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Annals of Diagnostic Pathology Feb 2022Charcot neuropathic arthropathy is a degenerative, debilitating disease that affects the foot and ankle in patients with diabetes and peripheral neuropathy, often...
Charcot neuropathic arthropathy is a degenerative, debilitating disease that affects the foot and ankle in patients with diabetes and peripheral neuropathy, often resulting in destruction, amputation. Proposed etiologies include neurotraumatic, inflammatory, and neurovascular. There has been no previous animal model for Charcot. This study proposes a novel rodent model of induced neuropathic arthropathy to understand the earliest progressive pathologic changes of human Charcot. High-fat-diet-induced obese (DIO) Wild-type C57BL/6J mice (n = 8, diabetic) and age-matched low-fat-diet controls (n = 6) were run on an inclined high-intensity treadmill protocol four times per week for 7 weeks to induce mechanical neurotrauma to the hind-paw, creating Charcot neuropathic arthropathy. Sensory function and radiologic correlation were assessed; animals were sacrificed to evaluate hindpaw soft tissue and joint pathology. With this model, Charcot-DIO mice reveals early pathologic features of Charcot neuropathic arthropathy, a distinctive subchondral microfracture callus, perichondral/subchondral osseous hypertrophy/osteosclerosis, that precedes fragmentation/destruction observed in human surgical pathology specimens. There is intraneural vacuolar-myxoid change and arteriolosclerosis. The DIO mice demonstrated significant hot plate sensory neuropathy compared (P < 0.01), radiographic collapse of the longitudinal arch in DIO mice (P < 0.001), and diminished bone density in DIO, compared with normal controls. Despite exercise, high-fat-DIO mice increased body weight and percentage of body fat (P < 0.001). This murine model of diet-induced obesity and peripheral neuropathy, combined with repetitive mechanical trauma, simulates the earliest changes observed in human Charcot neuropathic arthropathy, of vasculopathic-neuropathic etiology. An understanding of early pathophysiology may assist early diagnosis and intervention and reduce patient morbidity and mortality in Charcot neuropathic arthropathy.
Topics: Animals; Arthropathy, Neurogenic; Cartilage, Articular; Disease Models, Animal; Fractures, Stress; Mice; Obesity; Osteosclerosis
PubMed: 34953234
DOI: 10.1016/j.anndiagpath.2021.151878 -
Neurology Mar 2022Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that...
BACKGROUND AND OBJECTIVES
Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies.
METHODS
Participants were community-dwelling older adults from 2 cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We use Alzheimer disease (AD) to refer to pathologically defined disease and Alzheimer dementia to refer to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TAR DNA binding protein encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified with mass spectrometry-based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer dementia, including angiotensin-converting enzyme, calcium-regulated heat-stable protein 1 (CHSP1), procathepsin H (CATH), double C2-like domain-containing protein α, islet cell autoantigen 1-like protein, serine β-lactamase-like protein LACTB, mitochondrial, pleckstrin homology domain-containing family A member 1, replication termination factor 2, sorting nexin-32, syntaxin-4, and syntaxin-6 (STX6), were previously identified with an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices.
RESULTS
A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. In contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Furthermore, while higher STX6 expression increased the risk of Alzheimer dementia, the protein was not associated with any of the neuropathologic indices investigated.
DISCUSSION
Cortical proteins implicated in Alzheimer dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases and other pathways are at play. Furthermore, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.
Topics: Aged; Alzheimer Disease; Brain; Cerebral Amyloid Angiopathy; Humans; Lewy Bodies; Membrane Proteins; Mitochondrial Proteins; Neurodegenerative Diseases; beta-Lactamases
PubMed: 34937778
DOI: 10.1212/WNL.0000000000013252 -
Renal Failure Nov 2019We aimed to evaluate the relationship between biopsy-proven kidney lesions, subclinical markers of atherosclerosis and intrarenal resistive index (RRI) in chronic...
