Dementia and Pressure Ulcers: Is There a Close Pathophysiological Interrelation?

Abstract

The current theoretical investigation aimed to explore common pathophysiological mechanisms underlying dementia and pressure ulcers (PU). Along with the increased longevity, especially in frail elderly patients, there is a higher rate of functional and cognitive impairment with dementia coinciding with immobility, which results in a higher rate of PU. Understanding common etiological paths resulting in pressure ulcers and dementia is likely to produce new treatment strategies that could lead to the prevention of comorbid complications. Data collected from elderly dementia patients indicate a deterioration of several neurophysiological subsystems associated with motor, sensory, autonomic, cognitive, or behavioral pathways, supporting a “close pathophysiological interrelation” perspective linking PU with dementia progression. Overall, the authors’ theoretical systemic-model of disease progression and PU comorbidity proposes that increased clinician awareness to PU in mild to moderate dementia may suppress the accelerated development of PU, resulting in less patient suffering, reduced long-term care hospitalization, and hopefully PU prevention.

Keywords

Advanced dementia Alzheimer’s disease comorbidity pressure ulcers

INTRODUCTION

Dementia is caused by a variety of late-life neurodegenerative disorders. The prevalence of these disorders (e.g., Alzheimer’s disease (AD), vascular dementia) has increased significantly with longer life expectancy, especially in elderly patients, and has been found to be a leading cause of death [1]. In the United States, there are approximately 4 million people with dementia, and this number continues to grow [2]. There is less consideration for the advanced stages of dementia, and therefore a noticeable lack of informative knowledge of treatment effects and complications. The clinical course of advanced dementia as well as the associated symptoms and complications, is known primarily by general clinicians, family physicians, geriatricians and therapists (speech, physio, occupation) and insufficiently by clinicians from other disciplines [3]. However, with increasing numbers of affected patients, advanced dementia and related associated pathophysiological conditions are becoming more prevalent. Mitchell and colleagues [4] studied the last 18 months of life in elderly patients living with advanced dementia, the most prevalent symptoms included pneumonia, 41.1%; a febrile episode, 52.6%; an eating problem, 85.8% dyspnea (≥5 days per month), 46.0%; pain (≥5 days per month), 39.1%; pressure ulcers (stage II or higher), 38.7%; agitation, 53.6%; and aspiration, 40.6% [4]. Along with the increased longevity, there is a higher rate of functional impairment and immobility resulting in a higher rate of PU [5]. Pressure ulcers are characterized as a localized skin injury in underlying tissue, usually observed over a bony prominence, caused by strain and deformation of soft tissues [6]. The shared mechanisms by which stress and internal strain interact with damaged skin and subcutaneous tissue are likely to result in pressure ulcer development, including localized ischemia, reperfusion injury, impaired lymphatic drainage and sustained cell deformation [7]. The prevalence of PU in two long-term geriatric-care facilities in Canada was found to be 36.8% and 53.2%, respectively [8]. Approximately 70% of Americans with dementia will die in nursing homes [9]. The estimated total cost of PU treatment in the UK in 2004 was £1.4–£2.1 billion annually (4% of total NHS expenditure) [10].

The physiological impact of skin fibroblast activity in healing wounds, and specifically in pressure ulcers, is critical in promoting wound-healing processes including keratinocyte migration, release of growth factors, and neovascularization [11]. However, fibroblasts from pressure ulcers have been found to become prematurely senescent and dysfunctional [12]. In dementia patients, cognitive and skin tissue deterioration imply a possible shared mechanism (e.g., interruptions in cellular signal transductions) for the development of pressure ulcers in patients with dementia.

