Amyloid Deposits Research Articles

GLP-1/GIP Agonist as an Intriguing and Ultimate Remedy for Combating Alzheimer's Disease through its Supporting DPP4 Inhibitors: A Review.

Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease. This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD. This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD. The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions. With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients.

Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer's disease.

Communication between glial cells has a profound impact on the pathophysiology of Alzheimer's disease (AD). We reveal here that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation. Additionally, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD.

Electrocardiographic features in the early differential diagnosis of cardiac amyloidosis from cardiac sarcoidosis

Abstract Introduction Amyloidosis and sarcoidosis are both systemic infiltrative diseases which can cause cardiac involvement. Differentiating early-stage cardiac amyloidosis (CA) from cardiac sarcoidosis (CS) is still challenging, although hypertrophy for CA and septal thinning for CS are characteristic echocardiographic findings in each late-stage. The diagnosis is a time-sensitive issue, given the therapies for CA and CS likely to be effective at early disease stages. Purpose We aimed to evaluate the utility of electrocardiography (ECG) for distinguishing CA from CS before or early in the course of cardiomyopathy. Methods This study enrolled 36 consecutive patients (20 male, 75±13 years) diagnosed with transthyretin-CA in 25 (CA group) and isolated CS in 11 patients (CS group) according to accepted criteria at our institute from July 2014 to July 2023. We retrospectively reviewed electrocardiographic characteristics and clinical outcomes of early-stage CA and CS. Results The CS group were younger than the CA group at the time of diagnosis (59±9 vs 83±7 years, P<0.01) and had a shorter period between the date of their first ECG recording at our institute and the date of diagnosis (18±3 vs 62±67 months, P=0.012). Furthermore, the CA group showed specific P-waves with longer duration (142±19 vs 126±8 ms, P=0.003) and more notches and/or fragmentation (91% vs 33%, P=0.003) in the limb leads on the initial ECG than the CS group, although prolonged PR-interval is common in both CA and CS (191±44 vs. 208±43 ms, P=0.359). Unexpectedly, the CA group had a shorter QRS duration (103±25 vs 123±31 ms, P=0.047) and a higher R-wave in V5 (2.0±0.9 vs 1.3±1.1 mV, P=0.039) than the CS group. In addition, the low voltage in all limb leads, pseudoinfarct pattern and bundle branch block morphology characteristic of CA patients did not differ between diagnosis and initial examination. There were also no differences in atrial and ventricular arrhythmias. During the follow-up period, 5 patients (20%) in the CA group, but no patients in the CS group died. Conclusion CA and CS shares several electrocardiographic features. Prolonged P-wave with notches and fragmentation, suggesting atrial conduction disturbance, may be associated with amyloid deposition in CA. This finding might be useful in the early differential diagnosis for CA from CS.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study

Background Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. Methods We retrospectively evaluated the medical records of 202 consecutive participants. Results A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4–36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of −1.2 mg/dL/year. Conclusions Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