We aimed to evaluate the relationship between biopsy-proven kidney lesions, subclinical markers of atherosclerosis and intrarenal resistive index (RRI) in chronic kidney disease (CKD) patients. This cross-sectional, single-center study prospectively enrolled 44 consecutive CKD patients (57% male gender, 54.1 (95%CI, 49.7-58.6) years, median eGFR 28.1 (15.0-47.7) mL/min) diagnosed by renal biopsy during 6 months in our clinic. RRI, carotid intima-media thickness (IMT), Kauppila score for abdominal aortic calcification (AACs) were assessed. Traditional and nontraditional atheroscleosis risk factors were also evaluated. Most of the patients had a diagnosis of glomerular nephropathy, with IgA nephropathy and diabetic nephropathy being the most frequent. RRI increased proportionally with CKD stages. Patients with RRI >0.7 (39%) were older, had diabetic and vascular nephropathies more frequently, higher mean arterial blood pressure, increased systemic atherosclerosis burden (IMT and AACs), higher percentage of global glomerulosclerois, GBM thickness, arteriolosclerosis and interstitial fibrosis/tubular atrophy. RRI directly correlated with age (rs = 0.55, < 0.001) and with all the studied atherosclerosis markers (clinical atherosclerosis score rs = 0.50, = 0.02; AACs rs = 0.50, < 0.01; IMT rs = 0.34, = 0.02). Also, global glomerulosclerosis (rs = 0.31, = 0.03) and interstitial fibrosis/tubular atrophy (rs = 0.35, = 0.01) were directly correlated with RRI. In multivariable adjusted binomial logistic regression models, only arteriolosclerosis was retained as independent predictor of RRI >0.7. The analysis of RRI may be useful in the evaluation of the general vascular condition of the patient with CKD, supplying information about both microvascular and macrovascular impairment. Moreover, RRI correlates well with renal histopathologic characteristics, particularly with arteriolosclerosis.
Topics: Adult; Aged; Arteriolosclerosis; Atherosclerosis; Biopsy; Carotid Intima-Media Thickness; Cross-Sectional Studies; Feasibility Studies; Female; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Male; Middle Aged; Prospective Studies; Regional Blood Flow; Renal Insufficiency, Chronic; Risk Factors; Vascular Resistance
PubMed: 31599199
DOI: 10.1080/0886022X.2019.1674159 -
Vascular Pharmacology Feb 2022A close relationship is emerging among the age-related neurodegenerative decline, and the age-related typical alterations, dysfunctions, and related diseases of the... (Review)
Review
A close relationship is emerging among the age-related neurodegenerative decline, and the age-related typical alterations, dysfunctions, and related diseases of the cerobro-and/or cardiovascular system, which contributes in a significative manner to the triggering and progressing of neurodegenerative diseases (NeuroDegD). Specifically, macroinfarcts, microinfarcts, micro-hemorrhages (and particularly their number), atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy have been documented to be significantly associated with the onset of the cognitive impairment. In addition, vascular alterations and dysfunctions resulting in a reduced cerebral blood flow, and anomalies in the brain blood barrier (BBB), have been also demonstrated to contribute to NeuroDegD pathophysiologic processes. At the same time, such vascular alterations are also observed in cognitively unimpaired subjects. Here, some of these aspects are described with a particular focus on some NeuroDegD, as well as potential strategies for delaying or stopping their onset and progression.
Topics: Blood-Brain Barrier; Humans; Neurodegenerative Diseases
PubMed: 34942382
DOI: 10.1016/j.vph.2021.106951 -
Neurology Jan 2022Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter...
BACKGROUND AND OBJECTIVES
Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested.
METHODS
This imaging-pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as ≤ 0.05.
RESULTS
The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; = 0.03) and CDS scores (unstandardized β 15.35, 95% CI -0.27, 30.97; = 0.05).
DISCUSSION
WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathologic correlation studies are needed.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.