Therefore, understanding common pathophysiological paths resulting in PU and dementia is likely to produce new treatment strategies associated with monitoring calorie and protein levels, hemoglobin levels, and infections. Taking into account these systemic effects could lead to the prevention of co-morbid complications. Is there a common pathophysiological mechanism underlying demented cognitive impairment and skin aberrations? Apparently, these are two separate conditions. One condition is manifested by functional and cognitive impairment, and the other is manifested by soft tissue damage. Recent data suggested a link between dementia and PU. In nursing homes, Mitchell et al. [4] found 38.7% of PU prevalence in people with advanced dementia. In a retrospective study of 135 patients with advanced dementia 47.4% suffered from PU (pressure ulcers grade 3 or 4) [13]. Data collected in the Skilled Nursing Department (in Herzog hospital, Jerusalem, Israel) indicated a higher prevalence of PU occurrence in people with dementia, and also a higher rate of patients with dementia in people with PU [14, 15]. In elderly patients with PU, 76% had dementia in comparison to people without PU, where only 32% had dementia. Hazard ratio (HR) for dementia was 3, p = 0.002 [14]. Dementia patients displayed a high rate (66.5%) of PU in comparison to people without dementia (33.5%) [15]. Regarding the investigation of PU prevalence in dementia, the current paper aims to present a potential pathophysiological link between advanced dementia and PU, in order to increase prevention-awareness of PU comorbidity in people with dementia, and to investigate clinical and ethical implications that arise in this encounter.

PROPOSED COMMON ETIOLOGICAL PATHWAY

Dementia is typically viewed as a neurodegenerative disease without peripheral implications. However, Gibson et al. [16] suggested that, “Considerable evidence suggests that Alzheimer Disease (AD) may not simply be a “brain disease”, but that changes occur in peripheral tissues as well [16]. Recent findings related to assessing human skin fibroblasts aggregation rates suggested that abnormal skin fibroblast aggregation rates can be considered as a new peripheral biomarker that clearly discriminates AD patients from age-matched healthy controls [17]. High density of human fibroblast cell aggregates (unlike abnormal cell-density increases in AD) increase cell-cell interaction and therefore increase the probability of further accelerating skin wound healing in healthy adults. In AD, intercellular adhesiveness of fibroblasts is abnormal. These AD-related differences in cell morphology population result in differences in intercellular adhesiveness, which may increase the risk of PU onset [17]. In our opinion abnormal fibroblast aggregation rates in AD cases, may reflect an etiological gateway that induces accelerated PU development and prevalence. The potential mechanisms mediating the “peripheral” impact of AD pathophysiology, leading to abnormal accelerated change in fibroblast aggregation rates, may be perceived as directly related to the ongoing deterioration of neurophysiological subsystems associated with motor, sensory, autonomic, cognitive, and behavioral pathways.

Motor pathway

The first proposed mechanism mediating the impact of dementia on pressure ulcer development is derived from the motor pathway. The impact on the motor pathway in vascular dementia is clear due to a compromise in blood supply to the peripheral nervous system. In non-vascular dementia such as AD, there are often symptoms of motor neuron deficits that might emerge from a common neurodegenerative mechanism [18]. The impact of motor neuron pathophysiology increases the likelihood for gait disorders, falls, weakness, and tendency towards complete immobility. Additionally, para-tonus and rigidity are typically found in patients with AD in advanced stages [19]. The increased tone and difficulty in mobilization increases the patient’s vulnerability to pressure points, and ultimately leads to the development of ulcers in these locations [20]. Apart from the damage to motor neurons, dementia also affects muscles involved in swallowing, resulting in malnutrition and aspiration pneumonia. Both malnutrition and infections are known risk factors for pressure ulcers [21, 22]. The process affecting the motor neurons (caused by the underlying neurodegenerative disease progression) could hypothetically result in increased rate of PU in patients with dementia. The motor neuron deficits observed in dementia could be inherently related to the structural changes detected in the supplementary motor area (SMA), and the lateral portion of the primary motor cortex (M1) in aging older individuals versus younger adults [23]. Clinically predefined levels of severity related to structural changes in the motor system could signal a “pathological-gateway” indicating the approaching onset of dementia. Aging is also related to increased risk for dementia, therefore, predominant SMA or M1 structural changes could be perceived as neurodegenerative pre-symptomatic stage preceding the onset of a neurodegenerative disorder, leading to dementia, and possibly, to PU co-morbidity. Assessment of structural MRI scans and PU in advanced dementia patients versus mild cognitive impairment (MCI) patients versus healthy elderly controls might confirm or reject this hypothesis. In support, motor-cortex areas show accelerated grey-matter atrophy in Alzheimer’s disease. More so, reduction in long-term potentiation activity associated with Ca^2 + dysregulation seems to impact motor memory formation, and is consistently reported in older aging individuals [24]. Accordingly, this negative impact on motor memory formation is associated with progressive loss of cortical neurotransmission capability in the early stages of dementia [25, 26], leading to reduced mobility, which is likely to result in an increased rate of PU.

