The Erlangen Score Algorithm in the diagnosis and prediction of the progression from subjective cognitive decline and mild cognitive impairment to Alzheimer-type dementia.

The evaluation of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) (ß-amyloid, t-tau, p-tau) can be used to estimate the risk of developing dementia in patients at the pre-clinical stages of AD, i.e. subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Erlangen Score Algorithm allows interpretation of CSF biomarker concentrations and is cut-off value independent. The aim of this study was to establish if this algorithm can be applied for routine diagnostic testing in clinical and preclinical subjects and has prognostic value. We analysed 217 patients from the memory clinic with the diagnosis of SCD (n = 31), MCI (n = 104), and AD (n = 82) with clinical follow-up amounting to 14.33 months (SD = 6.82). It was found that the highest Erlangen Score dominated in the AD group and was the rarest in the SCD group. In the group of patients with progression of symptoms during our period of observation, the AD pathology was confirmed in 93.75% of cases. Among the non-progressing subjects (n = 119) the algorithm indicated the risk of developing AD as possible in 40.34% and probable in 15.97% of cases. To conclude, the Erlangen Score Algorithm is a useful tool to determinate the risk of developing AD before the onset of dementia or to confirm the AD diagnosis. It is extremely valuable in preclinical stages of AD for planning purposes and early intervention as well as for future clinical trials.

Hypermethylation of TRIM59 and KLF14 Influences Cell Death Signaling in Familial Alzheimer's Disease.

Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer's disease (AD) pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer's disease (fEOAD) patient-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR) in both fibroblasts and reprogrammed neurons. Here, we show that the aging-correlated hypermethylation of KLF14 and TRIM59 genes associates with abnormalities in DNA repair and cell cycle control in fEOAD. Based on the resulting transcriptome networks, we found that the hypermethylation of KLF14 might be associated with epigenetic regulation of the chromatin organization and mRNA processing followed by hypermethylation of TRIM59 likely associated with the G2/M cell cycle phase and p53 role in DNA repair with BRCA1 protein as the key player. We propose that the hypermethylation of KLF14 could constitute a superior epigenetic mechanism for TRIM59 hypermethylation. The methylation status of both genes affects genome stability and might contribute to proapoptotic signaling in AD. Since this study combines data obtained from various tissues from AD patients, it reinforces the view that the genetic methylation status in the blood may be a valuable predictor of molecular processes occurring in affected tissues. Further research is necessary to define a detailed role of TRIM59 and KLF4 in neurodegeneration of neurons.

Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease.

The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-ß. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-ß pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-ß1-42 (Aß1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aß1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aß1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aß1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

The usefulness of diffusion-weighted/fluid-attenuated inversion recovery imaging in the diagnostics and timing of lacunar and nonlacunar stroke.

INTRODUCTION: The DWI/FLAIR mismatch is a potential radiological marker for the timing of stroke onset. The aim of the study was to assess if the DWI/FLAIR mismatch can help to identify patients with both lacunar and nonlacunar acute ischemic stroke within 4.5 h of onset. METHODS: A retrospective study was performed in which the authors analysed data from 86 ischemic lacunar and nonlacunar stroke patients with a known time of symptom onset, imaged within the first 24 h from stroke onset (36 patients <4.5 h, 14 patients 4.5-6 h, 15 patients 6-12 h, and 21 patients 12-24 h). Patients underwent the admission CT and MR scan. The presence of lesions was assessed in correlation with the duration of the stroke. RESULTS: The time from stroke onset to neuroimaging was significantly shorter in patients with an ischemic lesion visible only in the DWI (mean 2.78 h, n = 24) as compared to patients with signs of ischemia also in other modalities (mean 8.6 h, n = 62) (p = 0.0001, Kruskal-Wallis ANOVA). The DWI/FLAIR mismatch was characterised by a global sensitivity of 58%, specificity 94%, PPV 87.5%, and NPV 76% in identifying patients in the 4.5 h thrombolysis time window. For lacunar strokes (n = 20), these parameters were as follows: sensitivity 50%, specificity 92.8%, PPV 75 %, and NPV 81.2%. CONCLUSIONS: The presence of acute ischemic lesions only in DWI can help to identify both lacunar and nonlacunar stroke patients who are in the 4.5 h time window for intravenous thrombolysis with high specificity.