Journal of Alzheimer's Disease - Volume 70, issue 1

Authors: Eyler, Lisa T. | Elman, Jeremy A. | Hatton, Sean N. | Gough, Sarah | Mischel, Anna K. | Hagler, Donald J. | Franz, Carol E. | Docherty, Anna | Fennema-Notestine, Christine | Gillespie, Nathan | Gustavson, Daniel | Lyons, Michael J. | Neale, Michael C. | Panizzon, Matthew S. | Dale, Anders M. | Kremen, William S.

Article Type: Research Article

Abstract: Background: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer’s disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. Objective: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. Methods: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus …hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. Results: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z  = –3.1, p  < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. Conclusions: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk. Show more

Keywords: Alzheimer’s disease, default mode network, functional connectivity, mild cognitive impairment, posterior cingulate cortex, resting state functional magnetic resonance imaging

DOI: 10.3233/JAD-180847

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 107-120, 2019

Authors: Wu, Yahui | Zhao, Yuhua | Xu, Tong | You, LiWen | Zhang, Hao | Liu, Fang

Article Type: Research Article

Abstract: Recent studies suggest that severity of asthma can be modulated by neuropsychiatric conditions, while the underlying mechanisms are not clear. Here, we used ovalbumin (OVA) to induce asthma in APP/PS1 mice, a mouse model of Alzheimer’s disease (AD), or in their wildtype control C57BL/6J mice. We found that all hallmarks of asthma by OVA were significantly attenuated in APP/PS1 mice, compared to age- and gender-matched C57BL/6J mice. Interestingly, significantly higher number of regulatory T cells (Treg) was detected in the APP/PS1 mouse lung, compared to those in the C57BL/6J mouse lung. Since Foxp3 is crucial for differentiation of naive T …cells into Treg and is the most important marker for Treg, we examined the Foxp3 levels in the T cells from the lung of these mice. We found that the Foxp3 levels in the APP/PS1 mouse lung were significantly higher than those in the C57BL/6J mouse lung, likely resulting from reduced Foxp3 promoter methylation. Thus, our study suggests that AD may affect severity of asthma through methylation control of Foxp3 promoter in T cells. Show more

Keywords: Alzheimer’s disease, asthma, Foxp3, regulatory T cells (Treg cells)

DOI: 10.3233/JAD-190315

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 121-129, 2019

Authors: Rafii, Michael S. | Donohue, Michael C. | Matthews, Dawn C. | Muranevici, Gabriela | Ness, Seth | O’Bryant, Sid E. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Adults with Down syndrome (DS) are at very high risk for Alzheimer’s disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. Objective: To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. Methods: We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. Results: We found significant correlations between NF-L plasma concentrations …and amyloid pathology (r  = 0.73, p  = 0.007, pa  = 0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r  = –0.55, p  = 0.067, pa  = 0.067), Posterior cingulate r  = –0.90, p  < 0.001, pa  < 0.001), Lateral Temporal (r  = –0.78, p  = 0.004, pa  = 0.012), Frontal cortex (r  = –0.90, p  < 0.001, p pa  < 0.001), Parietal cortex (r  = –0.82, p  = 0.002, pa  = 0.008), Precuneus (r  = –0.73, pa = 0.010, pa  = 0.020), and with hippocampal volume (r  = –0.52, p  = 0.084, pa  = 0.084); and an inverse correlation with direct measures of cognition: CAMCOG (r  = –0.66 p  = 0.022, pa  = 0.066) and positive correlation with CANTAB Paired Associates Learning (PAL) error rate (r  = 0.68, p  = 0.015, pa  = 0.060). Finally, we found inverse relationships with informant-based functional measures (r  = –0.57, p  = 0.059, pa  = 0.084) and OMQ-PF (r  = –0.74, p  = 0.008, pa  = 0.041). Conclusion: Plasma NF-L is associated with progressive neurodegeneration as well as with declines in cognitive and functional measures in adults with DS. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, blood, Down syndrome, neurofilament light, plasma, tau

DOI: 10.3233/JAD-190322

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 131-138, 2019

Authors: Cavendish, John Z. | Sarkar, Saumyendra N. | Colantonio, Mark A. | Quintana, Dominic D. | Ahmed, Nadia | White, Brishti A. | Engler-Chiurazzi, Elizabeth B. | Simpkins, James W.

