Journal of Alzheimer's Disease - Volume 61, issue 1

Authors: dos Santos, João Paulo Almeida | Vizuete, Adriana | Hansen, Fernanda | Biasibetti, Regina | Gonçalves, Carlos-Alberto

Article Type: Research Article

Abstract:  O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer’s disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent …(at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD. Show more

Keywords: Astrocyte, GFAP, hippocampus, insulin-resistance, O-GlcNAc transferase, streptozotocin, S100B

DOI: 10.3233/JAD-170211

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 237-249, 2018

Authors: Addesi, Desirée | Maio, Raffaele | Smirne, Nicoletta | Laganà, Valentina | Altomari, Natalia | Puccio, Gianfranco | Colao, Rosanna | Cupidi, Chiara | Perticone, Francesco | Bruni, Amalia Cecilia

Article Type: Research Article

Abstract: Background: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia. Objective: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population. Methods: We randomly selected 650 medical records of outpatients referred to the “Neurogenetic Regional Centre” (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of …dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument. Results: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed. Conclusions: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients. Show more

Keywords: Delirium, dementia, prevalence, retrospective studies

DOI: 10.3233/JAD-170339

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 251-257, 2018

Authors: Hasegawa, Yu | Toyama, Kensuke | Uekawa, Ken | Ichijo, Hidenori | Kim-Mitsuyama, Shokei

Article Type: Research Article

Abstract: To examine the role of ASK1 in Alzheimer’s disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type …mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging. Show more

Keywords: Amyloid β, ASK1, brain aging, cognitive function, vascular injury

DOI: 10.3233/JAD-170645

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 259-263, 2018

Authors: Huber, Colin M. | Yee, Connor | May, Taylor | Dhanala, Apoorva | Mitchell, Cassie S.

Article Type: Research Article

Abstract:  We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer’s disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). “High” levels of Aβ (Aβ40 , Aβ42 ) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2  = 0.149, n  = 259, p  < 0.001; NOR: slope = 0.156, R2  = 0.064, n  = 116, p  < 0.05); only soluble Aβ or directly measured Aβ meaningfully contribute. Tau expression in 3xTg-AD mice was within 10–20% of wild type and not associated with cognitive decline. …In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2  = 0.275, n  = 371, p  < < 0.01) and NOR (slope = 0.319, R2  = 0.176, n  = 113, p  < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2  = 0.521, n  = 185, p  < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau’s lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau’s contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway. Show more

Keywords: 3xTg-AD, amyloid-β, GSK3, meta-analysis, phosphorylated tau, total tau

DOI: 10.3233/JAD-170490

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 265-281, 2018

Authors: Mehla, Jogender | Lacoursiere, Sean | Stuart, Emily | McDonald, Robert J. | Mohajerani, Majid H.

Article Type: Research Article

Abstract: In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning …and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer’s disease pathology. Show more

Keywords: Ameroid constrictor, balance beam test, choline acetyltransferase, fear conditioning test, gradual hypoperfusion, neurodegeneration, novel object recognition test, vascular dementia

DOI: 10.3233/JAD-170635

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 283-293, 2018

Authors: Kirson, Noam Y. | Scott Andrews, J. | Desai, Urvi | King, Sarah B. | Schonfeld, Sophie | Birnbaum, Howard G. | Ball, Daniel E. | Kahle-Wrobleski, Kristin

Article Type: Research Article

Abstract: Background: Effectiveness of Alzheimer’s disease (AD) treatments may depend critically on the timeliness of intervention. Objective: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline. Methods: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and …medication use following prAD diagnosis were compared. Results: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n  = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n  = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p  = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p  < 0.01). Conclusion: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis. Show more

Keywords: Alzheimer’s disease, dementia, early diagnosis, longitudinal studies

DOI: 10.3233/JAD-170078

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 295-307, 2018

Authors: Geijselaers, Stefan L.C. | Aalten, Pauline | Ramakers, Inez H.G.B. | De Deyn, Peter Paul | Heijboer, Annemieke C. | Koek, Huiberdina L. | OldeRikkert, Marcel G.M. | Papma, Janne M. | Reesink, Fransje E. | Smits, Lieke L. | Stehouwer, Coen D.A. | Teunissen, Charlotte E. | Verhey, Frans R.J. | van der Flier, Wiesje M. | Biessels, Geert Jan | on behalf of the Parelsnoer Institute Neurodegenerative Diseases study group

