Aß38 and Aß43 do not differentiate between Alzheimer's disease and cerebral amyloid angiopathy.

Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aß38 and Aß43 to a standard AD biomarker panel (Aß40, Aß42, t-tau, p-tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques. We found excellent discrimination between AD and controls and between CAA and controls, but not between AD and CAA. Adding Aß38 and Aß43 to the panel did not improve the discrimination between AD and CAA.

Frequency of deep-seated cerebral microbleeds in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a common disease and the most common cause of lobar hemorrhages in the elderly. Usually, deep-seated microhemorrhages preclude the diagnosis of CAA. In this study, we sought to estimate the frequency of deep-seated microbleeds on MRI in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy. In addition, we describe a cohort of patients with cortical and deep-seated microbleeds on MRI and a histopathological specimen available from lobar hematoma evacuation. Methods: Retrospective database search for histopathological specimens from lobar hematoma evacuation and review of imaging findings (CT and MRI) and patient charts was performed. Results: Between 1 January 2012 and 31 December 2020, 88 specimens from 88 patients were available. A total of 56 specimens were excluded (no brain tissue in the specimen n = 4, other diagnosis n = 8, no MRI n = 43, and no BOLD-based sequence n = 1). Of the remaining 32 patients, 25 patients (78%) did not harbor deep-seated lesions on MRI, of which 17 patients had histopathological features of CAA. A total of seven patients harbored deep-seated CMB. Of these seven patients, three (3/20, 15%) had histopathological features of CAA. Conclusion: Approximately 15% of patients with histopathologically diagnosed CAA harbor deep-seated microbleeds. This finding may add to the discussion on how to identify patients with CAA and deep-seated CMB.

Characterizing mixed location hemorrhages/microbleeds with CSF markers.

OBJECTIVE: Cerebral amyloid angiopathy (CAA) is a common cause of lobar and subarachnoid hemorrhages in the elderly. A diagnosis of CAA requires multiple lobar hemorrhagic lesions (intracerebral hemorrhage and/or cerebral microbleeds) and/or cortical superficial siderosis (cSS). In contrast, hemorrhagic lesions located in the deep structures are the hallmark of hypertensive arteriopathy (HTN-A). They are an exclusion criterion for CAA, and when present with lobar hemorrhagic lesions considered a separate entity: mixed location hemorrhages/microbleeds (MLHs). We compared clinical, radiological, and cerebrospinal fluid (CSF) marker data in patients with CAA, MLH, and Alzheimer's disease (AD), and healthy controls (HCs) and used it to position MLH in the disease spectrum. PATIENTS AND METHODS: Retrospective cohort study of consecutive patients with CAA (n = 31), MLH (n = 31), AD (n = 28), and HC (n = 30). Analysis of clinical, radiological, CSF biomarker (Aß42, Aß40, t-tau, and p-tau), and histopathological data in patients each group. RESULTS: cSS was significantly more common in CAA than MLH (45% vs 13%, p = 0.011), and cSS in MLH was associated with intracerebral hemorrhage (ICH) (p = 0.037). Aß42 levels and the Aß42/Aß40 ratio, diagnostic groups followed the order HC > MLH > CAA > AD and the opposite order for t-tau and p-tau. No clear order was apparent forAß40. Aß40 and Aß42 levels as well as the Aß42/Aß40 ratio were lower in both CAA and MLH patients with cSS than in patients without cSS. Aß40 and Aß42 levels were higher in CAA and MLH patients with lacunar infarcts than in those without. CONCLUSION: Our data suggest that MLH and CAA are mutually not exclusive diagnoses, and are part of a spectrum with variable contributions of both CAA and HTN-A.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy: New Data and Quantitative Meta-Analysis.

BACKGROUND: To evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort. METHODS: Beta-amyloid 1-40 (Aß40), beta-amyloid 1-42 (Aß42), total tau (t-tau), and phosphorylated tau 181 (p-tau181) were measured in 31 patients with probable CAA, 28 patients with Alzheimer's disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aß42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted. RESULTS: In our data Aß42/40 (AUC 0.88) discriminated best between CAA and controls while Aß40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau181 (AUC 0.75) discriminated best in this study while Aß40 (AUC 0.58) and Aß42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aß42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aß40 (AUC 0.76), and p-tau181 (AUC 0.71). P-tau181 (AUC 0.76), Aß40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aß42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aß42/40 discriminated excellently between AD and controls (AUC 0.92-0.96) in this study as well as the meta-analysis. CONCLUSION: The analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful.

