Journal of Alzheimer's Disease - Volume 85, issue 1

Authors: Kumari, Shiwani | Singh, Ambica | Singh, Abhinay Kumar | Yadav, Yudhishthir | Bajpai, Swati | Kumar, Pramod | Upadhyay, Ashish Datt | Shekhar, Shashank | Dwivedi, Sadanand | Dey, A.B. | Dey, Sharmistha

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the progressive brain disorder which degenerates brain cells connection and causes memory loss. Although AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage, and early diagnosis requires clear understanding of the pathogenesis at molecular level. Overactivity of GSK-3β and p53 accounts for tau hyperphosphorylation and the formation of amyloid-β plaques. Objective: Here, we explored GSK-3β and p53 as blood-based biomarkers for early detection of AD. Methods: The levels …of GSK-3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using western blot in serum from AD, mild cognitive impairment (MCI), and geriatric-control (GC) subjects. The neurotoxic SH-SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect. Results: GSK-3β, p53, and their phosphorylated states were significantly over expressed (p  > 0.001) in AD and MCI compared to GC and can differentiate AD and MCI from GC. The expression level of GSK-3β and p53 proteins were found to be downregulated in a dose-dependent manner after the treatment with EO in amyloid-b-induced neurotoxic cells. Conclusion: These proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future. Show more

Keywords: Alzheimer’s disease, Emblica Officinalis, GSK-3β, mild cognitive impairment, protein biomarker, SH-SY5Y , surface plasmon resonance

DOI: 10.3233/JAD-215347

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 249-260, 2022

Authors: Tan, Yan | Zhang, Jiani | Yang, Ke | Xu, Zihui | Zhang, Huawei | Chen, Weihang | Peng, Tiantian | Wang, Xu | Liu, Zhaoheng | Wei, Peng | Li, Na | Zhang, Zhenqiang | Liu, Tonghua | Hua, Qian

Article Type: Research Article

Abstract: Background: Chinese Herbal Medicines (CHMs), as an important and integral part of a larger system of medicine practiced in China, called Traditional Chinese Medicine (TCM), have been used in stroke therapy for centuries. A large body of studies suggest that some Chinese herbs can help reverse cognitive impairment in stroke patients, while whether these herbs also exert therapeutic benefits for Alzheimer’s disease remains to be seen. Objective: To address this issue, we selected four types of CHMs that are commonly prescribed for stroke treatment in clinical practice, namely DengZhanXiXin (D1), TongLuoJiuNao (T2), QingKaiLing (Q3), and …HuangQinGan (H4), and tested their effects on amyloid-β protein precursor (AβPP) processing in vitro . Methods: AβPP, β-secretase (BACE1), and 99-amino acid C-terminal fragment of AβPP (C99) stably transfected cells were used for the tests of AβPP processing. The production of Aβ, activity of BACE1, neprilysin (NEP), and γ-secretase were assessed by ELISA, RT-PCR, and western blot. Results: By upregulating BACE1 activity, D1 increased Aβ production whereas decreased the ratio of Aβ42 /Aβ40 ; by downregulating BACE1 activity and modulating the expression of γ-secretase, T2 decreased Aβ production and the ratio of Aβ42 /Aβ40 ; by downregulating BACE1 activity, Q3 decreased Aβ production; H4 did not change Aβ production due to the simultaneously downregulation of BACE1 and NEP activity. Conclusion: Our study indicates that these four anti-stroke CHMs regulate AβPP processing through different mechanisms. Particularly, T2 with relatively simple components and prominent effect on AβPP processing may be a promising candidate for the treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1, γ-secretase, NEP, Traditional Chinese Medicine

