Journal of Alzheimer's Disease - Volume 85, issue 4

Authors: McGrath, Emer R. | Himali, Jayandra J. | Levy, Daniel | Yang, Qiong | DeCarli, Charles S. | Courchesne, Paul | Satizabal, Claudia L. | Finney, Rebecca | Vasan, Ramachandran S. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. Objective: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer’s disease (AD) dementia. Methods: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998–2001 and subsequently followed them for incident dementia. Secondary outcomes included …stroke, structural MRI brain measures and neurocognitive test performance. Results: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18–2.64) and AD dementia (HR 1.76, 95% CI 1.11–2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, –0.28±0.11, p  = 0.01) and hippocampal volumes (–0.006±0.003, p  = 0.04) and impaired abstract reasoning (Similarities test, –0.18±0.08, p  = 0.018 per standard deviation increment in EFEMP1). Conclusion: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted. Show more

Keywords: Alzheimer disease, biomarkers, dementia, vascular brain injury

DOI: 10.3233/JAD-215053

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1657-1666, 2022

Authors: Dhaynaut, Maeva | Sprugnoli, Giulia | Cappon, Davide | Macone, Joanna | Sanchez, Justin S. | Normandin, Marc D. | Guehl, Nicolas J. | Koch, Giacomo | Paciorek, Rachel | Connor, Ann | Press, Daniel | Johnson, Keith | Pascual-Leone, Alvaro | El Fakhri, Georges | Santarnecchi, Emiliano

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild to moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, …and microglia PET imaging with [11 C]-PiB, [18 F]-FTP, and [11 C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18 F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11 C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11 C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression. Show more

Keywords: Amyloid, dementia, electroencephalography, gamma, neurostimulation, positron-emission tomography, protein clearance, protein misfolding, tau, transcranial electrical stimulation

DOI: 10.3233/JAD-215072

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1667-1676, 2022

Authors: Gerritsen, Lotte | Twait, Emma L. | Jonsson, Palmi V. | Gudnason, Vilmundur | Launer, Lenore J. | Geerlings, Mirjam I.

Article Type: Research Article

Abstract: Background: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. Objective: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. Methods: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter …hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. Results: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66–2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55–1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34–2.08). Conclusion: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia. Show more

Keywords: Cerebrovascular disorders, cohort studies, dementia, depression

DOI: 10.3233/JAD-215241

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1677-1687, 2022

Authors: Ahn, Hyejin | Yi, Dahyun | Chu, Kyungjin | Joung, Haejung | Lee, Younghwa | Jung, Gijung | Sung, Kiyoung | Han, Dongkyun | Lee, Jun Ho | Byun, Min Soo | Lee, Dong Young

Article Type: Research Article

Abstract: Background: Total score (TS) of semantic verbal fluency test (SVFT) is generally used to interpret results, but it is ambiguous as to specific neural functions it reflects. Different SVFT strategy scores reflecting qualitative aspects are proposed to identify specific cognitive functions to overcome limitations of using the TS. Objective: Functional neural correlates of the TS as well as the other strategy scores in subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia using Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET). Methods: Correlations between various SVFT scores (i.e., TS, mean cluster size, switching (SW), …hard switching, cluster switching (CSW)) and cerebral glucose metabolism were explored using voxelwise whole-brain approach. Subgroup analyses were also performed based on the diagnosis and investigated the effects of disease severity on the associations. Results: Significant positive correlation between TS and cerebral glucose metabolism was found in prefrontal, parietal, cingulate, temporal cortex, and subcortical regions. Significantly increased glucose metabolism associated with the SW were found in similar but smaller regions, mainly in the fronto-parieto-temporal regions. CSW was only correlated with the caudate. In the subgroup analysis conducted to assess different contribution of clinical severity, differential associations between the strategy scores and regional glucose metabolism were found. Conclusion: SW and CSW may reflect specific language and executive functions better than the TS. The SVFT is influenced by brain dysfunction due to the progression of AD, as demonstrated by the SW with larger involvement of temporal lobe for the AD, and CSW with significant association only for the MCI. Show more

Keywords: Alzheimer’s disease, dementia, fluorodeoxyglucose F18, mild cognitive impairment, neuropsychological tests, positron emission tomography

DOI: 10.3233/JAD-215292

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1689-1700, 2022

Authors: Streit, Wolfgang J. | Rotter, Jonas | Winter, Karsten | Müller, Wolf | Khoshbouei, Habibeh | Bechmann, Ingo

Article Type: Research Article

Abstract: Background: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown. Objective: Elucidate neuritic plaque pathogenesis. Methods: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron. Results: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary …tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl’s Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly. Conclusion: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques. Show more

Keywords: Amyloid-β protein, ferritin, ferroptosis, iron, late-onset Alzheimer’s disease, microglia, neuron loss

DOI: 10.3233/JAD-215334

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1701-1720, 2022

Authors: Black, Stefanie A.G. | Stepanchuk, Anastasiia A. | Templeton, George W. | Hernandez, Yda | Ota, Tomoko | Roychoudhury, Shyamosree | Smith, Eric E. | Barber, Philip A. | Ismail, Zahinoor | Fischer, Karyn | Zwiers, Angela | Poulin, Marc J. | Blennow, Kaj | Zetterberg, Henrik | Stys, Peter K. | Tsutsui, Shigeki

Article Type: Research Article

Abstract: Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with …confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease. Show more

Keywords: Aβ42, Alzheimer’s disease, cerebrospinal fluid, conformationally-sensitive amyloid probes, p-Tau, peripheral blood mononuclear cells, spectral confocal microscopy, t-Tau

