Journal of Alzheimer's Disease - Volume 73, issue 2

Authors: Carbonell, Felix | Zijdenbos, Alex P. | Bedell, Barry J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOE ɛ 4 genotype. It has been reported that APOE ɛ 4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer’s disease (AD) pathology. Objective: We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). …Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18 F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18 F]florbetapir PET, from the Alzheimer’s Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ. Results: From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOE ɛ 4 genotype or global measures of Aβ burden. Show more

Keywords: Alzheimer’s disease, amyloid-β , cross-correlation, glucose metabolism, positron emission tomography, singular value decomposition

DOI: 10.3233/JAD-190560

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 543-557, 2020

Authors: Reimand, Juhan | Groot, Colin | Teunissen, Charlotte E. | Windhorst, Albert D. | Boellaard, Ronald | Barkhof, Frederik | Nazarenko, Sergei | van der Flier, Wiesje M. | van Berckel, Bart N.M. | Scheltens, Philip | Ossenkoppele, Rik | Bouwman, Femke

Article Type: Research Article

Abstract: Background: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer’s disease. Objective: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. Methods: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. Results: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental …State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n  = 53, 74%), followed by incongruent MRI (n  = 16, 22%), unusual clinical presentation (n  = 11, 15%) and young age (n  = 8, 11%). An amyloid-β PET scan was rarely (n  = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n  = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n  = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. Conclusion: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography, tau proteins

DOI: 10.3233/JAD-190836

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 559-569, 2020

Authors: Naismith, Sharon L. | Duffy, Shantel L. | Cross, Nathan | Grunstein, Ron | Terpening, Zoe | Hoyos, Camilla | D’Rozario, Angela | Lagopoulos, Jim | Osorio, Ricardo S. | Shine, James M. | McKinnon, Andrew C.

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. Objective: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. Methods: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into …tertiles, with analyses comparing the lowest and highest tertiles (N = 48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. Results: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = –3.26, p  = 0.041, beta = –1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = –2.93, p  = 0.0034). Conclusions: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings. Show more

Keywords: Alzheimer’s disease, default mode network, memory, mild cognitive impairment, obstructive sleep apnea

DOI: 10.3233/JAD-190747

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 571-584, 2020

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | Melo, Helen M. | Lopes, Samantha C. | Ribeiro, Camila T. | Delanogare, Eslen | Moreira, José Claudio F. | Gelain, Daniel P. | Prediger, Rui D. | Gabilan, Nelson H. | Moreira, Eduardo Luiz G. | Ferreira, Sergio T. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/- ), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer’s disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein …1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/- mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels. Show more

Keywords: Familial hypercholesterolemia, LDLr-/- mice, memory impairment, amyloid-β, apoptosis

DOI: 10.3233/JAD-190742

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 585-596, 2020

Authors: Eckerström, Carl | Eckerström, Marie | Göthlin, Mattias | Molinder, Anna | Jonsson, Michael | Kettunen, Petronella | Svensson, Johan | Rolstad, Sindre | Wallin, Anders

Article Type: Research Article

Abstract: Background: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. Objective: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. Methods: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-β42 (Aβ42 ), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off …values which were then applied to the MCI groups. Results: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aβ42 differentiated incipient mixed dementia from incipient SVD. Conclusion: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, magnetic resonance imaging, mild cognitive impairment, neuropsychological test, vascular dementia

DOI: 10.3233/JAD-190651

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 597-607, 2020

Authors: Wang, Longcai | Qiao, Yanchun | Zhang, Haihua | Zhang, Yan | Hua, Jiao | Jin, Shuilin | Liu, Guiyou

Article Type: Research Article

Abstract: Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer’s disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin …D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D

DOI: 10.3233/JAD-190713

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 609-618, 2020

Authors: Robinson, Andrew C. | Chew-Graham, Stephen | Davidson, Yvonne S. | Horan, Michael A. | Roncaroli, Federico | Minshull, James | du Plessis, Daniel | Pal, Piyali | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie , to collect brains from both demented and non-demented individuals for …the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer’s disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more ‘polarized’, being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had ‘naturally’ evolved in the brains of both demented and non-demented participants. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, cohort studies, dementia, longitudinal studies, neuropathology

DOI: 10.3233/JAD-190580

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 619-632, 2020

Authors: Yoon, Bora | Choi, Seong Hye | Jeong, Jee Hyang | Park, Kyung Won | Kim, Eun-Joo | Hwang, Jihye | Jang, Jae-Won | Kim, Hee Jin | Hong, Jin Yong | Lee, Jong-Min | Kang, Ju-Hee | Yoon, Soo Jin

Article Type: Research Article

Abstract: Background: Balance impairments are common in patients with Alzheimer’s disease (AD) dementia. Objective: We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function. Methods: Our cross-sectional study included 295 participants; 71 were cognitively normal (CN), 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST). Results: Participants in the MCI …and AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p  < 0.001), whereas OLST score showed a precipitous impairment starting in the SCD group (all p  < 0.001), even after adjusting for age, sex, MMSE-KC, Geriatric depression scale, and body mass index. Based on subgroup analyses, in females and apolipoprotein E (APOE ) ɛ 4 carriers, there was significant balance/mobility impairment in the SCD group when compared to the CN group. Conclusion: Our results suggest that balance/mobility is related to cognitive function and that balance/mobility impairment can be observed beginning in the SCD stage. Furthermore, CN females and APOE ɛ 4 carriers had better balance and mobility when compared to females and APOE ɛ 4 carriers along the ADD spectrum/with cognitive impairment respectively. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognition, female, postural balance, subjective cognitive decline

DOI: 10.3233/JAD-190601

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 633-644, 2020

Authors: Fransquet, Peter D. | Ritchie, Karen | Januar, Vania | Saffery, Richard | Ancelin, Marie-Laure | Ryan, Joanne

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n  = 769) and buccal samples during follow-up (n  = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ 4. Multivariable logistic regression analyses determined the association between BDNF methylation and …both prevalent and incident dementia. Adjustment for gender, age, education, APOE ɛ 4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ–0.5%, 95% CI:–0.9,–0.04, p  = 0.03, p  = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p  = 0.02, p  = 0.14 adjusted and Δ–1.5%, OR:0.85, SE:0.06, p  = 0.03, p  = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r =–0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing. Show more

Keywords: BDNF, biomarkers, blood, dementia, DNA methylation, epigenetics

DOI: 10.3233/JAD-190738

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 645-655, 2020

Authors: Xiao, Shuo | Song, Lin-Lin | Li, Jiang-Tao | Wang, He | Yu, Na | Wang, Zi-Qi | Zhang, Ying | He, Jin-Sheng | Hung, Tao

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia, characterized by amyloid-β peptide (Aβ) aggregates, phosphorylated tau protein (p -tau), and progressive neurodegeneration. Amyloid-β peptide 42 (Aβ42 ) is considered an early trigger of AD pathogenesis. We have previously reported that Aβ N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aβ in the brains of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1Δ E9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 …treatment group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p  < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aβ and p -tau in the brains of APP/PS1 mice. Regarding Aβ levels, western blot results showed that Aβ42 oligomer (p  < 0.01) but not Aβ40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231 ) (p  < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p  < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p  < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, immunotherapy, Morris water maze test, phosphorylated tau protein, synapse

DOI: 10.3233/JAD-190874

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 657-670, 2020