Journal of Alzheimer's Disease - Volume 41, issue 2

Authors: Nelson, Lucy | Gard, Paul | Tabet, Naji

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is by far the most common sporadic neurodegenerative disorder. Clinically it is associated with cognitive and other neuropsychological impairments, and neuropathologically it is distinguished by presence of amyloid-β plaques and neurofibrillary tangles. Hypertension has been traditionally associated with the etiology of vascular dementia, however, vascular risk factors including hypertension are increasingly being implicated in AD. Likewise, the importance of neuroinflammation in AD pathogenesis is also widely recognized. Data from animal and non-AD human studies suggest a close reciprocal relationship between hypertension and inflammatory systems. Much less is known on the potential pathological interaction between hypertension and inflammation …in AD and its subsequent effects on amyloid and tau misfolding, aggregation, and propagation, events recognized as critical for the development and progression of AD. This review summarizes what is known about the mechanistic interactions between hypertension and inflammatory mediators and assesses their potential synergistic/additive role in AD genesis. Increasing our understanding of the pathological interactions between the recognized risk factors for AD is a worthwhile endeavor in a condition which currently has limited treatment options but an increasing number of potential preventative measures. Show more

Keywords: Alzheimer's disease, amyloid, cerebrovasculature, dementia, hypertension, inflammation

DOI: 10.3233/JAD-140024

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 331-343, 2014

Authors: Russell, Claire L. | Koncarevic, Sasa | Ward, Malcolm A.

Article Type: Review Article

Abstract: The ability to detect and diagnose Alzheimer's disease (AD) early is an ever pressing issue, and the development of markers of disease progression that are able to distinguish AD patients from normal aging and patients with alternative forms of dementia, is at the center of the issue. Protein markers of disease, or biomarkers, can be used not only to monitor the progression of AD, but also allow identification of patients suitable for potential therapy, and the response to therapy to be monitored. Cerebrospinal fluid protein biomarkers are important in this early AD diagnosis, and three such biomarkers have been extensively …studied and are reviewed here. In addition, post translational protein modifications of proteins important in AD pathology are also discussed. If additional biomarkers can be identified and thoroughly understood, potential therapeutic agents can be better designed, and the effects of therapeutic intervention on disease progression can be monitored. Show more

Keywords: Amyloid-β, biomarkers, cerebrospinal fluid, phosphorylation, post-translational modifications, tau

DOI: 10.3233/JAD-132312

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 345-364, 2014

Authors: Taddeo, Marta Anne | Lee, Sangmook | Shea, Thomas B.

Article Type: Short Communication

Abstract: Iron exacerbates amyloid-β (Aβ) toxicity, while zinc alleviates it. We examined the impact of these metals on Aβ-induced signaling inhibition. Murine embryonic cortical neurons on multi-electrode arrays received 0.1 μM FeCl2 0.1 μM zinc acetate and/or 10 nM oligomerized Aβ1-42 . No toxicity was observed. Spontaneous signaling was not altered by iron or Aβ individually, but was inhibited by both. Zinc did not impact signaling alone, but prevented inhibition by iron plus Aβ. Aβ can be detected years before cognitive decline. Subcytotoxic iron levels may potentiate Aβ-induced impairment of synaptic activity during these early stages; zinc supplementation may alleviate …this potentiation. Show more

Keywords: Amyloid-β, iron, metal toxicity, multi-electrode arrays, signaling, zinc

DOI: 10.3233/JAD-132696

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 365-369, 2014

Authors: Borroni, Barbara | Grassi, Mario | Bianchi, Marta | Bruni, Amalia Cecilia | Maletta, Raffaele Giovanni | Anfossi, Maria | Pepe, Daniele | Cagnin, Annachiara | Caffarra, Paolo | Cappa, Stefano | Clerici, Francesca | Daniele, Antonio | Frisoni, Giovanni B. | Galimberti, Daniela | Parnetti, Lucilla | Perri, Roberta | Rainero, Innocenzo | Tremolizzo, Lucio | Turla, Marinella | Zanetti, Orazio | Padovani, Alessandro