#2698 Regression of amyloid deposits after treatment with tocilizumab

Abstract Background and Aims AA amyloidosis is a multisystem disease characterized by the deposition of serum amyloid A protein, which is secondary to chronic inflammation. Tocilizumab (an interleukin-6 inhibitor monoclonal antibody) is effective in suppressing inflammation, normalizing serum amyloid A protein levels and inducing remission in patients with amyloidosis. Recently, tocilizumab treatment has been associated with the disappearance of amyloid deposits. Results We report a case of AA amyloidosis secondary to chronic arthritis in a 61-year-old woman referred to our hospital in 2011 due to oligoarthritis of the knees and elevation of acute-phase reactants. Corticosteroids and methotrexate were prescribed, without clinical response. Two years later, the patient presented with foamy urine, nocturia, sweating and dizziness. An elevated C-reactive protein (CRP), erythrocyte sedimentation rate and nephrotic-range proteinuria were found. Rectal and oral mucosa biopsies were performed and amyloid AA deposits were detected in both (Fig. 1A, B). Magnetic resonance imaging (MRI) of the right knee showed arthropathy due to amyloid deposition (Fig. 2). Intravenous monthly tocilizumab was prescribed with rapid improvement of CRP, proteinuria (Fig. 3) and nephrotic syndrome symptoms. Arthritis also improved significantly. Two years later, a new biopsy of the rectal mucosa did not show amyloid deposits (Fig. 1C, D) and right knee MRI was normal, without evidence of amyloid synovitis (Fig. 4). Eight years later, the patient continues treatment with tocilizumab and remains clinically stable, with no evidence of recurrence. Literature review: The efficacy of tocilizumab has been described mainly in patients with rheumatoid arthritis, but also in AA amyloidosis secondary to systemic juvenile idiopathic arthritis, familial Mediterranean fever, psoriatic arthritis, ankylosing spondylitis, Still's disease, Muckle-Wells syndrome, Behçet syndrome, polyarteritis nodosa and Takayasu arteritis. Some of the studies report long-term effectiveness of up to 9 years. In 11 case reports of patients with AA amyloidosis treated with tocilizumab, a follow-up biopsy was performed and a reduction or disappearance of the deposits was also observed. Lane et al. analyzed pre- and on-treatment serial scintigraphy scans in 20 patients with AA amyloidosis, showing that AA amyloid deposits either regressed or did not increase whilst on tocilizumab. We have not identified any study demonstrating the disappearance of amyloid arthropathy in MR images. Conclusion Tocilizumab treatment controls chronic inflammatory disease and improves symptoms of AA amyloidosis. Long-term treatment with tocilizumab may remove amyloid deposits from tissues, leading to a definitive cure of this disease.

Multimodal imaging investigation of structural rich club alterations in Alzheimer's disease and mild cognitive impairment: Amyloid deposition, structural atrophy, and functional activation differences.

Alzheimer's disease (AD) is characterized by significant cerebral dysfunction, including increased amyloid deposition, gray matter atrophy, and changes in brain function. The involvement of highly connected network hubs, known as the "rich club," in the pathology of the disease remains inconclusive despite previous research efforts. In this study, we aimed to systematically assess the link between the rich club and AD using a multimodal neuroimaging approach. We employed network analyses of diffusion magnetic resonance imaging (MRI), longitudinal assessments of gray matter atrophy, amyloid deposition measurements using positron emission tomography (PET) imaging, and meta-analytic data on functional activation differences. Our study focused on evaluating the role of both the structural brain network's core and extended rich club regions in individuals with mild cognitive impairment (MCI) and those diagnosed with AD. Our findings revealed that structural rich club regions exhibited accelerated gray matter atrophy and increased amyloid deposition in both MCI and AD. Importantly, these regions remained unaffected by altered functional activation patterns observed outside the core rich club regions. These results shed light on the connection between two major AD biomarkers and the rich club, providing valuable insights into AD as a potential disconnection syndrome.

Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aβ-Oligomer-Induced Neurotoxicity

Amyloid β-peptide (Aβ) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer’s disease (AD). Aβ oligomer (Aβo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aβo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants’ neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aβ-induced oxidative stress.

Patterns of Early Neocortical Amyloid-β Accumulation: A PET Population-Based Study.

The widespread deposition of amyloid-β (Aβ) plaques in late-stage Alzheimer disease is well defined and confirmed by invivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aβ deposition within the neocortex. Methods: This study investigated Aβ signals in the perithreshold SUV ratio range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB PET scans from 1,088 participants determined the early patterns of PiB loading in the neocortex. Results: Early-stage Aβ loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both apolipoprotein ε4 carriers and noncarriers. Clustering analysis shows groups with different patterns of early amyloid deposition. Conclusion: These findings of initial Aβ deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes.

