Association of Stroke and Cerebrovascular Pathologies With Scam Susceptibility in Older Adults.

Importance: Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about the role of cerebrovascular pathologies with scam susceptibility. Objective: To examine the association of diverse cerebrovascular pathologies (globally and regionally) with scam susceptibility. Design, setting, and Participants: This clinical-pathological cohort study included participants from 2 ongoing studies of aging that began enrollment in 1994 and 1997. In 2010, participants were enrolled in the decision-making and behavioral economics substudy and were followed up for a mean (SD) of 3.4 (2.6) years prior to death. From 1365 older persons with clinical evaluations, 69 were excluded for having dementia at baseline. From 538 older persons who died, 408 had annual assessments for scam susceptibility, cardiovascular risk burden, and cognitive function and consented to brain donation for detailed neuropathologic examination. Data were analyzed from June 2021 through September 2022. Exposures: Neuropathologic examination identified the presence of macroscopic and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and common neurodegenerative pathologies (Alzheimer disease, limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, and Lewy bodies). Results: There was a total of 408 participants. The mean (SD) age at death was 91 (6.1) years, the mean (SD) amount of education was 15.6 (3.1) years, and 297 (73%) were women. Participants included 4 Latino individuals (1%), 7 non-Latino Black individuals (2%), and 397 non-Latino White individuals (97%). The frequency of participants with macroscopic infarcts was 38% (n = 154), microinfarcts was 40% (n = 163), and moderate to severe vessel disease; specifically, atherosclerosis was 20% (n = 83), arteriolosclerosis was 25% (n = 100), and cerebral amyloid angiopathy was 35% (n = 143). In linear regression models adjusted for demographics and neurodegenerative pathologies, macroscopic infarcts were associated with greater scam susceptibility (estimate [SE], 0.18 [0.07]; P = .009). This association persisted after adjusting for cardiovascular risk burden and global cognition. Regionally, infarcts localized to the frontal, temporal, and occipital lobes and thalamus were associated with greater scam susceptibility. Neither arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, nor microinfarcts were associated with scam susceptibility. Conclusions and Relevance: Cerebrovascular pathologies, specifically cerebral infarcts, is linked with greater scam susceptibility in older adults, independent of common neurodegenerative diseases such as Alzheimer disease. Future studies examining in vivo magnetic resonance imaging markers of cerebrovascular pathologies with scam susceptibility and related decision-making outcomes will be important.

Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort.

Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.

Klotho Deficiency Induces Arteriolar Hyalinosis in a Trade-Off with Vascular Calcification.

Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to aging-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency, a state known to induce both renal and vascular phenotypes associated with aging. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared with Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice, and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho-/- mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, whereas the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells (SMCs). Finally, in Klotho-/- mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and SMC dedifferentiation. In the absence of a calcification-inducing stimulus, SMCs assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing aging-related arteriolar hyalinosis.

Long-term treatment with chaethomellic acid A reduces glomerulosclerosis and arteriolosclerosis in a rat model of chronic kidney disease.

The high prevalence of end-stage renal disease emphasizes the failure to provide therapies to effectively prevent and/or reverse renal fibrosis. Therefore, the aim of this study was to evaluate the effect of long-term treatment with chaethomellic acid A (CAA), which selectively blocks Ha-Ras farnesylation, on renal mass reduction-induced renal fibrosis. Male Wistar rats were sham-operated (SO) or subjected to 5/6 renal mass reduction (RMR). One week after surgery, rats were placed in four experimental groups: SO:SO rats without treatment (n=13); SO+CAA: SO rats treated with CAA (n=13); RMR:RMR rats without treatment (n=14); and RMR+CAA:RMR rats treated with CAA (n=13). CAA was intraperitoneally administered in a dose of 0.23µg/kg three times a week for six months. Renal fibrosis was evaluated by two-dimensional ultrasonography and histopathological analysis. The kidneys of the RMR animals treated with CAA showed a significantly decrease in the medullary echogenicity (p<0.05) compared with the RMR rats that received no treatment. Glomerulosclerosis and arteriolosclerosis scores were significantly lower (p<0.001) in the RMR+CAA group when compared with the RMR group. There were no significant differences in interstitial fibrosis, interstitial inflammation and tubular dilatation scores between the RMR+CAA and RMR groups. These data suggest that CAA can be a potential future drug to attenuate the progression of chronic kidney disease.

Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation.

