Journal of Alzheimer's Disease - Volume 70, issue 4

Authors: Alm, Kylie H. | Bakker, Arnold

Article Type: Review Article

Abstract:  Recently, the field of Alzheimer’s disease (AD) research has adopted a new framework that places the progression of AD along a continuum consisting of a preclinical stage, followed by conversion to mild cognitive impairment, and ultimately dementia. Important neuropathological changes occur in the preclinical phase, necessitating the identification of metrics that can detect such early changes. While cerebrospinal fluid (CSF) measures of amyloid and tau are generally accepted as biomarkers of AD pathology, neuroimaging measures used to index white matter alterations throughout the brain remain less widely endorsed as candidate biomarkers. To explore the relationship between white matter alterations and …AD pathology, we review the literature on multimodal studies that assessed both CSF markers and white matter indices, derived from diffusion tensor imaging (DTI) methods, across cohorts primarily in the early phases of AD. Our review indicates that abnormal CSF measures of Aβ42 and tau are associated with widespread alterations in white matter microstructure throughout the brain. Furthermore, white matter variability is related to individual differences in behavior and can aid in tracking longitudinal changes in cognition. Our review advocates for the utilization of DTI metrics in investigations of early AD and suggests that the combined use of DTI and CSF markers may better explain individual differences in cognition and disease progression. However, further research is needed to resolve certain mixed findings. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, diffusion tensor imaging, mild cognitive impairment

DOI: 10.3233/JAD-181210

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 965-981, 2019

Authors: Nance, Christin | Ritter, Aaron | Miller, Justin B. | Lapin, Brittany | Banks, Sarah J.

Article Type: Research Article

Abstract: Background: Variable rate of cognitive decline among individuals with Alzheimer’s disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus. Objective: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD. Methods: Neuropsychology test and autopsy data was pulled from the National Alzheimer’s Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all …others were NCD. Results: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p  < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p  = 0.007), TMT Part B (187[86.1] versus 159[79.0], p  = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p  = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p  = 0.04). RCD had more thyroid disease (30% versus 16%, p  = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p  = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62[1.0] versus 1.13[1.0], p  = 0.002), more neocortical Lewy bodies (20% versus 10%, p  = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p  = 0.04). A model combining select variables was significant above chance (χ 2  = 25.8, p  = 0.002), but not to clinical utility (AUC < 0.70; 95% CI). Conclusion: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, neuropathology, neuropsychological tests

DOI: 10.3233/JAD-190302

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 983-993, 2019

Authors: Caunca, Michelle R. | Simonetto, Marialaura | Alperin, Noam | Elkind, Mitchell S.V. | Sacco, Ralph L. | Wright, Clinton B. | Rundek, Tatjana

Article Type: Research Article

Abstract: Background: Adiposity may increase risk for dementia and Alzheimer’s disease (AD), but mechanisms are unclear. Objective: To examine associations between measures of adiposity with AD-signature region cortical thickness and hippocampal volume. Methods: We used data from the Northern Manhattan Study, a clinically stroke-free cohort of mostly Hispanic participants. Exposures of interest included body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC), and adiponectin concentration, measured at study entry. AD-signature region cortical thickness and hippocampal volume were obtained using Freesurfer. We estimated associations using multivariable linear regression, adjusting for sociodemographics and health behaviors. We re-examined estimates after …adjustment for APOE ɛ 4 allele status or carotid intima-media thickness (cIMT), among those cognitively unimpaired, and after weighting for the inverse probability of selection into the MRI sub-study. We also repeated analyses for cortical thickness in non-AD signature regions. Results: The sample (N  = 947, 63% women, 66% Hispanic/Latino, 26% obese) had a mean (SD) age = 63 (8) years. Greater BMI and WC (both z-scored) were associated with thinner AD-signature region cortex (also z-scored) (BMI: β [95% CI] = –0.09 [–0.18, –0.01], WC: β [95% CI] = –0.11 [–0.20, –0.02]). We did not find evidence that adiposity was related to hippocampal volume. Results were consistent after adjustment for APOE ɛ 4 allele status or cIMT, after weighting for selection, among those cognitively unimpaired, and for non-AD signature region cortical thickness. Conclusion: Greater BMI and WC were related to cortical thinning within and outside the AD-signature region, suggesting a global effect not specific to AD. Show more

Keywords: Adiposity, brain aging, epidemiology, neuroimaging, structural MRI

DOI: 10.3233/JAD-190092

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 995-1004, 2019

Authors: McDonough, Ian M. | Letang, Sarah K. | Stinson, Elizabeth A.

