Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. Methods: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aβ42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. Results: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. Conclusion: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.
<b><i>Background:</i></b> Neuropathological studies indicate concomitant Alzheimer’s disease (AD) pathology in patients with dementia with Lewy bodies (DLB). <b><i>Objectives:</i></b> To measure cerebrospinal fluid (CSF) levels of β-amyloid peptide with 42 amino acids (Aβ<sub>42</sub>), total tau protein (τ<sub>T</sub>), and tau phosphorylated at threonine 181 (τ<sub>P-181</sub>) in 38 patients fulfilling the diagnostic criteria of probable DLB according to the most recent (4th consensus) report. <b><i>Methods:</i></b> Double-sandwich commercial ELISAs (Innotest; Fujirebio, Gent, Belgium) were used for measurements. <b><i>Results:</i></b> According to the current cutoff values of our laboratory, 4 biomarker profiles were noted: abnormal levels of Aβ<sub>42</sub> only (44.7%), full AD profile (39.5%), abnormal levels of τ<sub>T</sub> only (5.3%), and normal levels of all 3 biomarkers (10.5%). AD profile was associated with female sex, older age, lower education, and lower MMSE scores. <b><i>Conclusions:</i></b> Reduction in Αβ<sub>42</sub> in DLB may be more common (>80% of patients) than previously thought, and ∼40% may have the typical CSF AD biomarker profile. AD biochemistry in DLB may be an evolving process showing increasing frequency with disease progression.
Caffeine may be protective against Alzheimer's disease (AD) by modulating amyloid-β (Aβ) metabolic pathways. The present work aimed to study a possible association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ. The study included 88 patients with AD or mild cognitive impairment. The consumption of caffeine and theobromine was evaluated using a validated food questionnaire. Quantification of caffeine and main active metabolites was performed with liquid chromatography coupled to tandem mass spectrometry. The levels of A(1-42), total tau, and phosphorylated tau in the CSF were determined using sandwich ELISA methods and other Aβ species, Aβ(X-38), Aβ(X-40), and Aβ(X-42), with the MSD Aβ Triplex assay. The concentration of caffeine was 0.79±1.15 μg/mL in the CSF and 1.20±1.88 μg/mL in the plasma. No correlation was found between caffeine consumption and Aβ42 in the CSF. However, a significant positive correlation was found between the concentrations of theobromine, both in the CSF and in the plasma, with Aβ42 in the CSF. Theobromine in the CSF was positively correlated with the levels of other xanthines in the CSF, but not in the plasma, suggesting that it may be formed by central metabolic pathways. In conclusion, caffeine consumption does not modify the levels of CSF biomarkers, and does not require to be controlled for when measuring CSF biomarkers in a clinical setting. Since theobromine is associated with a favorable Aβ profile in the CSF, the possibility that it might have a protective role in AD should be further investigated.
Glutamate dehydrogenase (GDH) catalyzes the reversible deamination of L-glutamate to α-ketoglutarate and ammonia. In mammals, GDH contributes to important processes such as amino acid and carbohydrate metabolism, energy production, ammonia management, neurotransmitter recycling and insulin secretion. In humans, two isoforms of GDH are found, namely hGDH1 and hGDH2, with the former being ubiquitously expressed and the latter found mainly in brain, testis and kidney. These two iso-enzymes display highly divergent allosteric properties, especially concerning their basal activity, ADP activation and GTP inhibition. On the other hand, both enzymes are thought to predominantly localize in the mitochondrial matrix, even though alternative localizations have been proposed. To further study the subcellular localization of the two human iso-enzymes, we created HEK293 cell lines stably over-expressing hGDH1 and hGDH2. In these cell lines, immunofluorescence and enzymatic analyses verified the overexpression of both hGDH1 and hGDH2 iso-enzymes, whereas subcellular fractionation followed by immunoblotting showed their predominantly mitochondrial localization. Given that previous studies have only indirectly compared the subcellular localization of the two iso-enzymes, we co-expressed them tagged with different fluorescent dyes (green and red fluorescent protein for hGDH1 and hGDH2, respectively) and found them to co-localize. Despite the wealth of information related to the functional properties of hGDH1 and hGDH2 and the availability of the hGDH1 structure, there is still an ongoing debate concerning their metabolic role and their involvement in disease processes. Data on the localization of hGDHs, as the ones presented here, could contribute to better understanding of the function of these important human enzymes.
Background: Apolipoprotein E gene (APOE) ɛ4 allele increases the risk for Alzheimer’s disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited. Objective: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n = 49) and MCI (n = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing on Crete, Greece. Methods: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders. Results: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3 h, respectively, p = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5 h, respectively, p = 0.012). Conclusion: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment.
Total tau (τT), phosphorylated tau (τP-181) and amyloid beta (Aβ42) are cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). There is no consensus on the interpretation criteria of these biomarkers. The aim of this study was to apply three different sets of criteria for CSF AD biomarker interpretation in a cohort of corticobasal degeneration (CBD) patients. Method: SForty patients fulfilling diagnostic criteria for "probable CBD" were included. The AT(N), BIO-MARKAPD/ABSI and the τP-181/Aβ42 ratio criteria were applied. Results:The AT(N) criteria categorized 50% of "probable CBD" patients as AD, and 62.5% as harboring amyloid pathology. The BIOMARKAPD/ABSI and τP-181/Aβ42 criteria categorized ~40% of "probable CBD" patients as AD. Discussion: Use of different interpretation criteria for CSF AD biomarkers produces diverse results. AD pathology is common in patients fulfilling "probable" CBD criteria. CBD diagnostic criteria may have suboptimal positive predictive value. A consensus regarding interpretation criteria of CSF AD biomarkers is pivotal.
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