#2078 Study of spectrum of renal dysfunction in cancer patients on ICPI as mono or combination with conventional chemo in north India

Abstract Background and Aims Although use of ICPI's have revolutionized the treatment of cancer patient with significantly improving the longevity of these patients but it also is associated with various adverse reactions known as iRAE's related to its use, which in due course is being revealed gradually. Kidney related iRAE's are important and also limitation to therapy, which could be a detrimental factor for these patients availing the beneficial effects of these revolutionary medications. Previous literature on these therapeutics had the limitations of being retrospective, small case series and case reports and evaluating only one or two parameters of kidney dysfunction, also the criteria used for evaluations had the limitation of standardization. With this we aimed to study the spectrum of renal dysfunction in cancer patients, receiving ICPI with or without conventional chemotherapy using standard criteria. Method Study involved patients with malignancy who had received at least 1 dose of ICPI as mono or combination with conventional chemotherapy. The primary end-point was 6 month assess the clinical spectrum & outcome of renal dysfunction, and the secondary end-points were the patient-level risk factors for renal dysfunction, the impact of renal dysfunction on clinical outcomes. Results Conducted through October 2021-2022, enrolled N = 156 (66 male & 90 females) & followed up for 6 months. 109 (69.9%) subjects developed KDIGO–AKI—Stage I (51.4%) & Stage II (35.8%) & non required RRT. The median duration for onset of AKI was 131 days. Proteinuria was observed in n = 143 (91.67%). n = 116 (74.3%) developed new-onset proteinuria. n = 40 (25.6%) were proteinuric at the start of the study & 27/40 (67.5%) were observed to have >50% increase in proteinuria, qualifying for proteinuria with therapy. 92/143 proteinuric subjects (64.3%) developed >1 g/day proteinuria. On subcategorizing proteinuria it was observed that 82/92 (57.3%) had 1–3 g/day proteinuria and ≥3.0 g/day proteinuria was observed in 10/92 (7.0%). Definitive ICPI–AKI could be attributed to only 2 subjects, as they underwent kidney biopsy for their kidney dysfunction and significant proteinuria. Secondary amyloid deposits in the glomeruli and mesangium was found in 1 subject & the other subject showed acute tubulointerstitial deposits with granular cast. Proteinuria and kidney dysfunction resolved with stoppage of the ICPI and steroids administration, which was consistent with the limited literature available for the management of ICPI related amyloidosis & iRAE. n = 88 had partial recovery of kidney dysfunction following an AKI event & complete recovery was seen in n = 3 (2.7%). >50% recovery in eGFR was observed in n = 41 (37.6%). Electrolyte abnormality commonly observed were hyponatremia, hypokalemia & hypomagnesemia & was seen in distributed almost equally, followed by hypocalcemia. Hypernatremia, hyperkalemia, hypermagnesemia & hypercalcemia were less commonly reported. Lastly mortality was also observed in n = 16 (10.2%), but could not be directly attributed to ICPI use, kidney dysfunction, malignancy type, comorbid conditions & other concomitants medication use. Conclusion To conclude this present prospective cohort study is a comprehensive assessment of the spectrum of renal dysfunction in cancer patients, among recipients of ICPI with or without conventional chemotherapy using standard criteria to the best of our knowledge, which has been the limitation of previous literature. We have shown a vast spectrum of kidney dysfunction possibly attributed to the ICPI's in malignancy patients. Viewed in respect to better QoL with ICPI therapy in malignancy patients, kidney related iRAE's could limit the patients from their beneficial effects. A possible persistent immune injury might have led to partial recovery of kidney dysfunction in majority. An unusual finding of secondary amyloid deposits with pembrolizumab, which possible might have occurred due to persistence of high levels of inflammatory markers due to these drugs. Thus underscoring the need for a close follow-up and recommend kidney biopsy to better & definitively identify the glomerular pathology & treatment accordingly.

