Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Kehoe, Patrick G. | Al Mulhim, Noura | Zetterberg, Henrik | Blennow, Kaj | Miners, James S.

Article Type: Research Article

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 …(ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42 , total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p  = 0.008) and positively correlated with ACE2 in AD (r  = 0.420, p  = 0.007). CSF ACE1 weakly correlated with t-tau (r  = 0.294, p  = 0.066) and p-tau (r  = 0.329, p  = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r  = 0.426, p  = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r  = 0.422, p  = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD. Show more

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Tian, Jing | Wang, Tienju | Wang, Qi | Guo, Lan | Du, Heng

Article Type: Research Article

Abstract: Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer’s disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α ), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at …the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, growth hormone secretagogue receptor 1α, hippocampus, MK0677

DOI: 10.3233/JAD-190779

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Forbes, Harriet J. | Wong, Angel Y.S. | Morton, Caroline | Bhaskaran, Krishnan | Smeeth, Liam | Richards, Marcus | Schmidt, Sigrun A.J. | Langan, Sinéad M. | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. Objective: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. Methods: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a …partnership. Multivariate cox regression was performed. Results: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20–1.71) and first six months (HR 1.24, 95% CI 1.09–1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89–0.98). Conclusions: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals. Show more

Keywords: Bereavement, Clinical Practice Research Datalink, dementia, diagnosis, epidemiology

DOI: 10.3233/JAD-190571

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Zhou, Guoyu | Zhao, Xinjing | Lou, Zhiyin | Zhou, Shengnian | Shan, Peiyan | Zheng, Ning | Yu, Xiaolin | Ma, Lin

Article Type: Research Article

Abstract: Background: Vasculature changes have been observed in Alzheimer’s disease (AD). AD-related vascular pathology might impair cerebral autoregulation (CA). Objective: This study was designed to evaluate CA of AD patients by using transcranial doppler (TCD). Methods: A total of 61 participants were included in the study, including 31 AD patients and 30 controls. The trend curves of cerebral blood flow velocities (CBFV), pulsatility index, and resistance index were obtained using TCD during supine-to-standing posture changes. CA was measured by the changes of CBFV curves during supine-to-standing test. Results: There were two spikes named X spike …and W spike that appeared in the CBFV curve when the subjects stood abruptly. The slope of the X spike descending branch, the slope of the W spike ascending branch, and the angle between X and W spikes (α angle), showed significant differences between the experimental and control groups (2.34±0.99 versus 3.15±1.61 cm/s2 , p  = 0.021; 2.31±0.81 versus 3.38±1.18 cm/s2 , p  < 0.001; and 52.71±20.26 versus 41.4±12.87 degrees, p  = 0.012, respectively). ROC analysis showed that AUCα angle is 0.664 (p  = 0.028) and that AUCSAB and AUCadjustedSAB are 0.775 and 0.738, respectively (both p  < 0.001). Conclusions: Our study demonstrated that supine-to-standing TCD test is a valuable tool for the evaluation of CA in AD patients. Impaired CA in AD patients manifested as decreased efficiency of changes in the CBFV curve. Neurovascular units were involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, cerebral autoregulation, supine-to-standing test, transcranial Doppler

DOI: 10.3233/JAD-190296

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Yoshida, Koji | Hata, Yukiko | Ichimata, Shojiro | Nishida, Naoki

Article Type: Research Article

Abstract: Background: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer’s disease (AD). Objective: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. Method: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and …the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE ) genotype was also examined. Results: Tau pathology was detected in 135 cases (71.4%; 13–39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOE ɛ 2 allele were found in 10–39 years of age natural death cases (p  < 0.05). Amyloid-β deposition was found in only 7 cases, along with a significantly high frequency of the ɛ 4 allele (p  < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. Conclusions: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects. Show more

Keywords: Alzheimer’s disease, amyloid-β, ApoE, neuropathology, suicide, tau

DOI: 10.3233/JAD-190196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Liu, Xi-Xi | Jiao, Bin | Liao, Xin-Xin | Guo, Li-Na | Yuan, Zhen-Hua | Wang, Xin | Xiao, Xue-Wen | Zhang, Xin-Yue | Tang, Bei-Sha | Shen, Lu

Article Type: Research Article

Abstract: Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer’s disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOE ɛ 4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different …in those patients who were APOE ɛ 4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella , Leptotrichia , and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOE ɛ 4 (–) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOE ɛ 4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development. Show more

Keywords: Alzheimer’s disease, APOE , oral microbiome, 16S rRNA

DOI: 10.3233/JAD-190587

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Rossini, Paolo Maria | Cappa, Stefano F. | Lattanzio, Fabrizia | Perani, Daniela | Spadin, Patrizia | Tagliavini, Fabrizio | Vanacore, Nicola

Article Type: Research Article

Abstract: Alzheimer’s disease is the most common age-related neurodegenerative disorder and its burden on patients, families, and society grows significantly with lifespan. Early modifications of risk-enhancing lifestyles and treatment initiation expand personal autonomy and reduce management costs. Many clinical trials with potentially disease-modifying drugs are devoted to mild cognitive impairment (MCI) prodromal-to-Alzheimer’s disease. The identification of biomarkers for early diagnosis may thus be crucial for early intervention and identification of high-risk subjects, the most appropriate target of new drugs as soon as they will be discovered. INTERCEPTOR is a strategic project by the Italian Ministry of Health and the Italian Medicines …Agency (AIFA), aiming to validate the best combination (highly accurate, non-invasive, available on the whole national territory and financially sustainable) of biomarkers and organizational model for early diagnosis. 500 MCI subjects will be enrolled at baseline and followed-up for 3 years for at least 400 of them in order to define a “hub & spoke” nationwide model with recruiting (spokes) centers for MCI identification and expert (hubs) centers for risk diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, early diagnosis, healthcare organizational models, mild cognitive impairment, prodromal Alzheimer’s disease, public health

DOI: 10.3233/JAD-190670

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Richards, Emma | Bayer, Antony | Tree, Jeremy | Hanley, Claire | Norris, Jade | Tales, Andrea

Article Type: Research Article

Abstract: In this study, reaction time (RT), intraindividual variability (IIV), and errors, and the effects of practice and processing load upon such function, were compared in patients with subcortical ischemic vascular cognitive impairment (SIVCI) [n  = 27] and cognitively healthy older adults (CH) [n  = 26]. Compared to CH aging, SIVCI was characterized by a profile of significantly slowed RT, raised IIV, and higher error levels, particularly in the presence of distracting stimuli, indicating that the integrity and/or accessibility of the additional functions required to support high processing load, serial search strategies, are reduced in SIVCI. Furthermore, although practice speeded RT in SIVCI, …unlike CH, practice did not lead to an improvement in IIV. This indicates that improvement in RT in SIVCI can in fact mask an abnormally high degree of IIV. Because IIV appears more related to disease, function, and health than RT, its status and potential for change may represent a particularly meaningful, and relevant, disease characteristic of SIVCI. Finally, a high level of within-group variation in the above measures was another characteristic of SIVCI, with such processing heterogeneity in patients with ostensibly the same diagnosis, possibly related to individual variation in pathological load. Detailed measurement of RT, IIV, errors, and practice effects therefore reveal a degree of functional impairment in brain processing not apparent by measuring RT in isolation. Show more

Keywords: Intra-individual variability, methodology, reaction time, subcortical ischemic vascular cognitive impairment

DOI: 10.3233/JAD-190889

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Krolak-Salmon, Pierre | Maillet, Audrey | Vanacore, Nicola | Selbaek, Geir | Rejdak, Konrad | Traykov, Latchezar | Politis, Antonios | Georges, Jean | Borson, Soo | Leperre-Desplanques, Armelle

Article Type: Review Article

Abstract: Neurocognitive disorders causing progressive cognitive, functional, and behavioral impairment remain underdiagnosed. The needs for a timely diagnosis are now widely acknowledged since person-centered care helps to preserve life quality and prevent crises. One powerful barrier to detection in primary care is the lack of an easy-to-follow stepwise approach, grounded in evidence and consistent with high-quality specialty practice. To help fill this gap, the current European Joint Action proposes a graduated diagnosis strategy tailored to the patients’ needs and wills, clarifying appropriate components for primary and specialty care. This strategy considers a first evaluation in primary care that may detect a …neurocognitive disorder, that would lead to a second evaluation step allowing etiological diagnosis hypotheses performed mostly by the specialist. A third evaluation stage considering some biological, electrophysiological, or neuroimaging complementary techniques would be proposed to atypical cases or patients willing to consider access to research. Show more

Keywords: Alzheimer’s disease, detection, diagnosis, general practitioner, memory, neurocognitive disorder

DOI: 10.3233/JAD-190461

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Goldstein, Felicia C. | Loring, David W. | Thomas, Tiffany | Saleh, Sabria | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: The utility of recognition memory for identifying persons with biomarker evidence of Alzheimer’s disease (AD) is unclear since prior studies of mild cognitive impairment (MCI) relied only on clinical diagnosis and did not include simultaneous measures of central amyloidosis and tauopathy. Objective: We evaluated whether recognition memory and associated indices, including discriminability and response bias from signal detection theory, differentiate persons with amnestic MCI (aMCI) due to prodromal AD from non-prodromal AD. Method: Sixty older adults with aMCI were classified as prodromal AD (n  = 28) or non-prodromal AD (n  = 32) based upon cerebrospinal fluid levels …of amyloid-β and tau. Memory was assessed using the Hopkins Verbal Learning Test-Revised which includes free recall and recognition. Results: ANCOVAs adjusting for age indicated comparable (all p  > 0.05) performances between prodromal and non-prodromal MCI groups respectively on traditional HVLT-R recognition measures of hits (mean±SD: 9.5±3.0 versus 10.9±1.7), false alarms (1.8±1.8 versus 1.5±1.5), and hits minus false alarms (7.7±3.0 versus 9.2±2.6). In contrast, discriminability (d’), which reflects how easily targets and distractors are distinguished, was significantly (p  = 0.009) poorer in the prodromal versus non-prodromal groups (3.1±1.9 versus 4.8±2.0, effect size = 0.87). In addition, only d’ significantly predicted group membership (OR = 0.66, CI = 0.48–0.92, p  = 0.04). Response bias, the tendency to report that a target did or did not appear, was comparable between groups (0.08±1.1 versus –0.04±1.3). Conclusion: Recognition discriminability is significantly poorer in aMCI with biomarker evidence of prodromal AD. In contrast to traditional recognition indices, discriminability from signal detection theory may be superior in identifying aMCI due to AD versus non-AD etiologies. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloidosis, biomarkers, mild cognitive impairment, prodromal Alzheimer’s disease, recognition memory, signal detection, tau

DOI: 10.3233/JAD-190468

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019