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) has a strong genetic basis, with familial forms occurring in 30–50% of cases. Causative genes have been identified, with an autosomal dominant pattern of inheritance. Notwithstanding, in a number of cases with positive family history no pathogenetic mutation has been reported, and the role of genetics in sporadic cases is still unclear. In the present study, we aim to estimate the genetic contribution to FTD using concordance among parent-offspring pairs. Heritability of early-onset (EO, <65 years) and late-onset (LO, ≥65 years) FTD was estimated by examining the concordance between parents and offspring. Probands with at least one …parent whose dementia status was known were recruited from 15 Italian centers, and the presence or absence of dementia was considered in siblings. Different prevalence estimates, as available by literature data, were tested. A total of 260 probands and 1619 family members were considered in this study. We found that parent-offspring concordance in FTD was 6.25%, resulting in hereditability of 98.5% (95% confidence interval (CI): 85.0%–100.0%). Equal heritability for both sexes regardless of parental gender was reported. EO-FTD showed hereditability of 86.3% (95% CI: 77.0%–95.0%) and LO-FTD of 75.7% (95% CI: 65.0%–86.0%). Estimating the contribution of genetics in FTD may help in driving future genetic studies to identify new pathogenetic determinants. We suggest that in most of the cases FTD is a genetic-based disease, even in the elderly. Different inheritance modality might be considered in future work, beyond autosomal dominant disease. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, genetics, heritability, inheritance

DOI: 10.3233/JAD-130128

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 371-376, 2014

Authors: Sauvée, Mathilde | DidierLaurent, Guerric | Latarche, Clotilde | Escanyé, Marie-Christine | Olivier, Jean-Luc | Malaplate-Armand, Catherine

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for the diagnosis of Alzheimer’s disease (AD). Since interpretation of CSF profile requires the combination of three parameters, biological data are not always conclusive and isolated elevation of phosphorylated tau (P-tau) or reduction of amyloid-β (Aβ)42 alone can be observed. In these cases, Aβ42 /Aβ40 ratio could be more relevant than Aβ42 absolute values by considering inter-individual variations in the total amyloid load. Objective: The objective of this study was to assess the use of Aβ42 /Aβ40 ratio to improve the accuracy …of biological conclusions in the diagnosis of patients with ambiguous CSF Aβ42 or tau results. Methods: Among 386 lumbar punctures analyzed in the lab in 2 years, 122 showed ambiguous biological data that were completed by CSF Aβ40 quantification and Aβ42 /Aβ40 ratio calculation. A biological conclusion was then made using 0.05 as the Aβ42 /Aβ40 ratio cut-off. Results: Our results showed that one-third of the biological profiles of patients with atypical dementia were ambiguous. The addition of Aβ42 /Aβ40 ratio increased the proportion of interpretable biological profiles from 69% to 87%, without changing the conclusion when usual biomarkers (Aβ42 and P-tau) were concordant. Conclusion: Our results support the use of the Aβ42 /Aβ40 ratio in addition to the usual CSF AD biomarkers for patients with ambiguous biological profiles. This method could be specifically directed to this population in order to improve the level of certainty for clinical routine practice. Show more

Keywords: Aβ40 peptide, Aβ40/Aβ42 ratio, Aβ42 peptide, Alzheimer's disease, cerebrospinal fluid, diagnosis, differential diagnosis, P-tau

DOI: 10.3233/JAD-131838

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 377-386, 2014

Authors: Tiwari, Vivek | Patel, Anant B.

