Predicting Walking Ability and Prosthetic Candidacy Following Lower Extremity Amputation: Systematic Review, Treatment Pathway and Algorithm

Purpose: The purpose of this study is a systematic review (SR) of existing literature to examine characteristics of persons with amputation which predict walking ability and prosthetic candidacy following lower extremity amputation (LEA). The identification, synthesis and summary of this evidence could assist in developing clinical practice guidelines, including a physical rehabilitation treatment pathway and a clinical algorithm. The importance of this project is the establishment to further develop evidence based LEA clinical practice guidelines. This evidence will assist the healthcare team in decision making, specifically considering evidence and patient-centric predictive characteristics. Background: Currently, there is no multi-disciplinary physical rehabilitation instrument known that can predict walking ability and prosthetic candidacy nor support a treatment pathway and algorithm for the LEA. Also, there is not a patient centric decision making protocol under consideration when determining prosthetic candidacy. Further, the evidence to support these guidelines and protocols has not been aggregated and summarized in a formal systematic approach, such as a comprehensive systematic review. In previous literature the prediction of walking ability has been reported. However, these studies are outdated and not comprehensive, nor do they offer a clinical treatment pathway regarding the prediction of walking ability and prosthetic candidacy following lower LEA. A comprehensive reporting of aggregated and newly synthesized evidence with information from current literature can develop an evidence based patient centric treatment pathway and a prosthetic candidacy algorithm to assist LEAs to receive the correct, initial definitive prosthesis to match their functional abilities. Methods: This search strategy was designed and similarly implemented considering previous systematic reviews based on a similar topic. It is a more comprehensive update of previously valuable predictive factors of walking ability and prosthetic candidacy. An electronic literature search was executed from 8/1/2007 to 12/31/2015 using MEDLINE, EMBASE, CINAHL, and Cochrane. Results: This SR performed a more comprehensive search and discovered an additional 26 articles. A total of 104 quality studies were identified through the electronic search. Of these, 78 were systematically reviewed by two former authors, leaving a total of 26 for full evaluation. Conclusions from this updated study are drawn from a total recruited sample of 46,651 subjects. This updated study increases the size of the original Kahle et al. report by including 300% more subjects for a total of 61,858 subjects studied in the two SRs. Conclusion: In these two combined SRs, cause of amputation (etiology), physical fitness, pre- amputation living status, amputation level, age, physical fitness, cognitive/mood disturbances, social support and comorbitities are included as moderate to strongly supported predictive factors of walking ability and prosthetic candidacy. These factors are supported in an earlier literature review and should be strongly considered in a complete history and physical examination by multi-disciplinary team. Predictive factors should be part of a patient healthcare record

Cerebrovascular disease in ageing and Alzheimer's disease

Cerebrovascular disease (CVD) and Alzheimer’s disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease

Differing associations between Aβ accumulation, hypoperfusion, blood–brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer's disease

Recent studies implicate loss of pericytes in hypoperfusion and blood–brain barrier (BBB) leakage in Alzheimer's disease (AD). In this study, we have measured levels of the pericyte marker, platelet-derived growth factor receptor-β (PDGFRB), and fibrinogen (to assess blood–brain barrier leakage), and analyzed their relationship to indicators of microvessel density (von Willebrand factor level), ante-mortem oxygenation (myelin-associated glycoprotein:proteolipid protein-1 ratio and vascular endothelial growth factor level), Aβ level and plaque load, in precuneus and underlying white matter from 49 AD to 37 control brains. There was reduction in PDGFRB and increased fibrinogen in the precuneus in AD. These changes correlated with reduction in oxygenation and with plaque load. In the underlying white matter, increased fibrinogen correlated with reduced oxygenation, but PDGFRB level was unchanged. The level of platelet-derived growth factor-ββ (PDGF-BB), important for pericyte maintenance, was increased in AD but mainly in the insoluble tissue fraction, correlating with insoluble Aβ level. Loss of the PDGFRB within the precuneus in AD is associated with fibrinogen leakage and reduced oxygenation, and related to fibrillar Aβ accumulation. In contrast, fibrinogen leakage and reduced oxygenation of underlying white matter occur independently of loss of PDGFRB, perhaps secondary to reduced transcortical perfusion. </jats:p

Pericyte Contractile Responses to Endothelin-1 and Aβ Peptides:Assessment by Electrical Impedance Assay

Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer’s disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aβ). We have used electrical impedance analysis to monitor the contractile and proliferative response of cultured human fetal and adult brain-derived pericytes to EDN1 in real-time. EDN1 caused transient, dose-dependent contraction of fetal and adult brain pericytes that was mediated by EDN1 type A receptors and increased the subsequent proliferation of fetal but not adult cells. The contractile responses to EDN1 were weaker in the adult pericytes. The EDN1-mediated contractile response of fetal pericytes was unchanged after exposure to Aβ1–40 or Aβ1–42 (0.1–10 μM) for 1 h but both contraction and subsequent relaxation were significantly impaired upon exposure to Aβ for 24 h. These data suggest that chronic exposure to Aβ interferes with EDN1-mediated pericyte contractility, potentially contributing to neurovascular uncoupling and reduced cerebral blood flow in AD

The Social Participation Development for Individuals with Unilateral and Bilateral Lower Extremity Amputation

This occupation-based program aims to help maintain and increase social participation for individuals with unilateral or bilateral lower extremity amputations. It was developed with an occupational therapy (OT) lens targeting adults with a lower limb amputation with a population of various ages (18-70), genders, and causes of injury to develop an occupation-based program with an OT focus. Individuals living with amputation often experience hardship when developing crucial ADL/IADL skills that can be vital for social participation regardless of age or cause of injury. This program focuses on developing social participation skills lost due to decreased functional mobility and skills caused by amputation and looks at the improvements made through occupational therapy interventions. It provides activity adaptation, prosthesis education, and mental health promotion. The program outcomes involve a needs assessment, the development of a program manual, the program implementation, and a data analysis. The significance is to educate and train amputees on daily life skills, prosthetic use, social techniques, pain strategies, and exercise training. In summary, this amputee program aims to bridge the literature gap in understanding an amputee’s challenges through developing an OT-focused program to enhance their social participation, ultimately improving their quality of life.https://soar.usa.edu/otdcapstonesspring2024/1063/thumbnail.jp

Pathophysiology of hypoperfusion of the precuneus in early Alzheimer’s disease

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor