Journal of Alzheimer's Disease - Volume 74, issue 4

Authors: Cicognola, Claudia | Satir, Tugce Munise | Brinkmalm, Gunnar | Matečko-Burmann, Irena | Agholme, Lotta | Bergström, Petra | Becker, Bruno | Zetterberg, Henrik | Blennow, Kaj | Höglund, Kina

Article Type: Research Article

Abstract: Background: Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD. Objective: Previous studies have shown cleavage from calpain proteases at sites …adjacent to aa 224. Our aim was to investigate if calpain-1 or -2 could be responsible for cleavage at aa 224. Methods: Proteolytic activity of calpain-1, calpain-2, and brain protein extract was assessed on a custom tau peptide (aa 220–228), engineered with fluorescence resonance energy transfer (FRET) technology. Findings were confirmed with in-gel trypsination and mass spectrometry (MS) analysis of brain-derived bands with proteolytic activity on the FRET substrate. Finally, knock-down of the calpain-2 catalytic subunit gene (CAPN2 ) was performed in a neuroblastoma cell line (SH-SY5Y). Results: Calpain-2 and brain protein extract, but not calpain-1, showed proteolytic activity on the FRET substrate. MS analysis of active gel bands revealed presence of calpain-2 subunits, but not calpain-1. Calpain-2 depletion and chemical inhibition suppressed proteolysis of the FRET substrate. CAPN2 knock-down caused a 76.4% reduction of N-224 tau in the cell-conditioned media. Conclusions: Further investigation of the calpain-2 pathway in the pathogenesis of tauopathies is encouraged. Show more

Keywords: Alzheimer’s disease, calpain, fragments, tau, tauopathy

DOI: 10.3233/JAD-191130

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1143-1156, 2020

Authors: Morin, Alexandre | Samper-Gonzalez, Jorge | Bertrand, Anne | Ströer, Sébastian | Dormont, Didier | Mendes, Aline | Coupé, Pierrick | Ahdidan, Jamila | Lévy, Marcel | Samri, Dalila | Hampel, Harald | Dubois, Bruno | Teichmann, Marc | Epelbaum, Stéphane | Colliot, Olivier

Article Type: Research Article

Abstract: Background: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers have been evaluated mostly in the artificial setting of research datasets. Objective: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic. Methods: We studied 239 patients with cognitive troubles from a …single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria. Results: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM. Conclusion: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis. Show more

Keywords: All cognitive disorders/dementia, Alzheimer’s disease, assessment of cognitive disorders/dementia, magnetic resonance imaging, volumetric MRI

DOI: 10.3233/JAD-190594

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1157-1166, 2020

Authors: Kiss, Eva | Groeneweg, Femke | Gorgas, Karin | Schlicksupp, Andrea | Kins, Stefan | Kirsch, Joachim | Kuhse, Jochen

Article Type: Research Article

Abstract: Early changes in inhibitory synapse connectivities are thought to contribute to the excitation/inhibition imbalance preceding neurodegeneration in Alzheimer’s disease (AD). Recently, we reported a robust increase in the level of different key-proteins of inhibitory synapses in hippocampal subregions of pre-symptomatic APPswe-PS1 mice, a model of cerebral amyloidosis. Besides increased inhibitory synaptic clusters on parvalbumin-positive projections in CA1 and CA3, we observed impaired communication between these two hippocampal areas of young APP-PS1 mice. Interestingly, the phosphorylation of gephyrin, a major organizer of inhibitory synapses, was also increased. Here, we demonstrate that the protein levels of CDK5, a kinase involved in the …phosphorylation of gephyrin, and its regulatory protein p35 are also significantly increased in hippocampal subregions of young APP-PS1 mice. Consistently, the expression of hAPP-swe in cultured hippocampal neurons resulted in higher p35-protein levels, indicating a possible molecular link between increased Aβ-production and the elevated p35/CDK5 levels seen in vivo . Further, a shRNA mediated downregulation of p35-expression in hippocampal neurons correlated with a decrease in gephyrin phosphorylation and in a reduced density of synaptic γ 2-GABAA -receptor clusters. These findings, together with the detection of gephyrin colocalization with CDK5 and p35 by immunostaining and proximity ligation experiments in vivo and in vitro , are supporting our hypothesis that Aβ has a profound impact on inhibitory network properties, likely mediated at least in part by p35/CDK5 signaling. This further underscores the impact of altered inhibitory synaptic transmission in AD. Show more