Sensory pathway

Dementia is also known to result in sensory deficits leading to altered perception and reduced day-to day functioning. Dementia patients may suffer from impaired astereognosis, which is tactile agnosia for texture, density, shape, and weight [27]. Both the Braden scale and the improved Norton scale risk assessments include sensory perception as part of the scoring system for pressure ulcers. Whether these deficits are central (e.g., brain) or peripheral (e.g., somatic nervous system) is not known. Additionally, dementia has been shown to impair patients’ perception of pain, especially as the disease progresses [28]. The limited capacity of patients to sense pain or pressure is likely to lead to increased immobility. Immobility and impaired body-repositioning results in poor oxygen perfusion and local ischemic damage [29]. Therefore, the collective sensory deficits in patients with dementia are a potential mechanism by which dementia leads to increased pressure ulcers due to decreased sensory activity, and the inability to initiate movements.

Autonomic pathway

The third potential shared systemic mechanism related to dementia and pressure ulcers involves the Autonomic Nervous System (ANS). In dementia, there is ANS dysfunction [30]. A number of mechanisms related to ANS dysfunction can lead to higher prevalence of pressure ulcers. Sympathetic system dysfunction can lead to blood pressure dysregulation with hypotensive episodes, increased heart rate variability and syncope leading to increase falls which are a known risk factor for fractures, immobility and eventually pressure ulcers [31]. In support, studies investigating heart rate variability (HRV) and pre-dementia stages in humans discovered an association between autonomic dysfunction and the prodromal stages of dementia. Specifically, their findings indicated a significant positive correlation between the performance on cognitive tests and HRV across different age groups and conditions, including MCI and AD patients [32]. Most importantly, reduced HRV has been found to be associated with increased all-cause mortality in the general elderly population. HRV regulation by the ANS is abnormal in elderly MCI patients and is significantly associated with blood pressure dysregulation, which leads to increased falling during hypotensive episodes. Autonomic symptom scores are reported to predict falls in dementia, thus, HRV deficits may represent an indirect risk for PU development via falls that lead to increased skin damage (followed by falling physical impact). Thus, excessive falls and BP dysregulation indirectly increases PU prevalence in dementia patients, which can lead to accelerated PU prevalence, and reduced survival [32]. In correspondence, sympathetic system peripheral vasoconstriction of microcirculation is increased in dementia [33]. The vasoconstriction limits blood flow to organs (ischemia), thereby increasing skin susceptibility to the development of pressure ulcers. Several neurodegenerative disorders have been associated with autonomic and endothelial dysfunction, which are explained by the vaso-constrictive role of endothelin-1 in the sympathetic response cascade (Renin-angiotensin, reactive oxygen species, nitric oxide, endothelin-1) and vascular function [33]

Cognitive pathway

The most dominant apparent aspect of dementia is pervasive cognitive impairment. Accelerated cognitive decline in dementia includes deterioration of higher brain-functions resulting in loss of memory and significant behavioral deficits in executive functioning, which exerts a negative impact on basic activities of daily living (ADL) [24, 34]. Reduced ADL parameters (e.g., immobility, bladder control, fecal incontinence, low hygiene) have been shown to be a risk factor for pressure ulcers [34]. Additionally, cognitive impairment in AD patients was recently found to correlate with changes in peripheral inflammatory signals such as TNF-alpha and IL-1B. The presence of amyloid- β, associated with neurodegenerative cognitive impairment, has been shown to limit signal transduction in cell cultures of skin fibroblasts [35]. In skin-healing, the signal transduction is critical for repairing wounds. Therefore, limited signal transduction due to accumulation of amyloid-β can increase the risk for the development of pressure ulcers in AD patients. Additionally, deficits in protein kinase C have been found in AD brain tissues and skin fibroblasts [35]. Increased oxidative stress observed in AD patients’ brains has also been shown to affect cognitive functioning, including a systemic effect on fluids (cerebrospinal fluid, plasma, and urine) and cells (platelets, lymphocytes, and fibroblasts). Thus, indicators of oxidative stress are associated with AD progression and possibly with PU comorbidity [16]. Prospective, longitudinal investigations assessing the relationship between oxidative stress, cognitive decline, and PU comorbidity in dementia are warranted in order to highlight the systemic shared etiology of PU prevalence and AD progression [36].