Because calcineurin inhibitor (CNI) immunosuppressive drugs induce arteriolar hyalinosis (ah) in kidney transplants, ah lesions can potentially provide information about drug exposure. We studied the relationship of ah lesions to findings and outcomes in 562 indication biopsies taken 3 days to 35 years after transplant. Prevalence of ah lesions increased with time of biopsy after transplant (TxBx). The ah scores correlated with arterial intimal thickening and atrophy-fibrosis but, unlike atrophy-fibrosis, did not increase until after 500 days because of a background of ah1 lesions in early biopsies reflecting donor aging. Correlation of ah scores with other features varied with TxBx-in early biopsies, donor age and related changes, and in very late biopsies, chronic antibody-mediated rejection and glomerulonephritis and associated lesions. After correction for TxBx, ah0 in intermediate time periods was associated with increased risk of T cell-mediated rejection and graft loss, probably because of underimmunosuppression and nonadherence. Thus, ah lesions in indication biopsies have multiple associations: donor age (early, usually ah1), chronic glomerular diseases (late, often ah2/3), and adequate exposure to CNIs at intermediate times. This threefold TxBx-dependent complexity must be considered when interpreting indication biopsies: ah lesions often indicate adequate CNI exposure, not toxicity, and unexpected ah0 should increase vigilance for nonadherence and underimmunosuppression.

TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia.

Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP ) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with ( n = 398) and without dementia ( n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer's-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer's disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer's-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer's disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia but only when extended beyond the amygdala.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

AIM: The role of post-reperfusion biopsy findings as a predictor of early and long-term graft function and survival is still a target of research. METHODS: We analyzed data from 136 post-reperfusion biopsies performed in deceased donor renal transplanted patients from November 2008 to May 2012. We analyzed the presence of acute tubular necrosis (ATN), arteriolar hyalinosis (AH), intimal thickness (IT), interstitial fibrosis (IF) and glomerulosclerosis (GS). We also analyzed the impact of donor features on the following outcomes: delayed graft function (DGF) and chronic allograft dysfunction defined as eGFR < 60 mL/min at 1 year. RESULTS: The mean donor age was 41 years, 26% of whom were extended criteria donors (ECD), 33% had hypertension and 50% had cerebral vascular accident (CVA) as the cause of death. ATN was present in 87% of these biopsies, AH in 31%, IF in 21%, IT in 27% and GS in 32%. DGF occurred in 80% and chronic allograft dysfunction was present in 53%. AH was the only histological finding associated with DGF and chronic allograft dysfunction at 1 year. Patients with AH had a lower eGFR at 1 year than patients without it (49.8 mL/min × 64.5 mL/min, P = 0.02). In the multivariate analysis, risk variables for development of chronic graft dysfunction were male sex (odds ratio [OR] = 3.159 [CI: 1.22-8.16]; P = 0.018), acute rejection (OR = 8.91 [CI: 2.21-35.92]; P = 0.002), donor hypertension (OR = 2.94 [CI: 1.10-7.84]; P = 0.031), AH (OR = 3.96 [CI: 1.46-10.70]; P = 0.007) and eGFR at discharge (OR = 0.96 [CI: 0.93-0.98]; P = 0.005). In multivariate analysis, risk factors for AH were donor age ≥ 50 years (OR = 2.46 [CI: 1.10-5.44]; P = 0.027) and CVA as the cause of donor death (OR = 2.33 [CI: 1.05-5.15]; P = 0.007). CONCLUSION: The presence of AH in post-reperfusion biopsies is a marker of ageing and vascular disease and was associated with DGF and a one year poorer renal function. AH in donor biopsies superimposed to long ischaemic time is a predictor of renal function. The management of immunosuppression based on the presence of AH in post-reperfusion biopsy could be useful to improve long term graft function.

C3d deposition in the media of renal arterioles is a useful marker for arteriolosclerosis in IgA nephropathy.

C3d deposition in peritubular capillaries has been demonstrated to indicate antibody-mediated alloresponse during renal transplantation. C3d deposition in renal arterioles in IgA nephropathy (IgAN), however, is poorly documented. Especially, its significance to the pathology of primary glomerulonephritis remains unclear. This retrospective study included 340 patients with IgAN who underwent renal biopsy at our center. C3d strongly positive deposition in arterioles was observed in 123 (36.2%) of the 340 cases, and weakly positive deposition of C3d was observed in 217 cases (63.8%). In the weakly positive group, C3d mainly deposited in the intima of arterioles. In the strongly positive group, C3d deposited in the intima and the media of arterioles, presenting as the medial thickening and sclerosis of varying severities. The prognosis was worse in the C3d strongly positive group than in the weakly positive group during a 2-year follow-up (P = .027). The predictive value of C3d deposition in the media of arterioles in patients with IgAN may be a useful marker for arteriolosclerosis indicating unfavorable clinical outcomes.

Effects of deranged glucose homeostasis on peripheral arterial stiffness index in patients with pre-diabetes mellitus.