Article Type: Research Article

Abstract: Mitochondrial dysfunction is often found in Alzheimer’s disease (AD) patients and animal models. Clinical severity of AD is linked to early deficiencies in cognitive function and brain metabolism, indicating that pathological changes may begin early in life. Previous studies showed decreased mitochondrial function in primary hippocampal neurons from triple-transgenic Alzheimer’s disease (3xTg-AD) mice and mitochondrial movement and structure deficits in primary neurons exposed to amyloid-β oligomers. The present study characterized mitochondrial movement, number, and structure in 3xTg-AD primary cortical neurons and non-transgenic (nonTg) controls. We found a significant reduction in mitochondrial number and movement in 3xTg-AD primary cortical neurons with …modest structural changes. Additionally, application of the sigma-1 receptor agonist, (+)SKF-10,047, markedly increased mitochondrial movement in both 3xTg-AD and nonTg primary cortical cultures after one hour of treatment. (+)SKF-10,047 also led to a trend of increased mitochondrial number in 3xTg-AD cultures. Embryonic mitochondrial movement and number deficits could be among the key steps in the early pathogenesis of AD that compromise cognitive or metabolic reserve, and amelioration of these deficits could be a promising area for further preclinical and clinical study. Show more

Keywords: Alzheimer’s disease, mitochondrial dynamics, mitochondrial size, sigma receptors

DOI: 10.3233/JAD-190143

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 139-151, 2019

Authors: Wharton, Whitney | Zhao, Liping | Steenland, Kyle | Goldstein, Felicia C. | Schneider, Julie A. | Barnes, Lisa L. | Gearing, Marla | Yasar, Sevil

Article Type: Research Article

Abstract: Background: Individuals taking renin angiotensin system (RAS) acting antihypertensives exhibit slower cognitive decline and are less likely to progress from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), but the mechanism remains unclear. Objective: We tested the hypothesis that individuals taking RAS acting antihypertensives exhibit less AD-related neuropathology and slower disease progression than individuals taking non-RAS acting antihypertensives. Method: Participants included 83 individuals with MCI who were taking an antihypertensive at baseline, had at least two follow-up visits, and had postmortem neuropathological data. Participants were old (M  = 83.1 years), 32% male, well educated (M  = 15.7 years), …and 9.2% Black. Results: RAS medication users (N  = 38) were less likely to progress to AD than non-RAS users (N  = 45). RAS users exhibited fewer neurofibrillary tangles than non-RAS users in the hippocampal CA1 region (p  < 0.01), entorhinal cortex (p  = 0.03), and the angular gyrus, inferior temporal, mid-frontal cortex, and superior frontal (p  = 0.01). Conclusion: Prevention or clearance of neurofibrillary tangles represents a mechanism by which RAS medications may slow disease progression. Show more

Keywords: Alzheimer’s disease, blood pressure, hypertension, mild cognitive impairment, neuropathology, prevention, renin angiotensin system, tau

DOI: 10.3233/JAD-190011

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 153-161, 2019

Authors: Samudra, Niyatee | Motes, Michael | Lu, Hanzhang | Sheng, Min | Diaz-Arrastia, Ramon | Devous, Michael | Hart, John | Womack, Kyle B.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved …neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01–0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p  < 0.03, α = 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO2 . We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, fractional amplitude of low frequency fluctuations, functional magnetic resonance imaging, sildenafil.

DOI: 10.3233/JAD-190128

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 163-170, 2019

Authors: Jones, Marggie | McDermott, Barry | Oliveira, Bárbara Luz | O’Brien, Aoife | Coogan, Declan | Lang, Mark | Moriarty, Niamh | Dowd, Eilis | Quinlan, Leo | Mc Ginley, Brian | Dunne, Eoghan | Newell, David | Porter, Emily | Elahi, Muhammad Adnan | O’ Halloran, Martin | Shahzad, Atif