DOI: 10.3233/JAD-210652

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 261-272, 2022

Authors: Blair, Emilie M. | Zahuranec, Darin B. | Forman, Jane | Reale, Bailey K. | Langa, Kenneth M. | Giordani, Bruno | Fagerlin, Angela | Kollman, Colleen | Whitney, Rachael T. | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: Older adults with mild cognitive impairment (MCI) receive fewer guideline-concordant treatments for multiple health conditions than those with normal cognition. Reasons for this disparity are unclear. Objective: To better understand this disparity, we describe physician understanding and experience with patient MCI, particularly physician identification of MCI, ability to distinguish between MCI and dementia, and perspectives on education and training in MCI and dementia. Methods: As part of a mixed-methods study assessing the influence of patient MCI on physician recommendations for acute myocardial infraction and stroke treatments, we conducted a descriptive qualitative study using semi-structured interviews …of physicians from three specialties. Key question topics included participants’ identification of MCI, impressions of MCI and dementia awareness within their practice specialty, and perspectives on training and education in MCI. Results: The study included 22 physicians (8 cardiologists, 7 neurologists, and 7 internists). We identified two primary themes: There is 1) a lack of adequate understanding of the distinction between MCI and dementia; and 2) variation in physician approaches to identifying whether an older adult has MCI. Conclusion: These findings suggest that physicians have a poor understanding of MCI. Our results suggest that interventions that improve physician knowledge of MCI are needed. Show more

Keywords: Cognition, dementia, diagnosis, physician knowledge

DOI: 10.3233/JAD-210565

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 273-282, 2022

Authors: Abdulrahman, Herrer | Richard, Edo | van Gool, Willem A. | Moll van Charante, Eric P. | van Dalen, Jan Willem

Article Type: Research Article

Abstract: Background: Older people with subjective memory complaints (SMC) and Instrumental Activities of Daily Living impairments (IADL-I) have an increased risk of developing dementia. Previous reports suggest that the predictive value of SMC and IADL-I may differ between sexes, leaving possible consequences for personalized risk prediction and prognosis. However, none of these studies addressed the competing risk of death, which may substantially differ between sexes. Objective: We investigated sex-differences in the association between IADL-I, SMC, and incident dementia and mortality as competing risk. Methods: 3,409 community-dwelling older people without dementia (mean age 74.3±2.5), were followed for 6.7 …years (median). Baseline SMC were assessed using the 15-item Geriatric Depression Scale memory question, and IADL-I using the Academic Medical Center Linear Disability Score. Potential sex-differences in the predictive value of SMC and IADL-I were assessed using Cox regression models with an interaction term for sex. Results: HRs for isolated SMC and SMC + IADL-I and risk of dementia were higher in women (HR: 2.02, 95% CI = 0.91–4.46, p  = 0.08; HR:2.85, 95% CI = 1.65–4.91, p  < 0.001) than in men (HR:1.52, 95% CI = 0.86–2.69, p  = 0.18; HR:1.24, 95% CI = 0.62–2.49, p  = 0.54), but these sex-differences were not significant. Conversely, HRs for isolated IADL-I and risk of mortality were higher in men (HR:1.56, 95% CI = 1.18–2.05, p  = 0.002) than in women (HR:1.14, 95% CI = 0.80–1.62, p  = 0.48), but again, these sex-differences were not significant. Conclusion: The predictive value of SMC and IADL-I for the risk of dementia and mortality was not significantly modified by sex. However, the competing risk of death for these factors differed considerably between men and women, suggesting it is an essential factor to consider when comparing sex-differences in IADL/dementia risk. Show more

Keywords: Alzheimer’s disease, dementia, Instrumental Activities of Daily Living, sex, subjective memory complaints

DOI: 10.3233/JAD-215191

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 283-294, 2022

Authors: Freak-Poli, Rosanne | Wagemaker, Nina | Wang, Rui | Lysen, Thom S. | Ikram, M. Arfan | Vernooij, Meike W. | Dintica, Christina S. | Vernooij-Dassen, Myrra | Melis, Rene J.F. | Laukka, Erika J. | Fratiglioni, Laura | Xu, Weili | Tiemeier, Henning

Article Type: Research Article

Abstract: Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health. Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association. Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4–11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged …72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor). Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08–1.67; SNAC-K: HR 2.16, 95%CI 1.12–4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk. Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms. Show more

Keywords: Aging, cognition, dementia, depressive symptoms, interpersonal relations, loneliness, social support

