort, or on biological and genetic mechanisms intrinsic to the very elderly subjects.

This first study on PD prevalence in subjects 100 years old and over needs replication in larger datasets but is interesting in suggesting future fields of investigation on protective factors against PD.