Journal of Alzheimer's Disease - Volume 87, issue 2

Authors: Wells, Lindsey F. | Risacher, Shannon L. | McDonald, Brenna C. | Farlow, Martin R. | Brosch, Jared | Gao, Sujuan | Apostolova, Liana G. | Saykin, Andrew J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function. Objective: We examined the relationship between CCI and ECog self and informant-based evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments. Methods: 950 participants (57.1% female, mean age = 71.2 years) from ADNI and the Indiana ADRC with self-based evaluations and 279 participants …(60.9% female, mean age = 71.8 years) with informant-based evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Spearman correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, age, years of education, race/ethnicity, APOE ɛ4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates. Results: CCI and ECog total scores were highly correlated for the self (r  = 0.795, p  < 0.001) and informant-based (r  = 0.840, p  < 0.001) versions, as expected. Frequency distributions of self and informant total scores were generated and plotted separately. Quadratic regressions for self (r2  = 0.626) and informant (r2  = 0.741) scores were used to create a translation table between the CCI and ECog total scores. Conclusion: Self and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome. Show more

Keywords: Alzheimer’s disease, co-calibration, cognitive assessment screening instrument,, cognitive decline,, harmonization, tau proteins, subjective cognitive decline

DOI: 10.3233/JAD-215388

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 761-769, 2022

Authors: Hosseini, Akram A. | Brown, Thomas | Mannino, Luca | Gran, Bruno | Junaid, Kehinde | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: The differentiation of a preclinical or prodromal Alzheimer’s disease (AD) is challenging particularly in patients with early onset Alzheimer’s or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020. Objective: To assess amyloid-β42 (Aβ42 ), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance. Methods: Thirty participants aged 32–68 years old (mean 59 years; 57% female) were …included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42 , total tau, and p-tau measurements. Results: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p  < 0.01 for CSF total and p-tau measures and p  < 0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42 . Conclusion: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis. Show more

Keywords: Alzheimer’s disease, amyloid-β , cerebrospinal fluid, early onset Alzheimer’s disease, mild cognitive impairment

DOI: 10.3233/JAD-215650

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 771-780, 2022

Authors: Hanyu, Haruo | Koyama, Yumi | Horita, Haruka | Aoki, Toshinori | Sato, Tomohiko | Takenoshita, Naoto | Kanetaka, Hidekazu | Shimizu, Soichiro | Hirao, Kentaro | Watanabe, Sadayoshi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a biologically heterogenous disease. Previous studies have reported the existence of various AD subtypes, and the various clinical features of the subtypes. However, inconsistent results have been obtained. Objective: To clarify the clinical characteristics of the various AD subtypes, by classifying probable AD into subtypes based on magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) findings. Methods: A total of 245 patients with probable AD were classified into the typical AD (TAD) subtype, limbic-predominant (LP) subtype, hippocampal-sparing (HS) subtype, and minimal-change (MC) subtype, based on the presence of medial …temporal lobe atrophy on MRI and posterior cerebral hypoperfusion on SPECT. Demographics, including age, sex, body mass index, disease duration, education years, comorbidities, frailty, leisure activity, and neuropsychological findings were compared between the AD subtypes. Results: he frequency of TAD, LP, HS, and MC subtypes was 49%, 20%, 18%, and 13%, respectively. Patients with the LP subtype were older and characterized by fewer major comorbidities, higher frailty, and slower progression of disease. Patients with the HS subtype were younger and characterized by shorter disease duration, lower frailty, and preserved memory, but had prominent constructional dysfunction. Patients of the MC subtype were characterized by shorter disease duration, lower education level, less leisure activity, less impaired memory and orientation, and slower progression. Conclusion: Patients with different AD subtypes differed in their demographic and clinical features. The characterization of patients’ AD subtypes may provide effective support for the diagnosis, treatment, and care of AD patients. Show more

Keywords: Alzheimer’s disease, atrophy, hypoperfusion, magnetic resonance imaging, neuropsychology, single-photon emission computed tomography

DOI: 10.3233/JAD-215674

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 781-789, 2022

Authors: Grangeon, Lou | Paquet, Claire | Guey, Stéphanie | Zarea, Aline | Martinaud, Olivier | Rotharmel, Maud | Maltête, David | Quillard-Muraine, Muriel | Nicolas, Gael | Charbonnier, Camille | Chabriat, Hugues | Wallon, David

Article Type: Research Article

Abstract: Background: There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). Objective: To describe the CSF levels of Aβ42 , Aβ40 , total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. Methods: We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD …biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman’s correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. Results: We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aβ42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aβ42 level and 14.3% patients with normal Aβ42 level. Compared to AD, CAA showed lower levels of Tau (p  = 0.008), p-Tau (p  = 0.004), and Aβ40 (p  = 0.001) but similar Aβ42 level (p  = 0.07). No correlation between Aβ42 or Aβ40 levels and neuroimaging was found. Conclusion: CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aβ40 appears as an interesting selective biomarker in differential diagnosis. Show more

