Journal of Alzheimer's Disease - Volume 91, issue 1

Authors: Rådestig, Maya Arvidsson | Skoog, Johan | Zetterberg, Henrik | Skillbäck, Tobias | Zettergren, Anna | Sterner, Therese Rydberg | Fässberg, Madeleine Mellqvist | Sacuiu, Simona | Waern, Margda | Wetterberg, Hanna | Blennow, Kaj | Skoog, Ingmar | Kern, Silke

Article Type: Research Article

Abstract: Background: Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. Objective: We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. Methods: The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid …β1 - 42 , total tau, and phosphorylated tau, were measured. Results: Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, p  = 0.013) and a language test (FAS, p  = 0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (p  = 0.035). When stratified according to CSF tau and Aβ42 concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, p  = 0.003). In participants with high NfL, those with pathologic Aβ42 concentrations performed worse on the Delayed recall memory (p  = 0.044). In the high Ng group, participants with pathological Aβ42 concentrations had lower MMSE scores (p  = 0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. Conclusion: Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds. Show more

Keywords: Biomarkers, cerebrospinal fluid, dementia, neurofilament protein, neurogranin

DOI: 10.3233/JAD-220452

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 291-303, 2023

Authors: Lukkarinen, Heikki | Vanninen, Aleksi | Tesseur, Ina | Pemberton, Darrel | Van Der Ark, Peter | Kokkola, Tarja | Herukka, Sanna-Kaisa | Rauramaa, Tuomas | Hiltunen, Mikko | Blennow, Kaj | Zetterberg, Henrik | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42 ), total tau (T-tau), and phosphorylated tau 181 (P-tau181 ) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. Objective: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. Methods: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples …of 41 patients were obtained 1–73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42 , T-tau, and P-tau181 were analyzed using commercial ELISA assays. Results: Preoperative L-CSF Aβ42 , T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ = 0.34–0.55, p  < 0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρ s Aβ42 : 0.77–0.88, T-tau: 0.91–0.94, P-tau181 : 0.94–0.96, p  < 0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ42 : V-CSF = 185+0.34*L-CSF, T-tau: Ln(V-CSF) = 3.11+0.49*Ln(L-CSF), P-tau181 : V-CSF = 8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ42 : V-CSF = 86.7+0.75*L-CSF, T-tau: V-CSF = 86.9+0.62*L-CSF, P-tau181 : V-CSF = 2.6+0.74*L-CSF). Conclusion: Aβ42 , T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted. Show more

Keywords: Aβ42, biomarkers, idiopathic normal pressure hydrocephalus, P-tau, T-tau

DOI: 10.3233/JAD-220652

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 305-319, 2023

Authors: Wagle, Jørgen | Selbæk, Geir | Benth, Jūratė Šaltytė | Gjøra, Linda | Rønqvist, Thale Kinne | Bekkhus-Wetterberg, Peter | Persson, Karin | Engedal, Knut

Article Type: Research Article

Abstract: Background: The CERAD Word List Memory Test (WLMT) is widely used in the assessment of older adults with suspected dementia. Although normative data of the WLMT exist in many different regions of the world, normative data based on large population-based cohorts from the Scandinavian countries are lacking. Objective: To develop normative data for the WLMT based on a large population-based Norwegian sample of healthy older adults aged 70 years and above, stratified by age, gender, and education. Methods: A total of 6,356 older adults from two population-based studies in Norway, HUNT4 70 + and HUNT4 Trondheim 70+, were …administered the WLMT. Only persons with normal cognitive function were included. We excluded persons with a diagnosis of mild cognitive impairment (MCI) and dementia, and persons with a history of stroke and/or depression. This resulted in 3,951 persons aged between 70 and 90 years, of whom 56.2% were females. Regression-based normative data were developed for this sample. Results: Age, gender, and education were significant predictors of performance on the WLMT list-learning subtests and the delayed recall subtest, i.e., participants of younger age, female sex, and higher education level attained higher scores compared to participants of older age, male sex, and lower level of education. Conclusion: Regression-based normative data from the WMLT, stratified by age, gender, and education from a large population-based Norwegian sample of cognitively healthy older adults aged 70 to 90 years are presented. An online norm calculator is available to facilitate scoring of the subtests (in percentiles and z-scores). Show more

Keywords: CERAD Word List Memory Test, cognition, memory, neuropsychological tests, normative data, older adults, population-based

DOI: 10.3233/JAD-220672

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 321-343, 2023

Authors: Kim, Jinhee | Jang, Hyemin | Park, Yu-hyun | Youn, Jinyoung | Seo, Sang Won | Kim, Hee Jin | Na, Duk L.