Premature arteriosclerosis may be one of the mechanisms linking pre-diabetes mellitus (pre-DM) and cardiovascular disease. We sought to characterize premature arteriosclerosis in pre-DM using different arterial stiffness indices and to find the independent contributors of this process. We recruited 33 patients without DM, 53 patients with pre-DM, and 34 subjects with DM. Both the compliance index (CI) and stiffness index (SI) were measured. Patients with pre-DM and DM had lower CI (3.8 ± 2.1 versus 5.2 ± 3.0 units; P < 0.05 and 3.6 ± 1.8 versus 5.2 ± 3.0 units; P < 0.05, respectively) and higher SI (8.0 ± 2.0 versus 6.7 ± 1.6 m/s; P < 0.01 and 9.4 ± 2.3 versus 6.7 ± 1.6 m/s; P < 0.001, respectively) than patients without DM. Using multivariate linear regression analysis, age, heart rate, and HOMA index were independent determinants for SI (whole model: R(2) = 0.47, P < 0.001), whereas male gender, hsCRP, and HOMA index were independent determinants for CI (whole model: R(2) = 0.34, P < 0.01). The HOMA index was an independent determinant for arterial stiffness. Increased insulin resistance may associate with increased arterial stiffness at peripheral arteries in pre-DM patients.

Relationship of red splenic arteriolar hyaline with rapid death: a clinicopathological study of 82 autopsy cases.

BACKGROUND: Little is known about the relationship between splenic arteriolar hyaline and cause of death. The purpose of this retrospective study was to evaluate the clinicopathological significance of splenic arteriolar hyaline in autopsy cases and estimate the applicability of hyaline for diagnosing the cause and rapidity of death. METHODS: Archival data and histological slides from 82 cases were reviewed retrospectively. One section of each spleen was evaluated microscopically. The tinctorial pattern of splenic arteriolar hyaline was examined with Heidenhain's Azan trichrome stain, and the relationships between this pattern and age, cause of death, and rapidity of death were investigated. RESULTS: Fifty-four cases demonstrated hyaline change, with 3 different tinctorial patterns: red, blue, and a combination of red and blue. The 3 patterns coexisted in various proportions in each tissue section. Frequency of the blue pattern increased with age (P < 0.01) and was unrelated to cause of death. By contrast, the red pattern was unrelated to age and appeared with different frequency according to cause of death. The red pattern appeared with significantly higher frequency in the circulatory disease group and the drowning and asphyxia group (both P < 0.01). Moreover, the presence of the red pattern had high specificity for the detection of rapidly fatal cases. The combination of the 2 colors was excluded from clinicopathological analyses due to its admixed nature. CONCLUSIONS: Estimation of splenic arteriolar hyaline with Heidenhain's Azan trichrome stain is useful for assessment of the cause and rapidity of death. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1132441651796836.

[The glucose, glycotoxins and glycation products: the involvement into pathogenesis of microangiopathies, arteriolosclerosis and atherosclerosis].

The hyperglycemia and diabetes and the concurrent increase of glucose's chemical glycation of (GLU) circulating and structured proteins are the conditions of occurring of various a physiological (GLU) metabolism processes: a) a polyolic way with the synthesis in cells' cytosol of sorbitol alcohol, organic osmolit producing hyperosmolarity of cytosol; a galactosamine way of GLU transformation leads to aminoglycotoxins' formation; the intensification of hexose transformation into trioses leads to the increase of synthesis and accumulation of glycotoxins of glyoxal and methylglyoxal in intercellular medium. The reaction of proteins' glycation, proportionally to the magnitude and duration of hyperglycosemia, results in sequential formation of Shiff bases, Amadori products and glycation end products. The glycation of proteins with glycotoxins results in the immediate formation of glycation end products. The derangement of biologic function of endoecology is determined by the accumulation in the intercellular medium of GLU which factually is a biologic "refuses" with lesser molecular mass; and the glycation end products becomes greater biologic "refuses". The disorders of GLU metabolism results informing of destructive inflammatory processes in the wall of muscular type arterioles, postarterioles, capillaries and venules--the vessels of microcirculatory component of circulatory system with the development of diabetic microangiopathies in various internal organs. The increase of endothelium thickness narrows the lumen of arterioles and capillaries intensifying the peripheral resistance to blood flow. The glycotoxins as bi-functional reagents form the cross-links in collagen fibers of areolar tissue enhancing the hardness of vessels' walls, the pericytes' malfunction, and increasing the velocity of pulse wave conduction. The tissue fixed glycation end products--the large endogenous phlogogens can be utilized only in citu under the realization of extracellular proteolysis, the activation of oxidation by O2 active forms and the biologic reaction of inflammation--phagocytosis by macrophages, the functional phagocytes. The surplus of GLU can be removed by the biologic reaction of excretion. The extracellular proteolysis forms the soluble fragments of glycation end products which in the intercellular medium bind the soluble fragments of receptors of macrophages. Under diabetes, it is reasonable to monitor in blood plasma the content of both GLU and such glycotoxins as glyoxal, methylglyoxal and malonic dialdehyde.

Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis of nephroangiosclerosis through functional impairment of renal microcirculation or primary Notch3-related vascular disease.