Chronic respiratory diseases and neurodegenerative disorders: a primer for the practicing clinician.

Abstract

Chronic respiratory disorders represent a world epidemic. Their incidence and prevalence in the world population is increasing and, especially among elderly subjects, they are commonly associated with other pathologies, often generating a status of high clinical complexity. Neurology, internal medicine and pneumology specialists should be aware of the common background of these disorders in order to treat correctly the patient’s comorbid state and optimize the treatment considering potential overlaps. In this review, we aim to focus on the relationships between chronic respiratory disorders and chronic neurodegenerative diseases at different levels; we review the shared risk factors and the interactions between disorders, the indications to explore respiratory function in neurodegenerative diseases, pathology-pathology and drug-pathology interactions in patients affected by both chronic neurologic and respiratory diseases. Introduction Both chronic respiratory and neurodegenerative disorders are increasing worldwide, along with the other noncommunicable diseases, mainly because of ageing of the population [1]. These diseases are both associated to a decreased quality and a reduced expentancy of life. The main link between these conditions is ageing itself, however other shared risk factors could increase the strength of this association. In this narrative review, we aimed to identify the shared risk factors, the pathology-pathology and drug-pathology interactions between neurodegenerative disorders and chronic respiratory diseases. Research Strategy We searched PubMed/Medline for case reports, reviews and original research articles in the timeframe from January 1, 2000 to February 1, 2020. We used MeSH major terms and considered: “Pulmonary Disease, Chronic Obstructive”[MeSH] or Lung Diseases, Interstitial [MeSH] or Asthma [MeSH] or Lung Neoplasms [MeSH] in combination with “Tauopathies”[MeSH] or “Alzheimer Disease”[MeSH] or “Parkinson Disease”[MeSH] or “Multiple System Atrophy”[MeSH] or “Supranuclear Palsy, Progressive”[MeSH] or “Corticobasal Degeneration”[MeSH]. The group of reviewers favoured the inclusion of papers from the past 5 years, although they did not exclude highly cited older reports; the reference lists of articles identified by this search strategy was also reviewed, and the working group selected those references judged to be relevant. Shared Risk Factors and Interactions Between Respiratory Diseases and AD Cigarette smoking has been associated with cognitive deterioration and represents a risk factor for Alzheimer’s disease (AD) [2]. The risk of developing AD increases proportionally with the time of exposure and it has been hypothesized a role of APOE genotype in the association between cigarette smoking and risk of Alzheimer’s disease [3]: all the evaluated studies report an increased risk for AD in active smokers, with a dose-dependent effect, and to a lesser extent in ex-smokers [4 – 6]; in the population of smokers, the highest risk has been observed among carriers of the APOE ε4 allele [7]. The typical neuroanatomic alterations observed among smokers are characterized by a reduction of hippocampal volume, while cognitive impairment is mainly due to a memory and learning deficit [8 – 10]. Smoking is associated with cognitive deterioration with several other shared physiopathogenetic mechanisms: for example, chronic cerebrovascular pathology, affecting both large and small vessels and COPD in the subset of chronic hypoxemic subjects is associated with cognitive deterioration [11]. The relationship between COPD, hypoxemia and cognitive deterioration has been extensively evaluated in different clinical settings; a cognitive deterioration without a definite neurodegenerative pathology is present in COPD subjects with a prevalence ranging between 10.4% and 48.5% [12 – 14]. This association, however, has been confirmed only in patients with more severe COPD forms after covariate adjustment [15]. Moreover, among COPD patients, some pre-clinical neurodegenerative pathologies such as non-amnestic mild cognitive impairment (MCI) are more represented than in general population [16]. A chronic obstruction of lung function in younger ages, as in COPD or in asthma, has been associated with a higher risk of MCI or dementia in the geriatric age [17]. AD is also associated with a higher prevalence of sleep disordered breathing (SDB), particularly OSAS [18, 19]. The association between AD and OSAS is secondary to both central and peripheral alterations and associated to a greater cognitive deterioration in respect to AD alone [20, 21]. In the last years, several authors found that OSAS could be considered a risk factor for progression of cognitive impairment [22, 23]. Moreover, in this subgroup of patients the cognitive deterioration could be slowed by CPAP treatment [24]. Cancer incidence [25], particularly lung cancer [26] seems to be lower in