Journal of Alzheimer's Disease - Volume 58, issue 3

Authors: Gordon, Rita | Podolski, Igor | Makarova, Ekaterina | Deev, Alexander | Mugantseva, Ekaterina | Khutsyan, Sergey | Sengpiel, Frank | Murashev, Arkady | Vorobyov, Vasily

Article Type: Research Article

Abstract: Primary memory impairments associated with increased level of amyloid-β (Aβ) in the brain have been shown to be linked, partially, with early pathological changes in the entorhinal cortex (EC) which spread on the whole limbic system. While the hippocampus is known to play a key role in learning and memory mechanisms, it is as yet unclear how its structures are involved in the EC pathology. In this study, changes in memory and neuronal morphology in male Wistar rats intrahippocampally injected with Aβ25-35 were correlated on days 14 and 45 after the injection to reveal specific cognitive-structural associations. The main …focus was on the dentate gyrus (DG) and hippocampal areas of CA1 and CA3 because of their involvement in afferent flows from EC to the hippocampus through tri-synaptic (EC → DG → CA3 → CA1) and/or mono-synaptic (EC → CA1) pathways. Evident memory impairments were observed at both time points after Aβ25-35 injection. However, on day 14, populations of morphological intact neurons were decreased in CA3 and, drastically, in CA1, and the DG supramedial bundle was significantly damaged. On day 45, this bundle largely and CA1 neurons partially recovered, whereas CA3 neurons remained damaged. We suggest that Aβ25-35 primarily affects the tri-synaptic pathway, destroying the granular cells in the DG supramedial area and neurons in CA3 and, through the Schaffer collaterals, in CA1. Intrahippocampal pretreatment with hydrated fullerene C60 allows the neurons and their connections to survive the amyloidosis, thus supporting the memory mechanisms. Show more

Keywords: Alzheimer’s disease, CA1, CA3, dentate gyrus, hippocampus, neurodegeneration

DOI: 10.3233/JAD-161182

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 711-724, 2017

Authors: Orgeta, Vasiliki | Tabet, Naji | Nilforooshan, Ramin | Howard, Robert

Article Type: Research Article

Abstract: Background: Depression is common in people with Alzheimer’s disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting. Objectives: To systematically review evidence on efficacy of antidepressant treatments for depression in AD. Methods: Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response …and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed. Results: Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97–3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD –0.13; 95% CI –0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials. Conclusion: Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs. Show more

Keywords: Antidepressants, Alzheimer’s disease, depression, effectiveness, meta-analysis, randomized controlled trials

DOI: 10.3233/JAD-161247

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 725-733, 2017

Authors: Chan, Sam C.C. | Chan, Chetwyn C.H. | Derbie, Abiot Y. | Hui, Irene | Tan, Davynn G.H. | Pang, Marco Y.C. | Lau, Stephen C.L. | Fong, Kenneth N.K.

Article Type: Research Article

Abstract: Background: Nonpharmacological intervention for individuals with mild cognitive impairment (MCI) needs further investigation. Objective: Test efficacy of an eight-week Chinese calligraphy writing training course in improving attentional control and working memory. Methods: Ninety-nine participants with MCI were randomized into the eight-week calligraphy writing (n  = 48) or control (tablet computer) training (n  = 51). Outcomes of the interventions were attentional control, working memory, visual scan and processing speed. They were measured at baseline, post-training, and six-month follow-up. Results: Calligraphy writing, when compared with control, significantly improved working memory as reflected from DST-Backward sequence (p  = 0.009) …and span scores (p  = 0.002), and divided attention as reflected from CTT2 (p  < 0.001), and at the post-training. The unique improvement in working memory (span: p  < 0.001; sequence: p  = 0.008) of the intervention group was also found at follow-up when comparing with those at baseline. Changes in the other outcome measures were not statistically significant. Conclusion: The findings provide support that Chinese calligraphy writing training for eight weeks using a cognitive approach would improve working memory and to a lesser extent attentional control functions of patients with early MCI. They also demonstrate the usefulness of using mind-and-body practice for improving specific cognitive functions. Show more

Keywords: Attention, Chinese calligraphy, mild cognitive impairment, randomized controlled trial, working memory

DOI: 10.3233/JAD-170024

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 735-746, 2017

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Caravaggio, Fernando | Iwata, Yusuke | Gerretsen, Philip | Kim, Julia | Takeuchi, Hiroyoshi | Shinagawa, Shunichiro | Patel, Raihaan | Chakravarty, M. Mallar | Graff-Guerrero, Ariel | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Suspected non-Alzheimer’s disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer’s Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND–), neither amyloid nor hypometabolism (Aβ–ND–), and SNAP (Aβ–ND+). Aβ+ND+(n  = 33), Aβ+ND–(n  = 32), and Aβ–ND–(n  = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n  = 40) were also matched to SNAP for age, gender, …and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ–ND–and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ–ND–and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ–ND–and controls, 2) no differences with Aβ+ND–, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades. Show more

Keywords: Functional decline, hippocampus, mild cognitive impairment, suspected non-Alzheimer’s pathology

DOI: 10.3233/JAD-170201

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 747-762, 2017

Authors: Pasquini, Lorenzo | Benson, Gloria | Grothe, Michel J. | Utz, Lukas | Myers, Nicholas E. | Yakushev, Igor | Grimmer, Timo | Scherr, Martin | Sorg, Christian | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in …areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments. Show more

Keywords: Alzheimer’s disease, amyloid-β, intrinsic functional connectivity, mild cognitive impairment, multimodal imaging