Topics: Brain; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Retrospective Studies; White Matter
PubMed: 34819338
DOI: 10.1212/WNL.0000000000013012 -
Global Health & Medicine Dec 2021Japan ranks the highest globally, in terms of longevity. The average life expectancy was 81.4 years for men and 87.5 years for women in 2019. Such success in health is... (Review)
Review
Japan ranks the highest globally, in terms of longevity. The average life expectancy was 81.4 years for men and 87.5 years for women in 2019. Such success in health is attributable to the substantial reduction in age-standardized mortality from cardiovascular diseases, especially stroke (136 per 10 in 1980 and 24 per 10 in 2015), when stroke mortality was the highest in the world between the 1960s and the 1990s. On the other hand, ischemic heart disease mortality was the lowest in the world between the 1960s and the 1980s and has continued to decline (40 per 10 in 1980 and 17 per 10 in 2015). Such a disease profile (larger burden of stroke compared to ischemic heart disease) was observed not only in Japan but also in some countries in central Asia and Africa, where small vessel disease (arteriolosclerosis) is assumed to be more common than large vessel disease (atherosclerosis). Between 1970 and 2015, a large decline in the population with high blood pressure levels was observed for both men and women. Meanwhile, there was a moderate decline in the smoking rate among men, and an increasing trend in serum cholesterol levels in both men and women. The sharp and extensive socioeconomic development between the 1960s and 1990s contributed to these health outcomes, while preventive measures and improved emergency medical care also contributed to the reduction of risk factors, disease incidence, case-fatality, and mortality. However, there is a threat of increasing incidence of ischemic heart disease in urban male employees and middle-aged male residents. Japan, with a super-aging society, needs to develop a new model for the prevention and control of cardiovascular disease and related health issues, with emphasis on efforts towards the early (primordial) prevention of cardiovascular disease as well as the attenuation of their progress towards chronic heart failure, chronic kidney disease, and vascular dementia.
PubMed: 35036616
DOI: 10.35772/ghm.2020.01113 -
Journal of Cerebral Blood Flow and... Apr 2024Research on the cerebrovasculature may provide insights into brain health and disease. Immunohistochemical staining is one way to visualize blood vessels, and digital...
Research on the cerebrovasculature may provide insights into brain health and disease. Immunohistochemical staining is one way to visualize blood vessels, and digital pathology has the potential to revolutionize the measurement of blood vessel parameters. These tools provide opportunities for translational mouse model research. However, mouse brain tissue presents a formidable set of technical challenges, including potentially high background staining and cross-reactivity of endogenous IgG. Formalin-fixed paraffin-embedded (FFPE) and fixed frozen sections, both of which are widely used, may require different methods. In this study, we optimized blood vessel staining in mouse brain tissue, testing both FFPE and frozen fixed sections. A panel of immunohistochemical blood vessel markers were tested (including CD31, CD34, collagen IV, DP71, and VWF), to evaluate their suitability for digital pathological analysis. Collagen IV provided the best immunostaining results in both FFPE and frozen fixed murine brain sections, with highly-specific staining of large and small blood vessels and low background staining. Subsequent analysis of collagen IV-stained sections showed region and sex-specific differences in vessel density and vessel wall thickness. We conclude that digital pathology provides a useful tool for relatively unbiased analysis of the murine cerebrovasculature, provided proper protein markers are used.
Topics: Male; Female; Mice; Animals; Brain; Collagen; Paraffin Embedding
PubMed: 37988134
DOI: 10.1177/0271678X231216142 -
Journal of Wound Care Apr 2022Martorell hypertensive ischaemic ulcers are often misdiagnosed and can be a clinical and therapeutic challenge. Controversy exists regarding both their underlying...
OBJECTIVE
Martorell hypertensive ischaemic ulcers are often misdiagnosed and can be a clinical and therapeutic challenge. Controversy exists regarding both their underlying triggers and the type of treatment that should be carried out. This study was designed to compare the effectiveness of punch grafting and conventional therapy in pain reduction.
METHOD
A single-centre retrospective study was performed, including 40 patients with a clinical diagnosis of a Martorell ulcer or post-traumatic ulcer secondary to arteriolopathy in the elderly, who were treated with punch grafting (n= 24) or conventional medical treatment (n=16).
RESULTS
There was a statistically and clinically significant reduction in pain after punch grafting. The minimal overall reduction was of three points in visual analogue pain scores. Of the patients who received punch grafting, 80% reported a VAS pain score of 0 at the third follow-up, in contrast with the 44% (n=4) patients who were treated without punch grafting. The mean time to epithelialisation was 82.1 days in patients who received conventional treatment and 43.5 days in those who received punch grafts.