Clinical and radiological differences between patients with probable cerebral amyloid angiopathy and mixed cerebral microbleeds.

BACKGROUND: The key imaging features of cerebral amyloid angiopathy (CAA) are lobar, cortical, or cortico-subcortical microbleeds, macrohaemorrhages and cortical superficial siderosis (cSS). In contrast, hypertensive angiopathy is characterized by (micro) haemorrhages in the basal ganglia, thalami, periventricular white matter or the brain stem. Another distinct form of haemorrhagic microangiopathy is mixed cerebral microbleeds (mixed CMB) with features of both CAA and hypertensive angiopathy. The distinction between the two entities (CAA and mixed CMB) is clinically relevant because the risk of haemorrhage and stroke should be well balanced if oral anticoagulation is indicated in CAA patients. We aimed to comprehensively compare these two entities. METHODS: Patients with probable CAA according to the modified Boston criteria and mixed CMB without macrohaemorrhage were retrospectively identified from our database. Comprehensive comparison regarding clinical and radiological parameters was performed between the two cohorts. RESULTS: Patients with CAA were older (78 ± 8 vs. 74 ± 9 years, p = 0.036) and had a higher prevalence of cSS (19% vs. 4%, p = 0.027) but a lower prevalence of lacunes (73% vs. 50%, p = 0.018) and deep lacunes (23% vs. 51%, p = 0.0003) compared to patients with mixed CMB. Logistic regression revealed an association between the presence of deep lacunes and mixed CMB. The other collected parameters did not reveal a significant difference between the two groups. CONCLUSIONS: CAA and mixed CMB demonstrate radiological differences in the absence of macrohaemorrhages. However, more clinically available biomarkers are needed to elucidate the contribution of CAA and hypertensive angiopathy in mixed CMB patients.

Susceptibility variation of Malassezia pachydermatis to antifungal agents according to isolate source.

Malassezia pachydermatis is associated with dermatomycoses and otomycosis in dogs and cats. This study compared the susceptibility of M. pachydermatis isolates from sick (G1) and healthy (G2) animals to azole and polyene antifungals using the M27-A3 protocol. Isolates from G1 animals were less sensitive to amphotericin B, nystatin, fluconazole, clotrimazole and miconazole.

Susceptibility variation of Malassezia pachydermatis to antifungal agents according to isolate source

Malassezia pachydermatisis associated with dermatomycoses and otomycosis in dogs and cats. This study compared the susceptibility of M. pachydermatis isolates from sick (G1) and healthy (G2) animals to azole and polyene antifungals using the M27-A3 protocol. Isolates from G1 animals were less sensitive to amphotericin B, nystatin, fluconazole, clotrimazole and miconazole.

In vitro synergisms obtained by amphotericin B and voriconazole associated with non-antifungal agents against Fusarium spp.

Fusarium spp is an opportunistic fungal pathogen responsible for causing invasive hyalohyphomycosis in immunocompromised patients. Due to its susceptibility pattern with a remarkable resistance to antifungal agents the treatment failures and mortality rates are high. To overcome this situation, combination therapy may be considered which must be subjected to in vitro tests. In vitro activities of amphotericin B, itraconazole, and voriconazole associated with azithromycin, ciprofloxacin, fluvastatin, ibuprofen, metronidazole, and also the combination of amphotericin B plus rifampin against 23 strains of Fusarium spp. through the checkerboard technique based on M38-A2 [Clinical and Laboratory Standards Institute (2008). Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. (CLSI document M38-A2) (ISBN 1-56238-668-9). Wayne, PA: CLSI] were evaluated. The best synergistic interactions with amphotericin B were with ibuprofen (43.5%) (FICI [fractional inhibitory concentration index] range = 0.25-2). Combinations with voriconazole showed synergism, mainly with ciprofloxacin (30.4%) (FICI range = 0.25-3) and metronidazole (30.4%) (FICI range = 0.1-4); however, all the combinations with itraconazole were indifferent. In general, antagonistic interactions were not registered. Our results showed that in vitro synergisms obtained by some combinations studied deserve attention since they were better than those showed by the antimycotic.