#2724 Renal amyloidosis cohort registry in our health area

Abstract Background and Aims Renal amyloidosis is the pathological phenomenon of amyloid deposition in the kidney with marked differences in renal function impairment, proteinuria, need for renal replacement therapy (RRT) and exitus, depending on the protein involved. Light chain amyloidosis (AL) and serum protein A (AA) amyloidosis are the most common. Typical symptoms are severe proteinuria, nephrotic syndrome, and end-stage chronic kidney disease (ESRD). Method Retrospective study of a cohort of patients with renal amyloidosis. Data extracted from the biopsy registry of the HUVM Nephrology Service (2013-2022). We collected demographic, clinical, analytical, histological and clinical outcome variables (RTT, Exitus). Results are analyzed using Mayo Clinic staging criteria. Results 19 patients with a mean age of 63.4a; 57.9% male. Mean laboratory values at diagnosis: creatinine (Cr) 1.56 mg/dl and proteinuria 3.9 g/24 h. Abdominal fat biopsy in 13 cases; 3 (23%) tested positive. Comparative analysis of AL vs non-AL forms, Cr values (1.14 vs 2.27 mg/dl respectively) (p=0.57) differed. Proteinuria according to the histological location of the amyloid: 4.6 g/24 h in glomerular involvement vs. 0.3 g/24 h in those who did not present it (p<0.05). 31.6% required RTT with a mean onset time of 250.6 d from biopsy. Exitus of 21.1%: average time of 426.5 d. (See analysis in attached table). Conclusion We did not observe significant deterioration of renal function, which is greater in non-AL forms of amyloidosis. Fat biopsy was less cost-effective than reported in the literature. Significantly lower levels of proteinuria were found in the amyloidosis group without glomerular involvement. In our series, the prognostic capacity associated with the MAYO staging was confirmed.

Detecting the effect of genetic diversity on brain composition in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There is considerable variation in the progression of clinical symptoms and pathology in humans, highlighting the importance of genetic diversity in the study of AD. To address this, we analyze cell composition and amyloid-beta deposition of 6- and 14-month-old AD-BXD mouse brains. We utilize the analytical QUINT workflow- a suite of software designed to support atlas-based quantification, which we expand to deliver a highly effective method for registering and quantifying cell and pathology changes in diverse disease models. In applying the expanded QUINT workflow, we quantify near-global age-related increases in microglia, astrocytes, and amyloid-beta, and we identify strain-specific regional variation in neuron load. To understand how individual differences in cell composition affect the interpretation of bulk gene expression in AD, we combine hippocampal immunohistochemistry analyses with bulk RNA-sequencing data. This approach allows us to categorize genes whose expression changes in response to AD in a cell and/or pathology load-dependent manner. Ultimately, our study demonstrates the use of the QUINT workflow to standardize the quantification of immunohistochemistry data in diverse mice, - providing valuable insights into regional variation in cellular load and amyloid deposition in the AD-BXD model.

Alzheimer's disease early screening and staged detection with plasma proteome using machine learning and convolutional neural network.

Alzheimer's disease (AD) stands as the prevalent progressive neurodegenerative disease, precipitating cognitive impairment and even memory loss. Amyloid biomarkers have been extensively used in the diagnosis of AD. However, amyloid proteins offer limited information about the disease process and accurate diagnosis depends on the presence of a substantial accumulation of amyloid deposition which significantly impedes the early screening of AD. In this study, we have combined plasma proteomics with an ensemble learning model (CatBoost) to develop a cost-effective and non-invasive diagnostic method for AD. A longitudinal panel has been identified that can serve as reliable biomarkers across the entire progression of AD. Simultaneously, we have developed a neural network algorithm that utilizes plasma proteins to detect stages of Alzheimer's disease. Based on the developed longitudinal panel, the CatBoost model achieved an area under the operating curve of at least 0.90 in distinguishing mild cognitive impairment from cognitively normal. The neural network model was utilized for the detection of three stages of AD, and the results demonstrated that the neural network model exhibited an accuracy as high as 0.83, surpassing that of the traditional machine learning model.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71ml (0.86) vs. 7.2ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Deactivation of the Unfolded Protein Response Aggravated Renal AA Amyloidosis in HSF1 Deficiency Mice.

Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N=299), mild cognitive impairment (MCI; N=192), or dementia (DEM; N=65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Plasma biomarkers differed across diagnostic groups (DEM>MCI>CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Plasma biomarkers differ across diagnostic groups (DEM>MCI>CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Changes in Astroglial Water Flow in the Pre-amyloid Phase of the STZ Model of AD Dementia.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.

Single episode of moderate to severe traumatic brain injury leads to chronic neurological deficits and Alzheimer's-like pathological dementia.