DOI: 10.3233/JAD-210330

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 295-308, 2022

Authors: Hoy, Kate E. | Emonson, Melanie R.L. | Bailey, Neil W. | Humble, Gregory | Coyle, Hannah | Rogers, Caitlyn | Fitzgerald, Paul B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive functioning for which there is a stark lack of effective treatments. Investigating the neurophysiological markers of symptom severity in AD may aid in the identification of alternative treatment targets. Objective: In the current study we used a multimodal approach to investigate the association between functional connectivity (specifically between scalp electrodes placed over frontal and parietal regions) and symptom severity in AD, and to explore the relationship between connectivity and cortical excitability. Methods: 40 people with AD (25 mild severity, 15 moderate severity) underwent neurobiological …assessment (resting state electroencephalography (EEG) and prefrontal transcranial magnetic stimulation (TMS) with EEG) and cognitive assessment. Neurobiological outcomes were resting state functional connectivity and TMS-evoked potentials. Cognitive outcomes were scores on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, and a measure of episodic verbal learning. Results: Greater contralateral functional theta connectivity between frontal scalp electrodes and parietal scalp electrodes was associated with poorer cognitive performance. In addition, significant correlations were seen between the contralateral theta connectivity and the N100 and P60 TMS-evoked potentials measured from electrodes over the left dorsolateral prefrontal cortex. Conclusion: Together these findings provide initial support for the use of multimodal neurophysiological approaches to investigate potential therapeutic targets in AD. Suggestions for future research are discussed. Show more

Keywords: Cognitive disorders, cortical excitability, experimental therapeutics, functional connectivity, non-invasive brain stimulation

DOI: 10.3233/JAD-210401

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 309-321, 2022

Authors: Reale, Marcella | Carrarini, Claudia | Russo, Mirella | Dono, Fedele | Ferri, Laura | Di Pietro, Martina | Costantini, Erica | Porreca, Annamaria | Di Nicola, Marta | Onofrj, Marco | Bonanni, Laura

Article Type: Research Article

Abstract: Background: Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. Objective: We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. Methods: Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and …8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. Results: Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. Conclusion: Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors. Show more

Keywords: Alzheimer’s disease, cholinergic imbalance, dementia with Lewy bodies, muscarinic receptors, real time-polymerase chain reaction

DOI: 10.3233/JAD-215285

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 323-330, 2022

Authors: Neuffer, Jeanne | Gourru, Marjorie | Thomas, Aline | Lefèvre-Arbogast, Sophie | Foubert-Samier, Alexandra | Helmer, Catherine | Delcourt, Cécile | Féart, Catherine | Samieri, Cécilia

Article Type: Research Article

Abstract: Background: Low blood status in several nutritional compounds, including long-chain omega-3 fatty acids (LC n-3 PUFA), carotenoids, and vitamin D, have been associated with a higher risk to develop dementia. Nutritional deficiencies may potentiate each other regarding dementia risk; yet the association of multiple nutritional deficiencies with dementia has been little explored. Objective: To develop an index of micronutritional biological status (MNBS) for the screening of multi-micronutritional deficiencies associated with the risk of dementia in a prospective population-based cohort of older persons. Methods: We included participants from the Bordeaux Three-City study, who were free of dementia …at baseline, had blood measurements of LC n-3 PUFA, carotenoids, and 25(OH)D, and who were followed for up to 18 years for dementia. We used penalized splines in Cox models to model dose-response relationships of each nutritional component with the risk of dementia and construct a risk index. Results: 629 participants with an average age of 73.1 years were included in the study. Each increase of 1 SD of the MNBS index was associated with a 46%higher risk of dementia (HR = 1.46, 95%CI 1.23; 1.73). Participants with highest index ([mean+1SD; max]) had a 4-fold increased risk of dementia compared with participants with a low index ([min; mean-1SD]) (HR = 4.17, 95%CI 2.30; 7.57). Conclusion: This index of assessment of micronutritional biological status is a practical tool that may help identify populations with inadequate nutritional status, screen eligible individuals for nutritional prevention in primary care, or for supplementation in preventive trials of dementia. Show more

Keywords: Biomarkers, cognitive aging, dementia, diet, elderly, food, molecular epidemiology, nutrients, nutritional status, prevention

DOI: 10.3233/JAD-215011

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 331-342, 2022

Authors: Yan, Xu-Dong | Qu, Xue-Song | Yin, Jing | Qiao, Jing | Zhang, Jun | Qi, Jin-Shun | Wu, Mei-Na

Article Type: Research Article

Abstract: Background: Cognitive deficit is mainly clinical characteristic of Alzheimer’s disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. Objective: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, …and testify its anti-inflammatory effects. Methods: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. Results: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. Conclusion: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice. Show more

Keywords: Adiponectin, 3xTg-AD mice, learning and memory, long-term depression, long-term potentiation, neuroinflammation