Article Type: Research Article

Abstract: Although pyruvate dehydrogenase (PDH) is the major pathway of glucose metabolism and source for energy production, pyruvate carboxylase (PC) and pentose phosphate pathway (PPP) account for a significant fraction of glucose oxidation in the mature central nervous system. Flux through the PDH pathway has been reported to be reduced in Alzheimer's disease (AD) patients as well as in animal models of AD. However, fluxes through the PPP and PC pathways have not been explored under conditions of AD. The present study investigates the fluxes of PC and PPP in a 20-month-old AβPP-PS1 mouse model of AD using 13 C NMR …spectroscopy together with an infusion of [2-13 C]glucose. Mice were also administered [1,6-13 C2 ]glucose or [1-13 C]glucose for 10 or 90 min, respectively, to investigate PDH flux. AβPP-PS1 mice exhibit a significant reduction in the level of NAA and increase in level of myo-inositol. The flux through PDH was found to be significantly lower in the cerebral cortex (AβPP-PS1 0.39 ± 0.08; control 0.77 ± 0.08 μmol/g/min), hippocampus (AβPP-PS1 0.31 ± 0.04; control 0.64 ± 0.12 μmol/g/min), and striatum (AβPP-PS1 0.34 ± 0.06; control 0.56 ± 0.03 μmol/g/min) of AβPP-PS1 as compared with control mice. The fluxes through PC (AβPP-PS1 0.037 ± 0.006, control 0.079 ± 0.013 μmol/g/min) and PPP (AβPP-PS1 0.024 ± 0.005; control 0.062 ± 0.022 μmol/g/min) were found to be significantly reduced in AβPP-PS1 mice when compared with age-matched controls. The reduction in the fluxes of PC and PPP may lead to a weakened neural defense system of ammonia detoxification and antioxidant reserve in AβPP-PS1 mice, which may be responsible for the compromised neuronal viability and functions in AD. Show more

Keywords: Alzheimer's disease, cerebral metabolism, glutamate, neurotransmitter cycle, nuclear magnetic resonance spectroscopy, pentose phosphate pathway, pyruvate carboxylase, pyruvate dehydrogenase

DOI: 10.3233/JAD-122449

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 387-399, 2014

Authors: Viticchi, Giovanna | Falsetti, Lorenzo | Vernieri, Fabrizio | Altamura, Claudia | Altavilla, Riccardo | Luzzi, Simona | Bartolini, Marco | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: The presence of apolipoprotein E (APOE) ε4 allele is the only recognized genetic risk factor for the sporadic form of Alzheimer's disease. The aim of this study was to investigate the relationship between APOE genotype and the functional and anatomic status of cerebral vessels in patients with mild cognitive impairment (MCI). Moreover, we explored whether the possible correlation between APOE genotype and cerebrovascular parameters influences the risk of conversion from MCI to dementia. 75 MCI patients underwent a complete neuropsychological battery at baseline and after 24 months to evaluate the possible conversion to dementia. Ultrasound assessment of neck and intracranial …vessels was performed to assess common carotid artery intima-media thickness (IMT), plaque index, and cerebrovascular reactivity (breath-holding index, BHI). APOE genotype was determined to classify patients as carriers (APOE ε4+) and non-carriers (APOE ε4−). Pathologic values of BHI and IMT were significantly more common in ε4 carriers than in non-carriers [OR 6.603 (95% CI: 1.678–25.997), p < 0.05 and OR 5.195 (95% CI 1.319–20.464), p < 0.05; logistic regression adjusted model]. The risk of conversion to dementia was significantly higher in APOE ε4+ patients than in APOE ε4− ones (OR: 6.818; 95% CI:1.894–24.545, p = 0.003). A path-analysis model showed that APOE genotype influences the progression to dementia directly and indirectly by increasing the risk of pathologic values of IMT or BHI. Our data, besides confirming an increased susceptibility of MCI patients with APOE ε4 to develop dementia, show an association between functional and anatomic impairment of the cerebral vessels and APOE ε4+ genotype. Show more

Keywords: Alzheimer's disease, apolipoproteins E, cerebrovascular diseases, cognition, ultrasonography

DOI: 10.3233/JAD-132480

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 401-410, 2014

Authors: Eriksson, Hanna | Fereshtehnejad, Seyed-Mohammad | Falahati, Farshad | Farahmand, Bahman | Religa, Dorota | Eriksdotter, Maria

Article Type: Research Article

Abstract: Background: Due to age of onset, Alzheimer’s disease (AD) is divided into early onset (EOAD) or late onset (LOAD), but emerging data also suggests that the underlying pathology may be different. Whether differences in clinical care exist is less well investigated. Objectives: To evaluate whether there are differences in demographics, diagnostic work-up, and pharmacological treatment between EOAD and LOAD. Material and Methods: Data on patients with newly diagnosed EOAD (n = 453) and LOAD (n = 4599) was obtained from the Swedish dementia registry (SveDem). Logistic regression models were used to adjust the comparisons for the …baseline confounders including gender, cognitive decline, and co-morbidity. Results: The majority of EOAD and LOAD were in the mild stage of the disease when diagnosed. The majority of patients with EOAD went through an extended diagnostic work-up including more technical investigations as well as assessments by neuropsychologists and speech therapists than patients with LOAD. EOAD patients were treated with overall fewer medications but obtained treatment with cholinesterase inhibitors to a higher extent than those with LOAD, while there were no differences between the groups in antidepressant and antipsychotics use. Conclusions: There are differences between EOAD and LOAD in demographics, diagnostic work-up, and pharmacological treatment. Based on our findings, an extensive work-up should be recommended when EOAD is suspected. Show more