CONCLUSION
Punch grafting is a simple, validated and cost-effective technique that can be performed on an outpatient basis, promotes wound healing and reduces pain. It may control pain and stimulate epithelialisation even if the wound does not present with optimum wound bed characteristics for graft taking. Pain reduction and faster epithelialisation are associated with improvements in patients' quality of life.
Topics: Aged; Arteriolosclerosis; Humans; Leg Ulcer; Pain; Quality of Life; Retrospective Studies; Skin Transplantation; Skin Ulcer; Ulcer
PubMed: 35404703
DOI: 10.12968/jowc.2022.31.4.356 -
Stroke Jun 2021The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the... (Clinical Trial)
Clinical Trial
BACKGROUND AND PURPOSE
The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies.
METHODS
We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies.
RESULTS
Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07-1.13], <0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], =0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], <0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], =0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy.
CONCLUSIONS
A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.
Topics: Age Factors; Aged; Aged, 80 and over; Autopsy; Brain; Cerebral Amyloid Angiopathy; Female; Humans; Intracranial Arteriosclerosis; Male; Risk Factors
PubMed: 33840227
DOI: 10.1161/STROKEAHA.120.030226 -
American Journal of Kidney Diseases :... May 2020Chronic kidney disease (CKD) is a potent risk factor for macrovascular disease and death. Peripheral artery disease (PAD) is more common in patients with CKD and is... (Observational Study)
Observational Study
RATIONALE & OBJECTIVES
Chronic kidney disease (CKD) is a potent risk factor for macrovascular disease and death. Peripheral artery disease (PAD) is more common in patients with CKD and is associated with lower-limb complications and mortality. We sought to compare the prevalence of PAD in and outside the setting of kidney disease and examine how PAD affects the risk for adverse health outcomes, specifically lower-limb complications, cardiovascular events, and survival.
STUDY DESIGN
Retrospective cohort study.
SETTING & PARTICIPANTS
453,573 adult residents of Manitoba with at least 1 serum creatinine measurement between 2007 and 2014.
EXPOSURE
PAD defined by hospital discharge diagnosis codes and medical claims.
OUTCOMES
All-cause mortality, cardiovascular events, and lower-limb complications, including foot ulcers and nontraumatic amputations.
ANALYTICAL APPROACH
Survival analysis using Cox proportional hazards models.
RESULTS
The prevalence of PAD in our study population was 4.5%, and patients with PAD were older, were more likely to be male, and had a higher burden of comorbid conditions, including diabetes and CKD. PAD was associated with higher risks for all-cause mortality, cardiovascular events, and lower-limb complications in patients with estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73m, those with CKD GFR categories 3 to 5 (G3-G5), and those treated by dialysis (CKD G5D). Although HRs for PAD were lower in the CKD population, event rates were higher as compared with those with eGFR≥60mL/min/1.73m. In particular, compared with patients with eGFR≥60mL/min/1.73m and without PAD, patients with CKD G5D had 10- and 12-fold higher risks for lower-limb complications, respectively (adjusted HRs of 10.36 [95% CI, 8.83-12.16] and 12.02 [95% CI, 9.58-15.08] for those without and with PAD, respectively), and an event rate of 75/1,000 patient-years.
LIMITATIONS
Potential undercounting of PAD and complications using administrative codes and the limited ability to examine quality-of-care indicators for PAD.
CONCLUSIONS
PAD is more common in patients with CKD G3-G5 and G5D compared with those with eGFR≥60mL/min/1.73m and frequently leads to lower-limb complications. Medical interventions and care pathways specifically designed to slow or prevent the development of lower-limb complications in this population are urgently needed.
Topics: Adult; Aged; Amputation, Surgical; Comorbidity; Creatinine; Female; Foot Ulcer; Humans; Insurance Coverage; International Classification of Diseases; Leg; Male; Manitoba; Middle Aged; Patient Discharge; Peripheral Arterial Disease; Prevalence; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome
PubMed: 31879218
DOI: 10.1053/j.ajkd.2019.08.028