Behavioral pathway

In dementia, behavioral disturbances are commonly associated with progressive loss of cortical connectivity, reduced medial temporal lobe volume, and decreased hippocampal activation [25, 26]. Additionally, reduced cholinergic neurotransmission is thought to be related to amyloid deposition and plaque formation observed in AD pathophysiology, which was found to be significantly correlated with memory loss and cognitive impairment [37]. These neurobehavioral changes are initially observed as pervasive behavioral disturbances. For instance, dementia patients are frequently agitated and engage in repetitive movements that lead to friction and shearing forces increasing the prevalence of pressure ulcers. Early detection of behavioral disturbances associated with pre-dementia memory loss may direct clinicians to employ earlier treatment interventions/strategies to suppress the prevalence of PU-comorbidity in the upcoming advanced stages of dementia.

CONCLUSION

Dementia and pressure ulcers are common in the frail elderly population, particularly becoming more prevalent as longevity increases. Therefore, our theoretical perspective implies that PU is a systemic symptom associated with the clinical course of advanced dementia and mortality. Accordingly, the authors highlighted common physiological systems associated with motor, sensory, autonomic, cognitive and behavioral mechanisms that underscore pathophysiological interrelations between dementia and PU. The major clinical question facing geriatric clinicians is— can PU be significantly reduced in order to improve survival in advanced dementia patients? The scientific literature indicates that the onset of PU in dementia patients is associated with reduced survival [4, 14]. In addition, the appearance of PU in dementia patients may affect ethical considerations related to end-of-life decisions. Therefore, in light of the strong association between neurodegenerative processes and PU, we propose that increased clinician awareness to PU in mild to moderate dementia patients may suppress the accelerated development of PU. Thus, ongoing clinical assessment of PU onset is likely to prevent co-morbid complications, which will attenuate patient suffering during the advanced stages of dementia.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-1134).

References

Lucca

, Tettamanti

, Logroscino

, Tiraboschi

, Landi

, Sacco

(2015) Prevalence of dementia in the oldest old: The Monzino 80-plus population based study. Alzheimers Dement 11, 258–270.

Alzheimer’s Association (2012) Alzheimer’s disease facts and figures. Alzheimer Dement 8, 131–168.

Vitale

, Monteleon

, Burke

, Della-Frazier

, Volicer

(2009) Strategies for improving care for patients with advanced dementia and eating of long term problems. Ann Care 17, 32–39.

Mitchell

, Teno

, Kiely

, Shaffer

, Jones

, Prigerson

(2009) The clinical course of advance dementia. N Engl J Med 361, 1529–1537.

Lindgren

, Unosson

, Fredrikson

, Ek

(2004) Immobility- a major risk factor for development of pressure ulcers among adult hospitalized patients: A prospective study. Scand J Caring Sci 18, 57.

European Pressure Ulcer Advisory Panel (EPUAP) (2009) International Guideline Pressure Ulcer Treatment Technical Report.

Bouten

, Oomens

, Baaijens

, Bader

(2003) The etiology of pressure ulcers: Skin deep or muscle bound? Arch Phys Med Rehabil 84, 616–619.

Davis

, Caseby

(2001) Prevalence and incidence studies of pressure ulcers in two long-term care facilities in Canada. Ostomy Wound Manage 47, 28–34.

Mitchell

, Teno

, Miller

, Mor

(2005) National study of the location of death for older persons with dementia. J Am Geriatr Soc 53, 299–305.

10.

Bennett

, Dealey

, Posnett

(2004) The cost of pressure ulcers in the UK. Age Aging 33, 230–235.

11.

Furukawa

, Ushida

, Sakai

, Kunii

, Suzuki

, Tanaka

, Tateishi

(2001) Tissue-engineered skin using aggregates of normal human skin fibroblasts and biodegradable material. J Artificial Organs 4, 353–356.

12.

Vande-Berg

, Rudolph

, Hollan

, Haywood-Reid

(1998) Fibroblast senescence in pressure ulcers. Wound Repair Regen 6, 38–49.

13.

Alonso

(2006) Pressure ulcers in advanced dementia may need a different approach. BMJ 332, 472.

14.

Jaul

, Calderon-Margalit

(2013) Systemic factors and mortality in elderly patients with pressure ulcers. Int Wound J 12, 254–259.

15.

Jaul

, Meiron

, Menczel

(2016) The effect of pressure ulcers on the survival in patients with advanced dementia and comorbidities, Exp Aging Res 42 382–389.