Article Type: Research Article

Abstract: Background: Abnormal insulin signaling in the brain has been linked to Alzheimer’s disease (AD). Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ 4 genotype. Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n  = 45), amnestic mild cognitive impairment (n  = 44), or AD (n  = 49), who completed a neuropsychological …assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42 , total (t-)Tau, and phosphorylated (p-)Tau. Results: CSF insulin levels did not differ between the diagnostic groups (p  = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p ≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ 4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient –0.483; p  = 0.008) and higher p-Tau levels (0.353; p  = 0.040). Among non-carriers of the APOE ɛ 4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p  = 0.008) and p-Tau (0.246; p  = 0.029). Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ 4 genotype when assessing the role of insulin. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognition, epidemiology, insulin

DOI: 10.3233/JAD-170522

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 309-320, 2018

Authors: Cuberas-Borrós, Gemma | Roca, Isabel | Boada, Mercè | Tárraga, Lluís | Hernández, Isabel | Buendia, Mar | Rubio, Lourdes | Torres, Gustavo | Bittini, Ángel | Guzmán-de-Villoria, Juan A. | Pujadas, Francesc | Torres, Mireia | Núñez, Laura | Castell, Joan | Páez, Antonio

Article Type: Research Article

Abstract: Background: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer’s disease (AD) treated with plasma exchange (PE) with albumin replacement. Objective: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Methods: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using …an automated software (NeuroGam® ) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. Results: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p  < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p  < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Conclusions: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion. Show more

Keywords: Albumin, Alzheimer’s disease, magnetic resonance imaging, plasma exchange, single-photon emission computed tomography

DOI: 10.3233/JAD-170693

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 321-332, 2018

Authors: Peter, Jessica | Schumacher, Lena V. | Landerer, Verena | Abdulkadir, Ahmed | Kaller, Christoph P. | Lahr, Jacob | Klöppel, Stefan

Article Type: Research Article

Abstract: In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n  = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n  = 20; ADNI cohort, n  = 302). The primary outcome …measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n  = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine. Show more

Keywords: Cognitive training, entorhinal cortex, episodic memory, mild cognitive impairment, response prediction

DOI: 10.3233/JAD-170580

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 333-345, 2018

Authors: Vasunilashorn, Sarinnapha M. | Fong, Tamara G. | Albuquerque, Asha | Marcantonio, Edward R. | Schmitt, Eva M. | Tommet, Douglas | Gou, Yun | Travison, Thomas G. | Jones, Richard N. | Inouye, Sharon K.

Article Type: Research Article

Abstract: Background: Delirium has been associated with more rapid cognitive decline. However, it is unknown whether increased delirium severity is associated with a higher rate of long-term cognitive decline. Objective: To evaluate delirium severity and the presence and rate of cognitive decline over 36 months following surgery. Methods: We examined patients from the Successful Aging after Elective Surgery Study, who were age ≥70 years undergoing major elective surgery (N = 560). Delirium severity was determined by the peak Confusion Assessment Method-Severity (CAM-S) score for each patient’s hospitalization and grouped based on the sample distribution: scores of 0–2, 3–7, and …8–19. A neuropsychological composite, General Cognitive Performance (GCP), and proxy-reported Informant Questionnaire for Cognitive Decline (IQCODE) were used to examine cognitive outcomes following surgery at 0, 1, and 2 months, and then every 6 months for up to 3 years. Results: No significant cognitive decline was observed for patients with peak CAM-S scores 0–2 (–0.17 GCP units/year, 95% confidence interval [CI] –0.35, 0.01). GCP scores decreased significantly in the group with peak CAM-S scores 3–7 (–0.30 GCP units/year, 95% CI –0.51, –0.09), and decreased almost three times faster in the highest delirium severity group (peak CAM-S scores 8–19; –0.82 GCP units/year, 95% CI –1.28, –0.37). A similar association was found for delirium severity and the proportion of patients who developed IQCODE impairment over time. Conclusion: Patients with the highest delirium severity experienced the greatest rate of cognitive decline, which exceeds the rate previously observed for patients with dementia, on serial neuropsychological testing administered over 3 years, with a dose-response relationship between delirium severity and long-term cognitive decline. Show more

Keywords: Aged, cognition, delirium, dementia

DOI: 10.3233/JAD-170288

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 347-358, 2018