AD and in other central neurodegenerative diseases. Several observations from animal models, transcriptomic meta-analyses and matrix factorization studies underline the existence of molecular substrates supporting the hypothesis of an inverse comorbidity relationship between AD and lung cancer [27 – 29]. Shared Risk Factors and Interactions Between Respiratory Diseases and PD The role of cigarette smoking in Parkinson’s Disease (PD) has been extensively studied. Recent meta-analyses underlined a reduced risk of developing PD in previous smokers, which is further reduced in active smokers at the time of the study [30, 31]. The biological rationale of this association is not known, but it is attributed to the effect of nicotine in stimulating dopamine release and modulating the central monoamino-oxydase activity. However, several authors postulated that, despite the high number of papers suggesting this hypothesis, this observation could be caused by some methodological biases, suggesting that the observed neuroprotective effect of smoking could be associated to reverse causality [32]. Moreover, some retrospective studies underlined a higher risk of PD among COPD patients [33]. Aspiration pneumonia represents the 70% of PD-associated deaths [34]. This pathology should be always suspected in PD patients developing fever or respiratory symptoms, particularly in those with known dysphagia or sialorrhea; a normal deglutition requires an appropriate pharyngeal and laryngeal stimulation, an adequate muscular tone and proper coordination between deglutition and action of respiratory muscles. If the bolus is accidentally sent in the airways, cough acts as a protective mechanism. With disease progression, mastication and deglutition are difficult due to bradykinesia, stiffness and dyskinesias. A sensitive deficit in the glossopharyngeal and vagus nerve territories can contribute to dysphagia [35]. Disturbances in deglutition that increase oral material and accidental aspiration are present in 60% of PD-affected patients. This is important, as aspiration of saliva itself can be a cause of pneumonia, with no relationship with meals. The coordination of breathing with deglutition is dysfunctional in these subjects, and cough becomes less effective for increased chest wall stiffness and a reduction of the sensorial component of cough reflex. The PD medical treatment can improve respiratory function, but levodopa does not seem to improve dysphagia. Sialorrhea can be treated with anticholinergic drugs, as clonidine, or with surgical resection of salivary glands, radiotherapy or local treatment with botulinic toxin. Tracheostomy can be suggested as last preventive measure, to be considered only after an extensive evaluation of the patient and his quality of life. Oropharyngeal dysphagia affects 4 out of 5 PD patients, and it is an often underestimated complication by both patients and caregivers [36]. This symptom, characterized by the chronic aspiration of oral or gastric material due to alterations of deglutition mechanisms, can cause anatomic alterations that can manifest with nodular, multilobular or centrilobular alterations, “tree-in-bud” and interstitial thickening which can evolve to lung fibrosis [45]. The most common histopathological finding in chronic aspirative pneumonia is compatible with bronchiolitis obliterans-organizing pneumonia (BOOP), often combined with suppurative granulomas, bronchiolitis and bronco-pneumopathy associated with suppurative granulomas [46]. The prevalence of restrictive diseases in patients affected by PD varies between 28% and 85% [36], with extreme variability caused by antiparkinsonian drugs use. Dyspnoea associated with restrictive diseases usually starts as an exertional dyspnoea which progressively evolves into a resting dyspnoea associated to a worsening of typical PD motor symptoms, such as falls or gait freezing [37]. The pathophysiological mechanisms underlying this are not well understood, The pathophysiological mechanisms of restrictive breathing disorders have still not been completely elucidated, albeit mainly associated with stiffness and bradykinesias of respiratory muscles and to reduced compliance of the thoracic wall. Spirometry is compatible with muscle weakness of thoracic wall muscle weakness which is similar to peripheral neuromuscular disease, but there is little evidence of this effect in PD [38]. Osteomuscolar alterations of the neck, as camptocormia, can contribute to restrictive pattern thus limiting thorax expansion and reducing respiratory volumes [39 – 41]. A restrictive respiratory insufficiency in the setting of PD usually improve with dopaminergic treatment, which could be less effective in the most advanced stages of disease [40]. In the subset of patients in whom camptocormia is present, respiratory exercises can be effective, but this indication comes from a single case-report [42]. A vigorous program of respiratory rehabilitation seems to be able to improve both respiratory and cardiovascular function