Article Type: Research Article

Abstract: Background: It is known that proteins associated with Alzheimer’s disease (AD) pathogenesis are significantly reduced by 40 Hz entrainment in mice. If this were to translate to humans, verifying that such a light stimulus can induce a 40 Hz entrainment response in humans and harnessing insights from these case studies could be one step in the development of a multisensory device to prevent and treat AD. Objective: Verify the inducement of a 40 Hz response in the human brain by a 40 Hz light stimulus and obtain insights that could potentially aid in the development of a multisensory device for the prevention …and treatment of AD. Methods: Electroencephalographic brain activity was recorded simultaneously with application of stimulus at different frequencies and intensities. Power spectral densities were analyzed. Results: Entrainment to visual stimuli occurred with the largest response at 40 Hz. The high intensity 40 Hz stimulus caused widespread entrainment. The number of electrodes demonstrating entrainment increased with increasing light intensity. Largest amplitudes for the high intensity 40 Hz stimulus were consistently found at the primary visual cortex. There was a harmonic effect at double the frequency for the 40 Hz stimulus. An eyes-open protocol caused more entrainment than an eyes-closed protocol. Conclusion: It was possible to induce widespread entrainment using a 40 Hz light stimulus in this sample cohort. Insights gleaned from these case studies could potentially aid in the development of a multisensory medical device to prevent and treat AD. Show more

Keywords: 40 Hz, Alzheimer’s disease, gamma band, human study, light stimulus

DOI: 10.3233/JAD-190299

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 171-185, 2019

Authors: McClure, Richard | Redha, Rey | Vinson, Paige | Pham, Wellington

Article Type: Research Article

Abstract: A robust fluorescent readout assay using topologically-sensitive dyes improves the screening of novel amyloid-binding molecules. One of the key components that make this assay more realistic is the use of endogenous amyloid obtained from 5XFAD mouse brains. The assay conditions were optimized for high throughput screening operation with Z -prime values >0.6. Using a combination of library of 3,500 compounds including known drugs, natural-derived molecules and random organic molecules, 8 unique molecules were identified as potential amyloid-binding agents.

Keywords: Alzheimer’s disease, amyloid, high throughput screening

DOI: 10.3233/JAD-190316

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 187-197, 2019

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Background: The latent variable “δ ” (for “dementia) is a transdiagnostic measure of dementia severity. δ can be reified and applied to individuals as a composite “d-score”. Like Spearman’s general intelligence factor “g ”, δ can be constructed from almost any cognitive battery. So many are available that we must further distinguish each composite as a δ “homolog”. Fourteen have been validated. All are strongly associated with dementia severity and potentially with mild cognitive impairment (MCI) conversion. Objectives: To assess δ ’s impact on MCI conversion risk. Methods: A new δ homolog …(dDx) was constructed in 1,230 Mexican-American (MA) and 2,215 non-Hispanic White (NHW) participants in the Texas Alzheimer’s Research and Care Consortium (TARCC). 1,445 normal controls (NC) and 723 MCI were followed annually for up to 6 years. Results: Each SD decrease in the dDx score increased the risk of conversion sixteen-fold [OR = 16.39 (CI: 5.0–52.6)]. Cases below the optimal diagnostic threshold for Alzheimer’s disease (AD) versus NC were labeled as having a functionally salient cognitive impairment (FSCI). Such cases were at a 73-fold increase risk of a diagnosis of AD [OR = 73.19 (95% CI: 58.3–92.0)]. However, 25.6% of MCI cases were also FSCI(+). They accounted disproportionately for prospective conversions. Age <80 years, the absence of an ɛ 4 allele, <12 years of education, and MA ethnicity independently increased the risk of diagnosing FSCI as MCI. Conclusion: A sizable minority of MCI cases may be misdiagnosed and they account disproportionately for AD conversions. Show more

Keywords: Aging, cognition, dementia, δ , functional status, g , intelligence, mild cognitive impairment

DOI: 10.3233/JAD-190266

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 199-210, 2019

Authors: Tort-Merino, Adrià | Olives, Jaume | León, María | Peñaloza, Claudia | Valech, Natalia | Santos-Santos, Miguel A. | Càmara, Estela | Grönholm-Nyman, Petra | Martínez-Lage, Pablo | Fortea, Juan | Molinuevo, José L. | Sánchez-Valle, Raquel | Laine, Matti | Rodríguez-Fornells, Antoni | Rami, Lorena

Article Type: Research Article

Abstract: Background: We investigated a sample of cognitively healthy subjects with normal Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. Objective: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. Methods: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a …linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau < 228.64 pg/ml; n  = 16) and CBN-Tau↑ (tau >  228.64 pg/ml; n  = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. Results: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B  = –0.17, p  < 0.05; r  = –0.414; p  < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p  < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. Conclusions: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects. Show more

Keywords: Aging, biomarkers, cognition, early detection, memory decline, tau, voxel-based morphometry

DOI: 10.3233/JAD-190046

Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 211-225, 2019