Keywords: Alzheimer’s disease, APP-PS1, CDK5, CDK5r1, γ2-GABAA receptor, inhibitory synapse, p35

DOI: 10.3233/JAD-190976

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1167-1187, 2020

Authors: Banerjee, Gargi | Ambler, Gareth | Keshavan, Ashvini | Paterson, Ross W. | Foiani, Martha S. | Toombs, Jamie | Heslegrave, Amanda | Dickson, John C. | Fraioli, Francesco | Groves, Ashley M. | Lunn, Michael P. | Fox, Nick C. | Zetterberg, Henrik | Schott, Jonathan M. | Werring, David J.

Article Type: Research Article

Abstract: Background: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). Objective: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. Methods: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. Results: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, …CAA patients had a distinctive CSF biomarker profile, with significantly lower (p  < 0.01) median concentrations of Aβ38 , Aβ40 , Aβ42 , sAβPPα , and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p  < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38 , Aβ40 , Aβ42 , and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n  = 5) and negative (n  = 5) scans, PET positive individuals had lower (p  < 0.05) concentrations of CSF Aβ42 , and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile. Conclusion: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed. Show more

Keywords: Alzheimer’s disease, amyloid-β , biomarkers, cerebral amyloid angiopathy, cerebrospinal fluid

DOI: 10.3233/JAD-191254

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1189-1201, 2020

Authors: Terrera, Graciela Muniz | Harrison, John E. | Ritchie, Craig W. | Ritchie, Karen

Article Type: Research Article

Abstract: Alterations in Alzheimer’s disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer’s Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from …the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cognition, diagnosis, neuropsychology, tau

DOI: 10.3233/JAD-191108

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1203-1210, 2020

Authors: Alifier, Marek | Olsson, Bob | Andreasson, Ulf | Cullen, Nicholas C. | Czyżewska, Jolanta | Jakubów, Piotr | Sieśkiewicz, Andrzej | Stasiak-Barmuta, Anna | Hirnle, Tomasz | Kornhuber, Johannes | Zetterberg, Henrik | Lewczuk, Piotr | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. Objective: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. Methods: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40 …, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. Results: Tau increased during surgery (1752%, p  = 0.0001) and NFL rose seven days post-surgery (1090%, p  < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42 . Conclusion: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia. Show more

Keywords: Cardiac surgery, cognitive impairment, dementia, extracorporeal circulation, neurofilament light protein, plasma, tau

DOI: 10.3233/JAD-191165

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1211-1220, 2020

Authors: Oesterhus, Ragnhild | Dalen, Ingvild | Bergland, Anne Katrine | Aarsland, Dag | Kjosavik, Svein R.

Article Type: Research Article

Abstract: Background: Patients with dementia are at high risk of being hospitalized, but there is little knowledge whether this applies to all forms of dementia. Objective: To investigate if there are differences in hospitalization between patients with Alzheimer’s disease (AD) and Lewy body dementia (LBD), and further, to compare admission rate with the general age-matched population. Methods: Patients (age 75.7±7.4) recently diagnosed with mild form of AD (n  = 110) or LBD (n  = 91) were included from outpatient clinics. The participants were followed from time of diagnosis, for five years or until death. Study outcomes were time to …first hospitalization after diagnosis, number of admissions, total number of hospital days, and length of stay. Age-standardized admission ratios were calculated. Time to first admission was analyzed using competing risks regression models, and differences in number of hospitalizations and hospital days were addressed using negative binomial regression models. Results: More than 77% of the patients were admitted, largely as unplanned hospitalizations. Patients with LBD had significantly shorter time until first hospitalization (median 1.28 years, 95% CI 0.93–1.67 versus AD: 2.32 years, 95% CI 1.74–3.31) and more days in hospital (median 13 days, IQR 4, 38), than patients with AD (7 days, IQR 0, 18). Conclusion: Our data indicates that patients with LBD have shorter time until first admission and higher admission rate than AD patients. This imposes a great burden on patients, their family, and the health care system. More knowledge about hospital admissions of people with dementia is needed. Future studies should investigate strategies to avoid potentially preventable admissions. Show more

Keywords: Alzheimer’s disease, dementia, hospitalization, length of stay, Lewy body dementia, patient admission