Keywords: Early onset Alzheimer's disease, cholinesterase inhibitors, dementia diagnostic work-up, late-onset Alzheimer's disease, quality registry

DOI: 10.3233/JAD-132273

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 411-419, 2014

Authors: Boespflug, Erin L. | Eliassen, James | Welge, Jeffrey | Krikorian, Robert

Article Type: Research Article

Abstract: Background: While diagnostic criteria for Alzheimer’s disease (AD) include neuroimaging biomarkers, there remains no definitive biomarker of mild cognitive impairment (MCI). MCI is a risk factor for AD that may be amenable to early intervention. Early decline in white matter (WM) integrity identified by diffusion tensor imaging (DTI) is a predictor of future progression of neurodegeneration. Objective: Identify regionally specific WM differences between individuals with MCI and those with age-associated memory impairment (AAMI) and relationships with specific memory decrements. Methods: DTI and neuropsychological data were acquired from 38 participants (23 MCI and 15 AAMI). A region …of interest approach was used to evaluate regional differences between groups and correlative relationships with performance on memory tasks. Results: Fornix WM had higher mean (MD), radial (DR), and axial (DA) diffusivity in MCI participants relative to AAMI. Temporal stem (TS) WM had higher MD and DR in MCI than in AAMI. In MCI, TS MD and DR varied, while fornix MD and DR was uniformly high, and in AAMI, TS MD and DR were uniformly low and fornix MD and DR varied. In MCI, TS MD and DA were inversely associated with associative learning but not list learning. Conclusions: In addition to supporting prior evidence implicating the fornix in early AD pathology, these data implicate a profile of neurodegeneration associated with early MCI. Further, they suggest that associative learning tasks are more sensitive to early neurodegeneration and may be useful in identifying individuals at risk for AD. Show more

Keywords: Alzheimer's disease, biomarker, diffusion tensor imaging, fornix, mild cognitive impairment, paired-associate learning

DOI: 10.3233/JAD-131682

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 421-430, 2014

Authors: Mignardot, Jean-Baptiste | Beauchet, Olivier | Annweiler, Cédric | Cornu, Christophe | Deschamps, Thibault

Article Type: Research Article

Abstract: Background: Cognitive impairment-related changes in postural sway increase fall risk among older adults. Better understanding this association could be helpful for fall prevention. Objective: To examine the center-of-pressure (COP) velocity association with cognitive status and history of falls, in cognitively healthy individuals (CHI), patients with mild cognitive impairment (MCI), and with mild-to-moderate Alzheimer’s disease (MMAD). Methods: Six hundred and eleven older community-dwellers (77.2 ± 7.9 years; 51.8% men) were separated into CHI, MCI, and MMAD participants. By computing the average absolute maximal velocity (AAMV), the bounding limits of COP velocity dynamics were determined while participants were …asked to maintain quiet stance on a force platform with eyes open or with eyes closed. Age, gender, history of falls, body mass index, medications, handgrip strength, Timed Up & Go score were used as covariates. Results: The multivariate ANCOVA, with AAMV in eyes open and eyes closed conditions as dependent variables, showed that the highest AAMVs that bound the COP velocity dynamics of postural sway were associated with cognitive impairment (p = 0.048) (i.e., lowest limits in CHI and MCI as compared with MMAD) and falls (p = 0.033) (i.e., highest limits in fallers). Conclusions: These findings identified the bounding limits of COP velocity as a hallmark feature of cognitive impairment-related changes in postural sway, in particular for MMAD. This point is of special interest for clinical balance assessment and fall prevention in MMAD patients in order to plan long-term targeted fall-prevention programs. Show more

Keywords: Accidental falls, Alzheimer's disease, mild cognitive impairment, postural balance

DOI: 10.3233/JAD-132657

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 431-439, 2014