16.

Gibson

, Huang

(2002) Oxidative processes in the brain and non-neuronal tissues as biomarkers of Alzheimer’s disease. Front Biosci 7, 1007–1015.

17.

Chirila

, Tapan

, Alkon

(2014) Fibroblast aggregation rate converges with validated peripheral biomarkers for Alzheimer’s disease. J Alzheimers Dis 42, 1279–1294.

18.

Greenfield

, Vaux

(2002) Parkinson’s disease, Alzheimer’s disease and motor neuron disease: Identifying a common mechanism. Neuroscience 113, 485–492.

19.

Vahia

, Cohen

, Prehogan

, Memon

(2007) Prevalence and impact of paratonia in Alzheimer disease in a multiracial sample. Am J Geriatr Psychiatry 15, 351–353.

20.

Jaul

(2014) Cohort study of atypical pressure ulcers development. Int Wound J 11, 696–700.

21.

Khor

, Tan

, Saedon

, Kamaruzzaman

, Chin

, Poi

(2014) Determinants of mortality among older adults with pressure ulcers. Arch Gerontol Geriatr 59, 36–41.

22.

Thomas

(2014) Role of nutrition in the treatment and prevention of pressure ulcers. Nutr Clin Pract 29, 466–472.

23.

Douaud

, Groves

, Tamnes

, Westlye

, Duff

, Engvig

(2014) A common brain network links development, aging, and vulnerability to disease. Proc Natl Acad Sci U S A 111, 17648–17653.

24.

Zimerman

, Nitsch

, Giraux

, Gerloff

, Cohen

, Hummel

(2013), Neuroenhancement of the aging brain. Ann Neurol 73, 10–15.

25.

Hedden

, Gabrieli

(2004) Insights into the ageing mind: A view from cognitive neuroscience. Nat Rev Neurosci 5, 87–96.

26.

Naatanen

, Kujala

, Escera

, Baldeweg

, Kreegipuu

, Carlson

(2012) The mismatch negativity (MMN) a unique window to disturbed central auditory processing in ageing and different clinical conditions. Clin Neurophysiol 123, 424–458.

27.

Davis

, Mazur-Mosiewicz

, Dean

(2010) The presence and predictive value of Astereognosis and Agraphesthesia in patients with Alzheimer’s disease. Appl Neuropsychol 17, 262–266.

28.

Beach

, Huck

, Miranda

, Bozoki

(2015) Autonomic behavioral and subjective pain responses in Alzheimer’s disease. Pain Med 16, 1930–1942.

29.

Defloor

, De Bacquer

, Grypdonck

(2005) The effect of various combinations of turning and pressure reducing devices on the incidence of pressure ulcers. Int J Nurs Stud 42, 37–46.

30.

Allan

, Ballard

, Allen

(2007) Autonomic dysfunction in dementia. J Neurol Neurosurg Psychiatry 78, 671–677.

31.

Idiaquez

, Roman

(2011) Autonomic dysfunction in neurodegenerative dementias. J Neurol Sci 305, 22–27.

32.

Nicolini

, Ciulla

, Malfatto

, Abbate

, Mari

, Rossi

(2014) Autonomic dysfunction in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study. Plos One 9, e96656.

33.

Bruno

, Ghiadoni

, Seravalle

, Dell’oro

, Taddei

, Grassi

(2012) Sympathetic regulation of vascular function in health and disease. Front Physiol 3, 284.

34.

Andersen

, Kim

, Wittrup-Jensen

, Lolk

, Kjeld

, Kragh-Sørensen

(2004) Ability to perform activities of daily living is the main factor affecting quality of life in patients with dementia. Health Qual Life Outcomes 2, 52.

35.

Khan

, Alkon

(2006) An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin. Proc Natl Acad Sci U S A 103, 13203–13207.

36.

Deiber

, Ibanez

, Missonnier

, Herrmann

, Fazio-Costa

, Gold

(2009) Abnormal-induced theta activity supports early directed-attention network deficits in progressive MCI. Neurobiol Aging 30, 1444–1452.

37.

Pennisi

, Ferri

, Lanza

, Cantone

, Pennisi

, Puglisi

(2011) Transcranial magnetic stimulation in Alzheimer’s disease: A neurophysiological marker of cortical hyper-excitability. J Neural Transm 118, 587–598.