Article Type: Research Article

Abstract: Background: Age at onset was suggested as one possible risk factor for motor dysfunction in Alzheimer’s disease (AD). Objective: We investigated the association of motor symptoms with cognition or neurodegeneration in patients with AD, and whether this association differs by the age at onset. Methods: We included 113 amyloid positive AD patients and divided them into early-onset AD (EOAD) and late-onset AD (LOAD), who underwent the Unified Parkinson’s Disease Rating Scale (UPDRS)-Part III (=UPDRS) scoring, Mini-Mental State Examination (MMSE)/Clinical Deterioration Rating Sum-of-Boxes (CDR-SOB), and magnetic resonance image (MRI). Multiple linear regression was used to evaluate the …association of UPDRS and MMSE/CDR-SOB or MRI neurodegeneration measures, and whether the association differs according to the group. Results: The prevalence of motor symptoms and their severity did not differ between the groups. Lower MMSE (β= –1.1, p  < 0.001) and higher CDR-SOB (β= 2.0, p  < 0.001) were significantly associated with higher UPDRS. There was no interaction effect between MMSE/CDR-SOB and AD group on UPDRS. Global or all regional cortical thickness and putaminal volume were negatively associated with UPDRS score, but the interaction effect of neurodegeneration and AD group on UPDRS score was significant only in parietal lobe (p for interaction = 0.035), which showed EOAD to have a more pronounced association between parietal thinning and motor symptoms. Conclusion: Our study suggested that the severity of motor deterioration in AD is related to the severity of cognitive impairment itself rather than age at onset, and motor symptoms might occur through multiple mechanisms including cortical and subcortical atrophy. Show more

Keywords: Alzheimer’s disease, neuropsychological tests, parkinsonian disorders

DOI: 10.3233/JAD-220745

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 345-354, 2023

Authors: Swerdlow, Neal R. | Joshi, Yash B. | Sprock, Joyce | Talledo, Jo | Molina, Juan L. | Delano-Wood, Lisa | Iwanaga, Dylan | Kotz, Juliana E. | Huege, Steven | Léger, Gabriel C. | Light, Gregory A.

Article Type: Research Article

Abstract: Background: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer’s disease (AD); conceivably, its acute impact on PPI might be used to predict a patient’s sensitivity to MEM’s therapeutic effects. Objective: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. Methods: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. Results: Fifteen out of 18 participants …exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p  < 0.04; d  = 0.40); this comparison reached a large effect size for the 60 ms interval (d  = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency (“latency facilitation”) and this effect was amplified after MEM (p  = 0.03; d  = 0.41; for 60 ms intervals, d  = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. Conclusion: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient’s neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a “biomarker” measured at the outset on treatment can predict sensitivity to MEM’s therapeutic effects. Show more

Keywords: Alzheimer’s disease, memantine, neurocognition, prepulse inhibition

DOI: 10.3233/JAD-220769

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 355-362, 2023

Authors: Abbate, Carlo | Trimarchi, Pietro D. | Fumagalli, Giorgio G. | Gallucci, Alessia | Tomasini, Emanuele | Fracchia, Stefania | Rebecchi, Isabella | Morello, Elisabetta | Fontanella, Anna | Parisi, Paola M.R. | Tartarone, Federica | Giunco, Fabrizio | Ciccone, Simona | Nicolini, Paola | Lucchi, Tiziano | Arosio, Beatrice | Inglese, Silvia | Rossi, Paolo D.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. Objective: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. Methods: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. …Results: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p  < 0.001), temporal disorientation (p  < 0.02), misidentification (p  = 0.013), other delusions (p  = 0.002), and logorrhea (p  = 0.004) than the CA-ADs. In addition, more social disinhibition (p  = 0.018), reduction of insight (p  = 0.029), and hallucination (p  = 0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. Conclusion: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia. Show more

Keywords: Alzheimer’s disease, amnesia, confabulation, delusions, memory rehabilitation, misidentification, presbyophrenia