Traumatic brain injury (TBI) is one of the foremost causes of disability and mortality globally. While the scientific and medical emphasis is to save lives and avoid disability during acute period of injury, a severe health problem can manifest years after injury. For instance, TBI increases the risk of cognitive impairment in the elderly. Remote TBI history was reported to be a cause of the accelerated clinical trajectory of Alzheimer's disease-related dementia (ADRD) resulting in earlier onset of cognitive impairment and increased AD-associated pathological markers like greater amyloid deposition and cortical thinning. It is not well understood whether a single TBI event may increase the risk of dementia. Moreover, the cellular signaling pathways remain elusive for the chronic effects of TBI on cognition. We have hypothesized that a single TBI induces sustained neuroinflammation and disrupts cellular communication in a way that results later in ADRD pathology. To test this, we induced TBI in young adult CD1 mice and assessed the behavioral outcomes after 11months followed by pathological, histological, transcriptomic, and MRI assessment. On MRI scans, these mice showed significant loss of tissue, reduced CBF, and higher white matter injury compared to sham mice. We found these brains showed progressive atrophy, markers of ADRD, sustained astrogliosis, loss of neuronal plasticity, and growth factors even after 1-year post-TBI. Because of progressive neurodegeneration, these mice had motor deficits, showed cognitive impairments, and wandered randomly in open field. We, therefore, conclude that progressive pathology after adulthood TBI leads to neurodegenerative conditions such as ADRD and impairs neuronal functions.

Four-dimensional computed tomography is useful for detection of apical sparing of cardiac amyloidosis.

A 73-year-old male was admitted because of recurrent syncope. He was diagnosed with transient bradycardia caused by a 2:1 atrioventricular block, and he underwent cardiac computed tomography (CT) using 320 detector-row CT to screen for coronary artery disease. Significant coronary artery stenosis was not detected, but diffuse late iodinate enhancement was found on the epi-myocardium and endo-myocardium of the interventricular septum, and endo-myocardium of the anterior and lateral left ventricular (LV) myocardium (LVM) on CT. The ejection fraction and global longitudinal strain (LS) of LVM were 53.97% and - 9.87% on CT. Apical sparing was present, meaning the LS of LV apical segments were preserved compared with basal segments on CT. Pathological findings of LVM demonstrated loss of myocardial cells and extra-cellular amyloid deposition on the direct fast scarlet staining. He was finally diagnosed with transthyretin amyloidosis.

Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain.

Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.

Localized Urinary Bladder Amyloidosis as Urothelial Cancer Mimicker.

Localized amyloidosis of the bladder is rare and often mimics bladder malignancy. It is typically associated with the extracellular deposition of monoclonal light chains, either κ or λ. The cause is unknown, but it is thought to be due to chronic inflammation/cystitis. To highlight the importance of localized urinary bladder amyloidosis as a rare mimicker of urothelial malignancy and elucidate its clinical, histopathologic, and cytopathologic manifestations. Cases of urinary bladder amyloidosis diagnosed during 2000-2023 were retrieved retrospectively from pathology archives. Electronic medical records, including cystoscopy findings and pathology slides including Congo red stain, were reviewed. Here we present 6 patients with localized urinary bladder amyloidosis. Four of the 6 patients were women, with ages ranging from 46 to 69 years, and a mean age of 58 years. Five of 6 patients presented with hematuria, while in 1 patient, bladder amyloidosis was discovered incidentally. Cystoscopy findings invariably were concerning for malignancy, with raised erythema in 5 patients and fungating mass protruding into the bladder lumen in 1 patient. Bladder biopsies and urine cytology were negative for malignancy in all cases. Congo red-positive amyloid deposits involved lamina propria with sparing of the detrusor muscle. In 5 cases, the deposits were typed as derived from the λ light chain, whereas no information was available for 1 patient. Subsequent clinical workup ruled out systemic amyloidosis. These cases of urinary bladder amyloidosis highlight the importance of considering rare amyloidosis in the differential diagnosis of hematuria and cystoscopy with a lesion mimicking malignancy.