DOI: 10.3233/JAD-215063

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 343-357, 2022

Authors: Sarant, Julia Z. | Harris, David C. | Busby, Peter A. | Fowler, Christopher | Fripp, Jurgen | Masters, Colin L. | Maruff, Paul

Article Type: Research Article

Abstract: Background: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. Objective: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. Methods: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n  = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds …within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. Results: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n  = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4 ) carrier status increased the risk of being Aβ positive (p  = 0.002). Conclusion: Degree of HL was not associated with positive Aβ status. Show more

Keywords: Amyloid, cognition, dementia, hearing loss, neuroimaging

DOI: 10.3233/JAD-215121

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 359-367, 2022

Authors: Qiao, Yanan | Sun, Yu | Guo, Jing | Chen, Yaojing | Hou, Wenjie | Zhang, Junying | Peng, Dantao

Article Type: Research Article

Abstract: Background: Lobar cerebral microbleeds (CMBs), which can impair white matter (WM), are often concomitant with definite Alzheimer’s disease (AD). Objective: To explore the features of cognitive impairments and WM disruptions due to lobar CMBs in patients with AD. Methods: There were 310 participants who underwent Florbetapir F18 (AV45) amyloid PET and susceptibility-weighted imaging. Participants with cognitive impairment and amyloid-β positive (ADCI) were included into three groups: ADCI without CMBs, with strictly lobar CMBs (SL-CMBs), and with mixed CMBs (M-CMBs). Tract-based spatial statistics were performed to detect the group differences in WM integrity. Results: There …were 82 patients and 29 healthy controls finally included. A decreasing tendency in memory and executive performance can be found among HCs > no CMBs (n  = 16) >SL-CMBs (n  = 41) >M-CMBs (n  = 25) group. Compared to no CMBs, M-CMBs group had significantly decreased fractional anisotropy in left anterior thalamic radiation (ATR), forceps major, forceps minor and inferior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus (IFOF), and superior longitudinal fasciculus. M-CMBs group also had lower fractional anisotropy in left ATR, IFOF, uncinate fasciculus, and forceps minor compared with SL-CMBs. Furthermore, analysis of Pearson correlation indicated damages in discrepant WMs were positively associated with impairment of memory, executive function, and attention. Conclusion: This study showed lobar CMBs had intensively aggravated cognitive impairments associated with extensive WM damages in definite AD. These findings highlight that lobar CMBs play an important role in AD progression and need to be taken into consideration for the early detection of AD. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cognitive impairment, diffusion tensor imaging, Florbetapir F18 amyloid PET

DOI: 10.3233/JAD-215251

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 369-380, 2022

Authors: Wilkins, Heather M. | Troutwine, Benjamin R. | Menta, Blaise W. | Manley, Sharon J. | Strope, Taylor A. | Lysaker, Colton R. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods: SH-SY5Y cells were transfected with AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was …also measured. All parameters listed were measured in ρ 0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promotes Aβ secretion while depressed mitochondrial activity minimizes Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function. Show more

Keywords: Amyloid, amyloid-beta protein precursor, membrane potential, mitochondria

DOI: 10.3233/JAD-215280

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 381-394, 2022

Authors: Bergamino, Maurizio | Keeling, Elizabeth G. | Baxter, Leslie C. | Sisco, Nicholas J. | Walsh, Ryan R. | Stokes, Ashley M.

Article Type: Research Article

Abstract: Background: Imaging biomarkers are increasingly used in Alzheimer’s disease (AD), and the identification of sex differences using neuroimaging may provide insight into disease heterogeneity, progression, and therapeutic targets. Objective: The purpose of this study was to investigate differences in grey matter (GM) volume and white matter (WM) microstructural disorganization between males and females with AD using voxel-based morphometry (VBM) and free-water-corrected diffusion tensor imaging (FW-DTI). Methods: Data were downloaded from the OASIS-3 database, including 158 healthy control (HC; 86 females) and 46 mild AD subjects (24 females). VBM and FW-DTI metrics (fractional anisotropy (FA), axial and …radial diffusivities (AxD and RD, respectively), and FW index) were compared using effect size for the main effects of group, sex, and their interaction. Results: Significant group and sex differences were observed, with no significant interaction. Post-hoc comparisons showed that AD is associated with reduced GM volume, reduced FW-FA, and higher FW-RD/FW-index, consistent with neurodegeneration. Females in both groups exhibited higher GM volume than males, while FW-DTI metrics showed sex differences only in the AD group. Lower FW, lower FW-FA and higher FW-RD were observed in females relative to males in the AD group. Conclusion: The combination of VBM and DTI may reveal complementary sex-specific changes in GM and WM associated with AD and aging. Sex differences in GM volume were observed for both groups, while FW-DTI metrics only showed significant sex differences in the AD group, suggesting that WM tract disorganization may play a differential role in AD pathophysiology between females and males. Show more

