Article Type : Research Article
Authors : Zarola F
Keywords : Anosmia, Parkinson’s disease, L-Dopa, Stroke, Cerebrovascular disease, Vascular parkinsonism, Pathogenesis
Loss of smell (anosmia) is a frequently
found symptom in Parkinson's disease. Moreover, numerous studies have
highlighted a significant incidence of cerebrovascular disease in patients with
Parkinson’s disease. The smell disorder has been framed as an indicator of a
sensory pathological process consistent with the hypothesis of the origin of
the disease from the peripheral and visceral nervous system, according to Braak
theory. In this study, we sought a correlation between vascular damage, a
possible contributing factor for 'central' type neurodegeneration, and anosmia
in a cohort of 118 patients with Parkinson’s disease of the outpatients’ clinic
for Movement Disorders. In this investigation we calculated the absolute and
relative percentages of the two considered parameters for the total population
and the subpopulations respectively; thereafter we performed the statistical
analysis for cerebrovascular disease and anosmia with the chi-square test,
which showed no correlation. This finding corroborates the idea of different
and independent mechanisms of pathogenic processes and compromises the symptom anosmia
as a unique marker or predictor of the disease.
There are many studies on the etiopathogenesis of
Parkinson's disease (PD), but to date there are no univocal models that can
lead to a single cause or pathogenic mechanism, and apart from the
investigation of genetic or toxic variants, the cases most commonly encountered
in clinical practice are universally accepted as probably due to multifactorial
causes and in high degree linked to aging factors. In particular, the
scientific debate is divided between the hypotheses of a "central
descending" origin of neurodegeneration, in which the loss of dopaminergic
receptor function originates from the encephalic network, and a
"peripheral ascending" origin (Braak's hypothesis) in which the
pathological alpha-synuclein and degenerative components originates at the gastrointestinal
level and the process then extends to the Central Nervous System (CNS) [1,2].
The latter case makes an elegant compatibility with the neurovegetative
disorders present in PD as well as in related neurodegenerative forms. In
recent studies by this Author, parameters of general occurrence in groups of
patients with PD such as cerebrovascular disease (CVD) and its significant,
non-random, incidence have been statistically evaluated. In agreement with
Braak's hypothesis, another parameter that is highlighted by researchers is the
frequency of the loss of smell (anosmia) in patients affected by PD, which can
even precede the clinical onset of the disease by many years. This symptom has
also been taken into consideration as a biomarker or predictor of the disease.
In the present study the Author investigated the statistical relation between
CVD and smell loss or impairment in a population of patients taken in charge on
the basis of data retrospectively analyzed from the database of the PD Center of
Albano Laziale. The incidence of the symptom anosmia hyposmia was firstly
evaluated in the total population of patients diagnosed with PD. External
causes of hyposmia, such as infectious or head traumas’ outcomes or other local
pathologies, were previously considered and excluded. The incidence of hyposmia
symptom was then studied in ratio to cerebrovascular damage in PD patients with
imaging lesions of CVD. The incidence of hypoanosmic or not PD patient’s
with\without CVD was then evaluated by means of percentages on total population
and subpopulations; afterwards statistical tests analysis was performed.
A total population of 130 patients with a definite
diagnosis of Parkinson's disease, carried out through clinical-instrumental
investigations, including objective examination, score scale examinations
(mainly Unified Parkinson's Disease Rating Scale, UPDRS, and Mini Mental State
Evaluation, MMSE), brain magnetic resonance (RM imaging), Iodine Ioflupane-123I
scintigraphy (daTscan), was initially available. Among these we counted 118,
after excluding the cases in which some of the parameters necessary for the
study were missing in the data stored in the database of the Center for
Movement Disorders between 2014 and 2024. The cohort includes a large age range
due to the heterogeneity of patients’ age at the different time of taking in
charge, and to the duration of taking in charge, generally rather long (between
3 and 12 years). The computer storage program used includes in the data screen
several parameters, among which the presence absence of the symptom anosmia hyposmia,
recorded, similarly to other parameters, as an 'absolute' value (yes\no) for
each patient when certainly related to the disease and not to other causes
(such as infectious or head traumas’ outcomes or other pathologies). All the
data could be extracted and processed ‘off-line’ with an excel system, able to
select the subpopulations and the parameters chosen for the statistical
analysis. As already mentioned, some of the cases in the subgroups were lacking
of sure information, therefore they were not counted into the numbers for the
analysis (Table1). We calculated the absolute percentage of patients reporting
the symptom anosmia in the total population of PD patients and the absolute percentage
of patients with CVD in the total population with PD, respectively. CVD was
defined based on the finding of multifocal Fazekas type 2\3 damage, or as a
result of stroke with the support of brain MRI and/or CT scan, with the same
criteria as previous research. Then, the percentage of subjects with anosmia
affected by CVD on the total subpopulation of anosmic subjects and that of
anosmic subjects without CVD were calculated. Conversely, the percentage of
anosmic patients on the total subpopulation of PD patients with CVD and that of
anosmic subjects on total PD subpopulatin without CVD were calculated as well (Table
2). Afterwards we applied a statistical analysis by the Chi-Square Calculator
contingency table considering subjects with CVD as the independent variables,
to check eventually a correlation with the anosmic condition (Table 3).