Keywords: Aβ42, Aβ40, cerebral amyloid angiopathy, cerebrospinal fluid biomarker, intracerebral hemorrhage

DOI: 10.3233/JAD-215208

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 791-802, 2022

Authors: Charidimou, Andreas

Article Type: Article Commentary

Abstract: An accurate diagnosis of sporadic cerebral amyloid angiopathy (CAA) is critical for patient management and research (including clinical trials) for this common small vessel pathology of the brain. While the “big bang” of the CAA field has been the device and wide adoption of the clinico-radiological Boston criteria which allowed for CAA diagnosis during life, these criteria are not without major shortcoming. As it is now becoming evident that CAA is probably not a single disease, but rather represents divergent pathophysiological phenotypes and clinical trajectories, new biomarker-driven diagnostic approaches should be sought. One such complimentary approach for CAA diagnosis is …the use of cerebrospinal fluid biomarkers (CSF), which could provide dynamic measures of the underlying disease process and is discussed in this commentary given exciting new advances. A hint on how the practicing clinician could apply the current CSF data for CAA diagnosis is also provided. Show more

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

DOI: 10.3233/JAD-220133

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 803-805, 2022

Authors: Abdulrahman, Herrer | Smedinga, Marthe | Verbeek, Marcel M. | Klijn, Catharina J.M. | Richard, Edo | Perry, Marieke

Article Type: Research Article

Abstract: Background: Sporadic cerebral amyloid angiopathy (sCAA) research of the past decade has increasingly focused on developing biomarkers that allow for an earlier and more accurate sCAA-diagnosis. Considering that sCAA does not have treatment options available (yet), more fundamental questions concerning the desirability of using such early-sCAA biomarkers in clinical practice need to be addressed. Objective: In this qualitative interview study, we aim to explore the views of vascular neurologists on the purpose and possible consequences of an earlier and more accurate sCAA-diagnosis, using new biomarkers. Methods: Vascular neurologists from around the world were approached via email …and interviewed via video call. Topics included views on current sCAA diagnostic practice, considerations on the use of new biomarkers, and expectations and hopes for the future. All interviews were transcribed ad verbatim using a transcription program (Otter.ai). Transcripts were analyzed using inductive content analysis. Results: We interviewed 14 vascular neurologists. Views regarding the desirability of new sCAA-biomarkers differed substantially between interviewees as to when and in whom these biomarkers could be of benefit in clinical practice. These differences were mainly reported with regards to prognosis, risk stratification, and biological precision, between general stroke neurologists and neurologists with specific sCAA-expertise. Conclusion: Views on the use of sCAA-biomarkers in clinical practice differ substantially between vascular neurologists. There is particularly no consensus regarding when, and in whom sCAA biomarkers could be useful in clinical practice. Show more

Keywords: Biomarkers, early diagnostics, ethics, interview study, sporadic cerebral amyloid angiopathy

DOI: 10.3233/JAD-220052

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 807-816, 2022

Authors: García-Pretelt, Francisco Javier | Suárez-Relevo, Jazmín Ximena | Aguillon-Niño, David Fernando | Lopera-Restrepo, Francisco Javier | Ochoa-Gómez, John Fredy | Tobón-Quintero, Carlos Andrés

Article Type: Research Article

Abstract: Background: The study of genetic variant carriers provides an opportunity to identify neurophysiological changes in preclinical stages. Electroencephalography (EEG) is a low-cost and minimally invasive technique which, together with machine learning, provide the possibility to construct systems that classify subjects that might develop Alzheimer’s disease (AD). Objective: The aim of this paper is to evaluate the capacity of the machine learning techniques to classify healthy Non-Carriers (NonCr) from Asymptomatic Carriers (ACr) of PSEN1 -E280A variant for autosomal dominant Alzheimer’s disease (ADAD), using spectral features from EEG channels and brain-related independent components (ICs) obtained using independent component analysis (ICA). …Methods: EEG was recorded in 27 ACr and 33 NonCr. Statistical significance analysis was applied to spectral information from channels and group ICA (gICA), standardized low-resolution tomography (sLORETA) analysis was applied over the IC as well. Strategies for feature selection and classification like Chi-square, mutual informationm and support vector machines (SVM) were evaluated over the dataset. Results: A test accuracy up to 83% was obtained by implementing a SVM with spectral features derived from gICA. The main findings are related to theta and beta rhythms, generated in the parietal and occipital regions, like the precuneus and superior parietal lobule. Conclusion: Promising models for classification of preclinical AD due to PSEN-1 -E280A variant can be trained using spectral features, and the importance of the beta band and precuneus region is highlighted in asymptomatic stages, opening up the possibility of its use as a screening methodology. Show more