DOI: 10.3233/JAD-191141

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1221-1230, 2020

Authors: Huang, Yaowei | Huang, Wei | Huang, Yingwei | Song, Pingping | Zhang, Melanie | Zhang, Han-Ting | Pan, Suyue | Hu, Yafang

Article Type: Research Article

Abstract: Background: Accumulation of p25 is thought to be a causative risk factor for Alzheimer’s disease (AD). As a cleaved product of p35, p25 binds to cyclin-dependent kinase 5 (Cdk5) and leads to the hyperactivity of Cdk5. Then, Cdk5/p25 phosphorylates many pathological substrates related to neurodegenerative diseases. p25 transgenic (Tg) mouse model recaptures some pathological changes of AD, including tau hyperphosphorylation, neurofibrillary tangles, neuroinflammation, and neuronal death, which can be prevented by transgenic expression of Cdk5 inhibitory peptide (CIP) before the insult of p25. Objective: In the present study, we would like to know whether adeno-associated virus serotype-9 (AAV9)-mediated …CIP can protect neurons after insult of p25 in p25Tg mice. Methods: Administration of AAV9-CIP or control virus were delivered in the brain of p25Tg mice via intracerebroventricular infusions following the induction of p25. Western blotting, immunohistochemistry and immunofluorescence assessment, and animal behavioral evaluation were performed. Results: Brain atrophy, neuronal death, tau phosphorylation and inflammation in the hippocampus, and cognitive decline were observed in p25Tg mice. Administration of CIP but not the control virus in p25Tg mice reduced levels of tau phosphorylation and inflammation in the hippocampus, which is correlated with inhibition of brain atrophy and neuronal apoptosis in the hippocampus, and improvement of cognitive decline. Conclusion: Our results provide further evidence that the neurotoxicity of p25 can be alleviated by CIP. Show more

Keywords: Cdk5, Cdk5 inhibitory peptide, p25 transgenic mice, tau phosphorylation, neurodegeneration

DOI: 10.3233/JAD-191098

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1231-1242, 2020

Authors: Luchsinger, José A. | Palta, Priya | Rippon, Brady | Soto, Luisa | Ceballos, Fernando | Pardo, Michelle | Laing, Krystal | Igwe, Kay | Johnson, Aubrey | Tomljanovic, Zeljko | He, Hengda | Reitz, Christiane | Kreisl, William | Razlighi, Qolamreza | Teresi, Jeanne | Moreno, Herman | Brickman, Adam M.

Article Type: Research Article

Abstract: Background: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer’s disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. Objective: To examine sex differences in in vivo AD neuropathology in late middle age. Methods: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio …(SUVR) with18 F-Florbetaben positron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18 F-MK-6240 in 75 of the 266 participants. Results: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. Conclusion: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males. Show more

Keywords: Amyloid, cognition, Hispanics, neurodegeneration, sex differences, tau

DOI: 10.3233/JAD-191183

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1243-1252, 2020

Authors: Yang, Hyun Ju | Kang, Na Ri | Jung, Young Eun | Kim, Moon Doo | Jeong, Hyun Ghang | Lee, Tae Jin | Han, Ji Won | Kim, Ki Woong | Park, Joon Hyuk

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE ) ɛ 4 allele carriers have an increased risk of late-onset Alzheimer’s disease (AD). However, in the “Choosing Wisely” campaign for avoiding unnecessary medical tests, treatments, and procedures, APOE genetic testing is not recommended as a predictive test for AD. Objective: The aim of this study was to investigate the potential value of APOE genetic testing in a specific clinical context. Methods: Subjects with poor performance in the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) with a Z-score of less than –1.5 were recruited from the …public health centers. All participants underwent APOE genetic testing. Family history of dementia (FHx) was confirmed if one or more first-degree relatives had dementia. Results: Among 349 subjects, 162 (46.4%) were diagnosed with AD. APOE ɛ 4 allele carriers had a much higher risk of AD in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74–91.21 versus OR = 1.82, 95% CI = 1.00–3.27, z  = 2.293, p  = 0.011). The sensitivity, specificity, positive predictive value, and negative predictive value for the APOE ɛ 4 allele were 47.7%, 90.9%, 91.3%, and 46.5% in the group with FHx. Conclusion: It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in subjects with poor performance in a screening test and a family history of dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein genetic testing, odds ratio, sensitivity, specificity

DOI: 10.3233/JAD-190983

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1253-1260, 2020