全身性アミロイドーシス

Cerebral amyloid angiopathy (CAA) is a common brain pathology in older people and has been recently recognized as a major risk factor for amyloid-related imaging abnormalities during anti-amyloid antibody therapy. CAA pathophysiology may involve iron released from ruptured vessels, but the association between postmortem CAA and brain iron is unclear. This study investigates the association between CAA and brain iron and whether elevated iron modifies the association between CAA and cognitive decline. We studied 626 Rush Memory and Aging Project decedents (mean age at death = 90 [SD = 6.1] years, 70% women) who completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, Alzheimer's disease neuropathologic changes (ADNC), and other brain pathologies. Brain iron content was assessed from the inferior temporal cortex using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Linear regression and mixed-effects models were used for analysis. CAA was common: 266 (42%) had mild, 153 (24%) had moderate, and 75 (12%) had severe CAA. In analyses adjusted for demographics, intermediate/high ADNC, and other pathologies, the presence and severity of CAA were associated with elevated cortical brain iron (Est = 0.033, SE = 0.011, p = 0.002; Est = 0.017, SE = 0.004, p < 0.001, respectively). When examining associations with nonlinear cognitive change before death (mean follow-up = 7.7 [SD = 3.9] years), both CAA and elevated iron were independently associated with faster annual rates of decline in global cognition and semantic memory (all p < 0.04). Elevated iron was also associated with faster declines in episodic and working memory and perceptual speed (all p < 0.02). When exploring whether brain iron modulates the association of CAA with cognitive decline, we found that CAA had steeper decline in perceptual speed when elevated iron was present compared to when low iron was present (p = 0.03). Together, these findings suggest that brain iron may contribute to the clinical impact of CAA in older age.

B-cell maturation antigen (BCMA)-targeted therapies have emerged as promising treatment options for patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. However, comprehensive data on their efficacy and safety remain limited. We conducted a systematic descriptive pooled analysis of published studies reporting outcomes of BCMA-directed therapies including chimeric antigen receptor T-cell (CAR-T) therapies, bispecific antibodies (BsAbs), and antibody-drug conjugate (ADC). The analysis included 256 patients. CAR-T therapy was administered to 89 patients (35%), BsAbs to 82 patients (32%), and ADCs to 85 patients (33%). The pooled overall response rate (ORR) was 83%, with CAR-T demonstrating 92% ORR, BsAbs 89%, and ADCs 68%. Deep hematologic responses (≥VGPR) were achieved in approximately 70% of CAR-T and BsAb recipients and 64% of ADC recipients. Minimal residual disease negativity was documented in 75% of evaluable CAR-T patients and in 86% evaluable BsAb patients with reported data. Organ responses were observed in 30% of evaluable patients, with cardiac responses in 41%. Cytokine release syndrome occurred in 74% of CAR-T and 49% of BsAb patients, predominantly grade 1-2. Grade ≥3 CRS was rare (9% CAR-T, 1% BsAb). Ocular toxicity was the predominant adverse event in ADC recipients (84% any grade, 29% grade ≥3). Grade ≥3 infections occurred in 13% of CAR-T, 20% of BsAb, and 6% of ADC patients. BCMA-targeted therapies result in high response rates with manageable safety profiles in heavily pretreated AL amyloidosis patients, supporting continued investigation and clinical application of these approaches.

PURPOSE: The aim of this study was to investigate the radiographic characteristics and distribution of bone cysts in the hands of patients with dialysis-related amyloidosis (DRA) undergoing surgery for carpal tunnel syndrome (CTS) and to identify factors associated with cyst formation using hand radiography. METHODS: We analyzed preoperative hand radiographs of 50 hands (mean age: 70 years) from hemodialysis patients and a 1:2 age- and sex-matched control group (100 hands). Bone cysts (≥ 2 mm) with sclerotic margins were evaluated across 15 sites per hand (radius, ulna, 8 carpal bones, and 5 metacarpals). Multivariate linear regression analysis incorporating clinical, biochemical, and localized parameters was performed to identify factors affecting the number of cysts in dialysis patients. Additionally, the presence of bone cysts in bones associated with osteoarthritis (OA) was assessed. RESULTS: The prevalence of bone cysts was significantly higher in the hemodialysis group than in the controls (94% vs. 74%), with a higher mean number of involved bones (5.2 vs. 2.9). The total area of bone cysts in the hemodialysis group (84.7mm2) was significantly larger than that in the controls (39.5mm2). Cysts were most frequent in the scaphoid and lunate (60%). Multivariate analysis identified only dialysis vintage and OA as independent factors associated with cyst number. Dialysis vintage showed a strong positive correlation with cyst count (r = 0.69). OA was significantly more frequent in the hemodialysis group (44% vs. 25%). Among 64 OA joints, 89.1% exhibited concomitant bone cysts, most commonly at the thumb carpometacarpal joint. CONCLUSION: Bone cysts were nearly ubiquitous in hemodialysis-related CTS patients, particularly in the scaphoid and lunate. The strong correlation between dialysis vintage and cyst count, along with a significantly larger total cyst area and a high association with OA, suggests that plain radiography remains a valuable and accessible clinical tool for assessing the cumulative burden of amyloidosis and joint degeneration.

Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.

BACKGROUND: Cardiac amyloidosis (CA) is an increasingly recognized cause of worsening heart failure (WHF) and is associated with poor outcomes, yet patients with CA-related WHF remain poorly characterized in real-world outpatient settings. METHODS: Patients with CA-related WHF, followed in a dedicated WHF Day Hospital clinic, were compared with matched (for age, sex, ejection fraction) non-CA WHF controls. Clinical outcomes included all-cause mortality and HF hospitalization. Frailty was assessed using the Frailty Index (FI) alongside functional and patient-reported measures. Associations with all-cause mortality were evaluated using Kaplan-Meier and Weibull models stratified by CA status. RESULTS: Among 154 WHF patients, 21 had CA and were matched to 42 non-CA controls. Median age was 81 (76-85) years, 23.8% were females. All-cause mortality was significantly higher in the CA-related WHF cohort, with an estimated occurrence of 72.0% vs. 25.9% (95%CI 50.7%-89.9% vs. 14.5%-43.7%) at 120 weeks (log-rank p = 0.001). As expected, in CA patients, the FI ≥ 0.38 and impaired health-related quality of life (EQ-5D) were associated with mortality (log-rank p = 0.002, p = 0.012, respectively). Among biomarkers, natriuretic peptides did not significantly discriminate risk among CA-related WHF, while discriminating in non-CA WHF. sST2 showed a similar prognostic relevance at the upper quartile in CA and non-CA WHF (log-rank p = 0.028, p = 0.009, respectively). CONCLUSIONS: In real-world WHF, despite comparable baseline biomarker profiles and frailty burden, CA identifies a subgroup with an adverse prognosis, worse than comparable patients with a different etiology. Frailty and biomarker profiles show etiology-specific prognostic behavior, supporting a phenotype-driven risk stratification strategy in WHF.