Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia.

BACKGROUND AND PURPOSE: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia. METHODS: Amyloid-ß (Aß) 1-42, total tau (t-tau), phosphorylated tau, Aß40 , Aß38 , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects. RESULTS: Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels. CONCLUSIONS: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia.

Intraoperative Sentinel Node Fine-Needle Aspiration Biopsy as a Substitute for Whole Sentinel Node Excisional Biopsy in Breast Cancer Patients. Initial Report.

INTRODUCTION: Sentinel Node Biopsy (SNB) is the choice procedure for axillary staging in Breast Cancer. Following the ACOSOG Z11 trial, axillary dissection is advised only in patients with more than 2 positive SNs. We aimed at exploring palpation-guided, intraoperative fine-needle aspiration biopsy of the SN as a replacement for whole SN excision in node-negative BC patients to minimize side-effects. PATIENTS AND METHODS: We included 80 patients with BC undergoing SNB between December 2020 and May 2022. After identification of the SN, the breast surgeon performed SN-FNAB. Results were compared with definitive pathological assessment. ResultsDiagnostic yield was 80%, including a "learning curve." 58 of 64 patients with suitable samples tested negative. In this group, the Negative Predictive Value was 77.6% (IC 64.7%-87.5 %). If micro metastasis is disregarded, the NPV would increase to 86.2% (IC 74.6%-93.9%). If we accept the Z11 criterion for axillary dissection, the NPV would rise to 100%. Six patients had a positive SN-FNAB. They were all confirmed as having macro metastatic-positive SNs at the final pathological assessment, and 3 of them also displayed extra nodal extension (ENE). CONCLUSION: We believe that intraoperative SN-FNAB is highly accurate for swiftly depicting both low axillary tumor burden/negative cases, in whom axillary dissection is to be omitted, as well as high axillary tumor burden cases.

Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia.

BACKGROUND: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended. OBJECTIVE: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. METHODS: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA. RESULTS: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-ß 1-42 (Aß42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aß42 ratio = 0.58. T-tau/Aß42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aß42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. CONCLUSIONS: CSF t-tau/Aß42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.