Article Type: Research Article

Abstract: Longitudinal research suggests that genetic, lifestyle, and environmental factors enhance one’s risk for developing Alzheimer’s disease and related dementias (ADRD). However, it is not known how an accumulation of such factors impact brain functioning. One barrier to this research is that increased risk for ADRD affects the cerebrovascular system and, therefore, alters the link between neural activity and the fMRI BOLD signal. To better interpret fMRI findings, several steps were taken to adjust fMRI activity thereby reducing such cerebrovascular effects. We hypothesized that as the number of ADRD risk factors increase, brain regions within the medial temporal lobes and the …default mode network would exhibit altered brain activity during an episodic memory retrieval task. Middle-aged and older adults (aged 50–74) free of dementia were recruited with varying levels of risk and underwent a neuropsychological battery and fMRI. In the memory task, participants viewed a pair of pictures. In an alternative-forced-choice test, participants viewed a picture cue and had to determine which of four pictures was paired with the cue. Increased dementia risk was positively associated with brain activity in regions of interest within the default mode network, the hippocampus, and the entorhinal cortex during memory retrieval. Whole-brain analyses revealed additional positive associations in prefrontal and occipito-temporal cortices. Risk factors most contributing to these elevated levels of brain activity included hypertension, diabetes, obesity, and cholesterol. We also ruled out confounds due to in-scanner performance and premorbid ability. Cumulative risk might represent early signs of burnout in brain regions underlying episodic memory. Show more

Keywords: Alzheimer’s disease, default mode network, dementia, episodic memory, functional magnetic resonance imaging, medial temporal lobe, minority health, risk factors

DOI: 10.3233/JAD-190035

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1005-1023, 2019

Authors: Gan, Qini | Yao, Hongbo | Na, Hana | Ballance, Heather | Tao, Qiushan | Leung, Lorene | Tian, Hua | Zhu, Haihao | Wolozin, Benjamin | Qiu, Wei Qiao

Article Type: Research Article

Abstract:  Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer’s disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone …induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β peptide, pramlintide, synapse, tauopathy, U-shape

DOI: 10.3233/JAD-190161

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1025-1040, 2019

Authors: Ihle-Hansen, Håkon | Vigen, Thea | Berge, Trygve | Hagberg, Guri | Engedal, Knut | Rønning, Ole Morten | Thommessen, Bente | Lyngbakken, Magnus N. | Nygård, Ståle | Røsjø, Helge | Tveit, Arnljot | Ihle-Hansen, Hege

Article Type: Research Article

Abstract: Background: Studies on the relationship between carotid atherosclerosis and cognitive function in subjects from the general population are few and results have been inconsistent. Objective: We aimed to investigate the association between carotid atherosclerotic burden and cognitive function in a cross-sectional analysis of a population-based cohort aged 63–65 years. Methods: All habitants born in 1950 from Akershus County, Norway were invited to participate. A linear regression model was used to assess the association between carotid atherosclerosis and cognitive function. We used carotid plaque score as a measure of carotid atherosclerotic burden and the Montreal Cognitive Assessment …(MoCA) for global cognitive function. Results: We analyzed 3,413 individuals aged 63–65 with mean MoCA score 25.3±2.9 and 87% visible carotid plaques. We found a negative correlation between carotid plaque score and MoCA score (r = –0.14, p  < 0.001), but this association was lost in multivariable analysis. In contrast, diameter or area of the thickest plaque was independently associated with MoCA score. Lower educational level, male sex, current smoking, and diabetes were also associated with lower MoCA score in multivariable analysis. Conclusion: Carotid atherosclerotic burden was, unlike other measures of advanced carotid atherosclerosis, not independently associated with global cognitive function. Show more

Keywords: Atherosclerosis, cardiovascular risk factors, carotid plaque, cognition, cognitive function, Montreal Cognitive Assessment, http://www.clinicaltrials.gov, NCT01555411

DOI: 10.3233/JAD-190327

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1041-1049, 2019

Authors: Pillai, Jagan A. | Bonner-Jackson, Aaron | Bekris, Lynn M. | Safar, Jiri | Bena, Jim | Leverenz, James B.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer’s disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels. Objective: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD. Methods: Retrospective comparative case study of 97 patients evaluated in a memory …clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOE ɛ 4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates. Results: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p  = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOE ɛ 4 , MoCA, and CSF Aβ42 . Logopenic AD had higher t-tau and p-tau levels compared to other variants. Conclusions: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant. Show more

Keywords: Alzheimer’s disease, atypical variant, biomarkers, cerebrospinal fluid, cortical atrophy, hippocampal atrophy, mild cognitive impairment, tau

DOI: 10.3233/JAD-190519

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1051-1058, 2019

Authors: Watts, Amber | Wilkins, Heather M. | Michaelis, Elias | Swerdlow, Russell H.