Keywords: Alzheimer’s disease, electroencephalography, independent component analysis, machine learning, PSEN1-E280A, spectral analysis

DOI: 10.3233/JAD-210148

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 817-832, 2022

Authors: Mansfield, Elise | Cameron, Emilie | Carey, Mariko | Boyes, Allison | Nair, Balakrishnan | Hall, Alix | Sanson-Fisher, Rob

Article Type: Research Article

Abstract: Background: Accurately identifying the unmet needs of community-dwelling people with dementia allows targeted support to be provided to assist these individuals to stay at home. Objective: We developed a self-report instrument to identify the unmet needs of community-dwelling people with dementia and used this to explore the prevalence and type of unmet needs present in this population. Methods: This was a cross-sectional survey of people with dementia living in the community in Australia. Participants were recruited from geriatric clinics, respite centers, aged care providers, and carers attending support groups. Eligible people with dementia were provided with …a study information pack and survey which included the self-report Unmet Needs Instrument for Dementia (UNI-D), sociodemographic characteristics and survey acceptability. Results: The UNI-D contained 26 items across 5 domains and demonstrated acceptable internal consistency, face and construct validity, and acceptability. Ninety-five eligible participants completed the survey (response rate 35%) with 85% identifying at least one unmet need (median = 4; IQR = 1–9). The items most frequently endorsed included needing more help with remembering things (64%), finding possible treatments for dementia (44%), understanding who to contact regarding a problem or concern related to dementia (36%), and to see friends and family more often (33%). Conclusion: The UNI-D is a promising tool to identify the self-reported needs of people with dementia. The development and rigorous testing of interventions targeting unmet needs related to health and wellbeing, dementia support, and meaningful activities appears warranted. Show more

Keywords: Alzheimer’s disease, dementia, measurement, unmet needs, validity

DOI: 10.3233/JAD-215183

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 833-842, 2022

Authors: Zhang, Rui | Jiang, Lei | Li, Guofeng | Wu, JingJing | Tian, Pei | Zhang, Di | Qin, Yushi | Shi, Zhongli | Gao, ZhaoYu | Zhang, Nan | Wang, Shuang | Zhou, Huimin | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: miR-34c has been found to be implicated in the pathological process of Alzheimer’s disease, diabetes, and its complications. Objective: To investigate the underlying mechanisms of miR-34c in the pathogenesis of diabetic encephalopathy (DE). Methods: Diabetes mellitus rats were developed by incorporating a high-fat diet and streptozotocin injection. Morris water maze test and novel object recognition test were used to assess the cognitive function of rats. Expression of miR-34c were detected by fluorescence in situ hybridization and qRT-PCR. Immunofluorescence and western blot were used to evaluate synaptotagmin 1 (SYT1) and AdipoR2 or other proteins. Golgi staining …was performed to investigate dendritic spine density. Results: The increased miR-34c induced by advanced glycation end-products (AGEs) was mediated by ROS-JNK-p53 pathway, but not ROS-Rb-E2F1 pathway, in hippocampus of DE rats or in HT-22 cells. miR-34c negatively regulated the expression of SYT1, but not AdipoR2, in hippocampal neurons. miR-34c inhibitor rescued the AGE-induced decrease in the density of dendritic spines in primary hippocampal neurons. Administration of AM34c by the intranasal delivery increased the hippocampus levels of SYT1 and ameliorated the cognitive function in DE rats. The serum levels of miR-34c were increased in patients with DE comparing with normal controls. Conclusion: These results demonstrated that AGE-induced oxidative stress mediated increase of miR-34c through ROS-JNK-p53 pathway, resulting in synaptic deficits and cognitive decline by targeting SYT1 in DE, and the miR-34c/SYT1 axis could be considered as a novel therapeutic target for DE patients. Show more

Keywords: Advanced glycation end products, diabetic encephalopathy, miRNA, P53 protein, synaptic deficits, synaptotagmin 1

DOI: 10.3233/JAD-215589

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 843-861, 2022

Authors: Ueno, Mariko | Yoshino, Yuta | Mori, Hiroaki | Funahashi, Yu | Kumon, Hiroshi | Ochi, Shinichiro | Ozaki, Tomoki | Tachibana, Ayumi | Yoshida, Taku | Shimizu, Hideaki | Mori, Takaaki | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. Objective: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. Methods: A blood expression study (45 AD subjects, 54 controls) in which total …RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2* 2 frequency and the risk of LOAD. Results: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p  = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2* 2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02–1.85; p  = 0.0348, I2  = 81.1%). Conclusion: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2* 2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population. Show more

Keywords: ALDH2, Alzheimer’s disease, gene expression, rs671, meta-analysis

DOI: 10.3233/JAD-215627

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 863-871, 2022