On (Table 1) there are the absolute numbers of
cross-referenced patients’ subpopulations, showing the missing values for a
total of 12 subjects on 130. The
values of the calculated percentages are shown on (Table 2). The results of the statistical analysis
with the Chi Square Calculator are shown in (Table 3).
Despite the amount of studies on the etiopathogenesis of Parkinson's disease, to date there are no univocal interpretation or scientific models that allow us to identify a cause or a univocal mechanism, but apart from the genetic variants’ description, the cases commonly encountered in clinical practice as idiopathic are universally accepted as probably of multifactorial origin. Various pathogenic models have been speculated to explain neurodegeneration, calling into question the histopathological findings of anomalous molecular structures (TAU proteins, alpha synuclein, neurofibrils, Lewy bodies, etc.) in nervous tissue of affected patients [2-6]. Recently Braak's theory has highlighted a possible primary role of the peripheral visceral component as the starting mechanism for the central neurodegenerative process, leading to the hypothesis of the "ascending track" in the development of Parkinson's disease. In the scenario of neurovegetative symptoms, the loss of smell has raised the attention of many researchers, as it can precede the onset of the extrapyramidal symptoms by many years, bringing them to consider it as a predictor of PD. Indeed, it has also been taken into consideration as a possible biomarker of the disease [7,8]. In more recent times, studies have been conducted on the possible role of cerebrovascular damage in PD [9-12]. In particular, a significant incidence of CVD has been observed in patients affected by the common, non-genetic form of PD, through statistical analysis on cohort’ patients or descriptions of single clinical cases [11,12]. The ‘central’ oxidative mechanism due to vascular impairment is therefore listed as a possible contributing factor to pathogenesis of PD, through a direct or indirect mechanism of the dopamine receptor network damage. This configuration is commonly clearly distinguished from the so-called vascular Parkinsonism, in which a poor response to dopaminergic therapy suggests in clinical practice a probable structural disruption of the extrapyramidal system, although with clinical phenomena superimposable to idiopathic PD. However, this clear distinction has recently been questioned with articles by several authors who report a good response to dopaminergic therapy in patients classified as having vascular parkinsonism, in which the clinical features did not allow a redefinition as PD (for example in patients with abrupt onset of the syndrome after a stroke, but with good response to dopaminergic therapy) [11, 13-15]. The aim of this retrospective study was to investigate the statistical relationship between the two parameters CVD and anosmia by means of the data extracted from the patients’ population in charge in the clinic for Parkinson’s disease and Movement Disorders. This in order to speculate whether there is any link or if there are possible independent or concurrent pathogenic mechanisms for idiopathic PD genesis. Although an initial look draws attention to the relevance of the numbers (patients with CVD and anosmia 39, patients with CVD without the symptom 59, patients with the symptom without CVD 11), which highlight a consistent coexistence of the two parameters, albeit with a prevalence of CVD alone (59 patients), the cross-statistical study did not give a positive result to confirm any significantl linkage (see table3, p=.20985). Again in this study the numbers show an absolute prevalence of the CVD in the observed population (98 out of 118, equal to 83%), if compared with the incidence of the anosmia symptom (50 out of 118, equal to 42.4%), while anosmic patients affected also by CVD resulted 39 on total subpopulation with anosmia (50), i.e. 78%. In other words, especially in light of the statistical verification, in this study CVD and anosmia seem to be independent parameters and therefore, they can be said not correlated or linked, although a concurrence in PD pathogenesis cannot be excluded, consistently with the multifactorial explanation. Ultimately, this finding can be considered a further confirmation of the non-exclusiveness of Braak's 'ascending' theory, being able to orient oneself towards the 'central' origin of the disease in a predominant part of the cases and assuming that CVD is indeed a critical factor in PD pathogenesis. Finally, it is well known to clinicians that olfactory disorder is not a constant but has a relatively low incidence in “sporadic” PD, which undermines its use as an absolute biomarker.
Acknowledgments
The Author wish to thank the coordinator of District H2,
Dr. Rita Bartolomei, the nurse coordinator Francesco Pepe, Mrs Marina Taddei
and the nurse staff of the 2nd District of ASL RM6.