Article Type: Research Article

Abstract: TOMM40 ‘523 is associated with Alzheimer’s disease (AD), but APOE linkage disequilibrium confounds this association. In 170 APOE ɛ 3 homozygotes, we evaluated relationships between short and very long TOMM40 alleles and longitudinal declines in three cognitive domains (attention, verbal memory, and executive function). We used factor analysis to create composite scores from 10 individual cognitive tests, and latent growth curve modeling adjusting for clinical status (normal, amnestic mild cognitive impairment, or AD) to summarize initial performance and change over three years. Relative to individuals with two very long TOMM40 alleles, APOE ɛ 3 homozygotes with …one or two short alleles showed lower baseline cognitive performance regardless of clinical status. The number of short or very long TOMM40 alleles was not associated with longitudinal cognitive changes. In APOE ɛ 3 homozygotes from the University of Kansas Alzheimer’s Disease Center cohort, an association between TOMM40 ‘523 and cognition is consistent with the possibility that TOMM40 influences cognition independent of APOE . Show more

Keywords: APOE , cognition, factor analysis, longitudinal, TOMM40

DOI: 10.3233/JAD-190293

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1059-1068, 2019

Authors: Esquerda-Canals, Gisela | Roda, Alejandro R. | Martí-Clúa, Joaquim | Montoliu-Gaya, Laia | Rivera-Hernández, Geovanny | Villegas, Sandra

Article Type: Research Article

Abstract: The intracellular deposition of amyloid-β (Aβ) peptides has been described in the brains of both Alzheimer’s disease (AD) patients and animal models. A correlation between the intracellular amyloid burden and neurodegeneration has recently been reported in a triple-transgenic AD (3xTg-AD) murine model. In the present study, we assessed the effect of scFv-h3D6, an anti-Aβ single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular Aβ clearance, neuronal survival, and functional abilities. We also examined neuroinflammation and the histology of peripheral organ samples to detect any adverse effects. A single intraperitoneal …injection of scFv-h3D6 dramatically reduced intracellular Aβ burden in the deep layers of the cerebral cortex, pyramidal cells layer of the hippocampus, and basolateral amygdalar nucleus. The treatment prevented neuronal loss in the hippocampus and amygdala, while neither astrogliosis nor microgliosis was induced. Instead, an increase in the size of the white pulp after the treatment indicated that the spleen could be involved in the clearance mechanism. Although the treatment did not ameliorate behavioral and psychological symptoms of dementia-like symptoms, the results of cognitive testing pointed to a noticeable improvement in spatial memory. These findings indicated that the mechanism underlying the therapeutic effect of scFv-h3D6 was the clearance of intracellular Aβ, with subsequent prevention of neuronal loss and amelioration of cognitive disabilities. The treatment was safe in terms of neuroinflammation and kidney and liver function, whereas some effects on the spleen were observed. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, amyloid-β , immunotherapy, scFv

DOI: 10.3233/JAD-190484

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1069-1091, 2019

Authors: Gu, Jianlan | Chu, Dandan | Jin, Nana | Chen, Feng | Liu, Fei

Article Type: Research Article

Abstract: Trans-active response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved and ubiquitously expressed nuclear protein. As a member of heterogeneous ribonucleoproteins, TDP-43 plays pivotal roles in mRNA processing. We recently found that TDP-43 promoted tau mRNA instability via acting on the 3’-untranslated region of its mRNA and enhanced tau exon 10 inclusion. TDP-43 is a phospho-protein. The function and the pathological aggregation of TDP-43 are regulated by the phosphorylation. In the present study, we determined phosphorylation of TDP-43 by cyclic AMP-dependent protein kinase (PKA). We found that TDP-43 was co-immunoprecipitated by and co-localized with PKA in the nucleus. …PKA phosphorylated TDP-43 at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells. Phosphorylation of TDP-43 at these sites enhanced mutually their phosphorylation by PKA in vitro and in cultured cells. Overexpression of PKA suppressed TDP-43’s activity in promoting tau mRNA instability and tau exon 10 inclusion. These findings shed light on the role of PKA in phosphorylation and function of TDP-43. Downregulation of PKA signaling in AD brain may attenuate the impact of TDP-43 pathology in tau pathogenesis. Show more

Keywords: mRNA processing, phosphorylation, PKA, tau, TDP-43

DOI: 10.3233/JAD-190368

Citation: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1093-1102, 2019