Keywords: Alzheimer’s disease, diffusion tensor MRI, free-water DTI, sexual dimorphism, voxel-based morphometry

DOI: 10.3233/JAD-210406

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 395-414, 2022

Authors: Barthélemy, Nicolas R. | Toth, Balazs | Manser, Paul T. | Sanabria-Bohórquez, Sandra | Teng, Edmond | Keeley, Michael | Bateman, Randall J. | Weimer, Robby M. | Wildsmith, Kristin R.

Article Type: Research Article

Abstract: Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18 F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18 F]GTP1) and amyloid PET ([18 F]florbetapir or [18 F]florbetaben). Cohort A included cognitively normal amyloid …negative (n  = 6) and positive (n  = 5) individuals, and amyloid positive prodromal (n  = 13), mild (n  = 12), and moderate AD patients (n  = 10); and Cohort B included amyloid positive prodromal (n  = 24) and mild (n  = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with SUVR measures from [18 F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18 F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, [18F]GTP1, PET, tau, NCT02640092, NCT03289143

DOI: 10.3233/JAD-210677

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 415-429, 2022

Authors: Contarino, Valeria Elisa | Siggillino, Silvia | Arighi, Andrea | Scola, Elisa | Fumagalli, Giorgio Giulio | Conte, Giorgio | Rotondo, Emanuela | Galimberti, Daniela | Pietroboni, Anna Margherita | Carandini, Tiziana | Leemans, Alexander | Bianchi, Anna Maria | Triulzi, Fabio Maria

Article Type: Research Article

Abstract: Background: Superficial white matter (SWM) alterations correlated with cognitive decline have been described in Alzheimer’s disease (AD). Objective: The study aims to extend the investigation of the SWM alterations to AD and non-AD neurodegenerative dementia (ND) and explore the relationship with cerebrospinal fluid (CSF) biomarkers and clinical data. Methods: From a database of 323 suspected dementia cases, we retrospectively recruited 55 ND with abnormal amyloid-β42 (AD) and 38 ND with normal amyloid-β42 (non-AD) and collected clinical data, CSF biomarkers, and magnetic resonance images. Ten healthy controls (HC) were recruited for imaging and Mini-Mental State …Examination (MMSE). Diffusion tensor imaging (DTI) measurements were performed in the lobar SWM regions and Kruskal Wallis tests were used for among-group comparison. Spearman’s correlation tests were performed between DTI measures, CSF biomarkers, and clinical data. Results: AD and non-AD showed significant differences in the DTI measures across the SWM compared to HC. Significant differences between AD and non-AD were detected in the left parietal lobe. DTI measures correlated with amyloid-β42 and MMSE diffusely in the SWM, less extensively with total-tau and phosphorylated tau, and with disease duration in the parietal lobe bilaterally. Conclusion: Widespread SWM alterations occur in both AD and non-AD ND and AD shows appreciably more severe alterations in the parietal SWM. Notably, the alterations in the SWM are strongly linked not only to the cognitive decline but also to the diagnostic CSF biomarkers. Further studies are encouraged to evaluate the DTI measures in the SWM as in vivo non-invasive biomarkers in the preclinical phase. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid proteins, dementia, diffusion tensor imaging, mental status and dementia tests, neurodegenerative diseases, white matter

DOI: 10.3233/JAD-215003

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 431-442, 2022

Authors: Sun, Xiaodi | Suo, Xinjun | Xia, Xianyou | Yu, Chunshui | Dou, Yan

Article Type: Research Article

Abstract: Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer’s disease (AD), DMF is a potential therapeutic option for AD. Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic …resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway. Show more

Keywords: Alzheimer’s disease, dimethyl fumarate, hippocampal atrophy, Nrf2 pathway, oxidative stress

DOI: 10.3233/JAD-215074

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 443-456, 2022