DOI: 10.3233/JAD-215402

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1721-1734, 2022

Authors: Botero-Rodríguez, Felipe | Córdoba Sastoque, Ana Melisa | Santacruz Escudero, José Manuel | Santamaría-García, Hernando

Article Type: Research Article

Abstract: Background: The neuropsychiatric symptoms (NPS) in patients with neurocognitive disorders (NCD) increases the risk of exhibiting significant cognitive and functional decline. However, to the best of our knowledge, few studies have evaluated to what extent the presence of chronic and early NPS impacts cognition and functionality in patients with minor or major stages of NCD. Objective: We aimed to assess the interplay between early and chronic NPS and cognitive and functional presentation of patients with mild and major forms of NCD. Methods: We used two NPS tools tracking early and late NPS and …assessed to what extent they determine cognitive and functional outcomes in patients with mild and major forms of NCD. Results: We found an inverse relationship between the presence of NPS, as measured by the Neuropsychiatric Inventory and Mild Behavioral Impairment Checklist (MBI-C), and cognitive and functional variables in major forms of NCD. In contrast, the minor stage of NCD was associated with increased MBI-C scores. Conclusion: Our results revealed that NPS are associated with cognitive and functional outcomes in mild and chronic forms of NCD. Crucially our results suggest that NPS could be considered as a pathological marker of the clinical course of dementia. Additionally, our study calls to study early and late forms of NPS as both impact cognition and functionality of NCD. Show more

Keywords: Assessment of cognitive disorders/dementia, behavioral disturbances, neurocognitive disorder, neurodegeneration, neuropsychiatric symptoms

DOI: 10.3233/JAD-215283

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1735-1744, 2022

Authors: Sun, Yuqing | Wang, Meng | Zhao, Yuxin | Hu, Ke | Liu, Yong | Liu, Bing | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Tauopathy is a primary neuropathological hallmark of Alzheimer’s disease with a strong relationship to cognitive impairment. In the brain, tau aggregation is associated with the regulation of tau kinases and the binding ability of tau to microtubules. Objective: To explore the potential for using specific polygenic risk scores (PRSs), combining the genetic influences involved in tau-protein kinases and the tau-protein binding pathway, as predictors of tau pathology and cognitive decline in non-demented individuals. Methods: We computed a pathway-specific PRS using summary statistics from previous large-scale genome-wide association studies of dementia. We examined whether PRS is …related to tau uptake in positron emission tomography (PET), tau levels, and the rate of tau level changes in cerebrospinal fluid (CSF). We further assessed whether PRS is associated with memory impairment mediated by CSF tau levels. Results: A higher PRS was related to elevated CSF tau levels and tau-PET uptake at baseline, as well as greater rates of change in CSF tau levels. Moreover, PRS was associated with memory impairment, mediated by increased CSF tau levels. The association between PRS and tau pathology was significant when APOE was excluded, even among females. However, the effect of PRS on cognitive decline appeared to be driven by the inclusion of APOE . Conclusion: The influence of genetic risk in a specific tau-related biological pathway may make an individual more susceptible to tau pathology, resulting in cognitive dysfunction in an early preclinical phase of the disease. Show more

Keywords: Alzheimer’s disease, cognitive function genetic risk scores, pathway, tau

DOI: 10.3233/JAD-215163

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1745-1754, 2022

Authors: Broberg, Dana N. | Wong, Dickson | Bellyou, Miranda | Montero-Odasso, Manuel | Beauchet, Olivier | Annweiler, Cedric | Bartha, Robert

Article Type: Research Article

Abstract: Background: Altered gait is a frequent feature of Alzheimer’s disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective: Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods: Male APPswe/PS1dE9 mice were split into four groups (n  = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups …started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. Results: Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p  < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p  < 0.01), while mice treated with memantine and vitamin D did not (p  = 0.21). Conclusion: Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD. Show more

Keywords: Alzheimer’s disease, animal model, CatWalk, gait, memantine, vitamin D

DOI: 10.3233/JAD-215188

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1755-1766, 2022

Authors: Alatorre-Cruz, Graciela C. | Fernández, Thalía | Castro-Chavira, Susana A. | González-López, Mauricio | Sánchez-Moguel, Sergio M. | Silva-Pereyra, Juan

Article Type: Research Article

Abstract: Background: In healthy older adults, excess theta activity is an electroencephalographic (EEG) predictor of cognitive impairment. In a previous study, neurofeedback (NFB) treatment reinforcing reductions theta activity resulted in EEG reorganization and cognitive improvement. Objective: To explore the clinical applicability of this NFB treatment, the present study performed a 1-year follow-up to determine its lasting effects. Methods: Twenty seniors with excessive theta activity in their EEG were randomly assigned to the experimental or control group. The experimental group received an auditory reward when the theta absolute power (AP) was reduced. The control group received the reward …randomly. Results: Both groups showed a significant decrease in theta activity at the training electrode. However, the EEG results showed that only the experimental group underwent global changes after treatment. These changes consisted of delta and theta decreases and beta increases. Although no changes were found in any group during the period between the posttreatment evaluation and follow-up, more pronounced theta decreases and beta increases were observed in the experimental group when the follow-up and pretreatment measures were compared. Executive functions showed a tendency to improve two months after treatment which became significant one year later. Conclusion: These results suggest that the EEG and behavioral benefits of this NFB treatment persist for at least one year, which adds up to the available evidence contributing to identifying factors that increase its efficacy level. The relevance of this study lies in its prophylactic features of addressing a clinically healthy population with EEG risk of cognitive decline. Show more

Keywords: Biofeedback, cognitive aging, EEG, follow-up, healthy aging, neurofeedback, older adults

DOI: 10.3233/JAD-215538

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1767-1781, 2022