DOI: 10.3233/JAD-170096

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 763-773, 2017

Authors: Manocha, Gunjan D. | Ghatak, Atreyi | Puig, Kendra L. | Kraner, Susan D. | Norris, Christopher M. | Combs, Colin K.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …deletion of NFATc2 was sufficient to attenuate the ability of the microglia to secrete cytokines. In order to determine whether the NFATc2 isoform, in particular, was a valid immunomodulatory target in vivo , we crossed an NFATc2–/– line to a well-known AD mouse model, an AβPP/PS1 mouse line. As expected, the AβPP/PS1 x NFATc2–/– mice had attenuated cytokine levels compared to AβPP/PS1 mice as well as reduced microgliosis and astrogliosis with no effect on plaque load. Although some species differences in relative isoform expression may exist between murine and human microglia, it appears that microglial NFAT activity is a viable target for modulating the proinflammatory changes that occur during AD. Show more

Keywords: Alzheimer’s disease, amyloid, cytokine, microglia, neuroinflammation, NFAT, transcription factor

DOI: 10.3233/JAD-151203

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 775-787, 2017

Authors: O’Driscoll, Ciarán | Shaikh, Madiha

Article Type: Research Article

Abstract: The Montreal Cognitive Assessment (MoCA) is widely used to screen for mild cognitive impairment (MCI). While there are many available versions, the cross-cultural validity of the assessment has not been explored sufficiently. We aimed to interrogate the validity of the MoCA in a cross-cultural context: in differentiating MCI from normal controls (NC); and identifying cut-offs and adjustments for age and education where possible. This review sourced a wide range of studies including case-control studies. In addition, we report findings for differentiating dementias from NC and MCI from dementias, however, these were not considered to be an appropriate use of the …MoCA. The subject of the review assumes heterogeneity and therefore meta-analyses was not conducted. Quality ratings, forest plots of validated studies (sensitivity and specificity) with covariates (suggested cut-offs, age, education and country), and summary receiver operating characteristic curve are presented. The results showed a wide range in suggested cutoffs for MCI cross-culturally, with variability in levels of sensitivity and specificity ranging from low to high. Poor methodological rigor appears to have affected reported accuracy and validity of the MoCA. The review highlights the necessity for cross-cultural considerations when using the MoCA, and recognizing it as a screen and not a diagnostic tool. Appropriate cutoffs and point adjustments for education are suggested. Show more

Keywords: Cross-cultural, dementia, mild cognitive impairment, Montreal Cognitive Assessment

DOI: 10.3233/JAD-161042

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 789-801, 2017

Authors: Swanson, Eric | Breckenridge, Leigham | McMahon, Lloyd | Som, Sreemoyee | McConnell, Ian | Bloom, George S.

Article Type: Research Article

Abstract: Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo . The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the …effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. Show more

Keywords: Alzheimer’s disease, axonal transport, BACE1, brain derived neurotrophic factor, neuropeptide Y, tau, tauopathies

DOI: 10.3233/JAD-170168

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 803-820, 2017

Authors: Edsbagge, Mikael | Andreasson, Ulf | Ambarki, Khalid | Wikkelsø, Carsten | Eklund, Anders | Blennow, Kaj | Zetterberg, Henrik | Tullberg, Mats

Article Type: Research Article

Abstract: Background: Neuropathologically, Alzheimer’s disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-β (Aβ42 ) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aβ42 , increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively. Objective: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in …CSF volumes, CSF production rate, and intracranial pressure in healthy individuals. Methods: CSF concentrations of Aβ42 , P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years). Results: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aβ38 , and Aβ40 ), and ventricular CSF volume, but apart from this finding, no significant correlations were observed. Conclusion: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, healthy subjects, production rate, tau protein, volume

DOI: 10.3233/JAD-161257

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 821-828, 2017

Authors: Sala-Llonch, Roser | Idland, Ane-Victoria | Borza, Tom | Watne, Leiv Otto | Wyller, Torgeir Bruun | Brækhus, Anne | Zetterberg, Henrik | Blennow, Kaj | Walhovd, Kristine Beate | Fjell, Anders Martin

Article Type: Research Article

Abstract: Amyloid deposition occurs in aging, even in individuals free from cognitive symptoms, and is often interpreted as preclinical Alzheimer’s disease (AD) pathophysiology. YKL-40 is a marker of neuroinflammation, being increased in AD, and hypothesized to interact with amyloid-β (Aβ) in causing cognitive decline early in the cascade of AD pathophysiology. Whether and how Aβ and YKL-40 affect brain and cognitive changes in cognitively healthy older adults is still unknown. We studied 89 participants (mean age: 73.1 years) with cerebrospinal fluid samples at baseline, and both MRI and cognitive assessments from two time-points separated by two years. We tested how baseline …levels of Aβ42 and YKL-40 correlated with changes in cortical thickness and cognition. Thickness change correlated with Aβ42 only in Aβ42 + participants (<600 pg/mL, n  = 27) in the left motor and premotor cortices. Aβ42 was unrelated to cognitive change. Increased YKL-40 was associated with less preservation of scores on the animal naming test in the total sample (r  = –0.28, p  = 0.012) and less preservation of a score reflecting global cognitive function for Aβ42 + participants (r  = –0.58, p  = 0.004). Our results suggest a role for inflammation in brain atrophy and cognitive changes in cognitively normal older adults, which partly depended on Aβ accumulation. Show more

Keywords: Aging, biomarkers, cerebrospinal fluid, cognition, cortical thickness, inflammation, memory, MRI, YKL-40

DOI: 10.3233/JAD-161146

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 829-840, 2017