DOI: 10.3233/JAD-220919

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 363-388, 2023

Authors: Maćkowiak, Maria | Libura, Agnieszka | Phillipson, Lyn | Szcześniak, Dorota | Rymaszewska, Joanna

Article Type: Research Article

Abstract: Background: With the increasing incidences of dementia in aging societies, attention should be paid to the social context in which people with dementia live. One of its aspects is language transmitting beliefs, perceptions, and behavioral patterns. An analysis of understanding the diagnostic label of dementia may reveal the role of semantics in the process of social cognition of this disease. Objective: The overall aim of this study was to investigate the understanding of the word dementia (otępienie ) in the Polish language. Methods: Frame semantics approach was applied. The structure of semantic information was uncovered with …the concept of frame utilizing The National Corpus of Polish (the biggest corpus of contemporary Polish language of 1,500 million words). Additional data was collected from Polish speaking adults in Poland. Results: The analyses allowed to identify the otępienie frame for Polish and verify how its elements are filled in by the general population, indicating the selectivity of colloquial knowledge about dementia. Dementia deviates from the prototypical disease. Need to care for the person with dementia outweighs treatment options. The cognitive symptoms and characteristics of the subject are salient. The perceptions of people with dementia embedded in semantics of the diagnostic label might create a basis for prejudicial attitudes among lay part of the society. Conclusion: Findings give foundation to further studies on relationship between semantics and social cognition of dementia which has a real impact on the social and clinical situation of people with dementia and may facilitate formulation of tailored messages aimed at building dementia-friendly society. Show more

Keywords: Dementia, language, semantics, social cognition, social stigma

DOI: 10.3233/JAD-220633

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 389-406, 2023

Authors: Hu, Li-Tian | Xie, Xiao-Yong | Zhou, Gui-Feng | Wen, Qi-Xin | Song, Li | Luo, Biao | Deng, Xiao-Juan | Pan, Qiu-Ling | Chen, Guo-Jun

Article Type: Research Article

Abstract: Background: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer’s disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. Objective: The present study was to investigate the role of HMGCS2 in Tau/p degradation. Methods: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II …were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. Results: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. Conclusion: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role. Show more

Keywords: Alzheimer’s disease, ANKRD24, autophagy, HMGCS2, ketone body, Tau

DOI: 10.3233/JAD-220640

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 407-426, 2023

Authors: Königsberg, Alina | Belau, Matthias H. | Ascone, Leonie | Gallinat, Jürgen | Kühn, Simone | Jensen, Märit | Gerloff, Christian | Cheng, Bastian | Thomalla, Götz

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered to be a preliminary stage of dementia, and its prevalence is increasing with age. Objective: We aimed to study the association of SCD with health-related quality of life (HRQoL) in a large population-based sample. Methods: We analyzed data of the first 10,000 participants from the Hamburg City Health Study in Germany, a single center prospective cohort study, aged between 45 and 74 years that scored higher than 25 points in the Mini-Mental State Examination and had no known pre-existing dementia. HRQoL was assessed by the EQ-5D-5 L index, as well …as the mental (MCS) and physical component summary (PCS) score of the Short Form-8. We computed linear regression analyses with 99% bias-corrected and accelerated (BCa) confidence intervals (CI) from 10,000 bootstrap samples to investigate the association between SCD and different indicators of HRQoL, while controlling for depression (PHQ-9), age, sex, and education as potential confounders. Results: Of 7,799 eligible participants (mean (SD) age 62.01 (8.41) years, 51.1% female), 3,708 (47.5%) reported SCD. Participants with SCD were older (62.7 versus 61.4 years) and more frequently female (54.2% versus 48.2%). SCD was independently associated with a lower EQ-5D-5 L index (β=–0.01, 99% BCa CI = [–0.020, –0.003], p  < 0.001) and PCS (β=–1.00, 99% BCa CI = [–1.48, –0.51], p  < 0.001) but not with MCS score. Conclusion: In a population of middle-aged to elderly participants, there is a significant negative association between SCD and HRQoL across different instruments of HRQoL measurement independent of depression, demographics, and education. Show more

Keywords: Health-related quality of life, population-based study, prospective study, subjective cognitive decline

DOI: 10.3233/JAD-220659

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 427-436, 2023

Authors: Wu, Bang-Sheng | Zhang, Ya-Ru | Yang, Liu | Zhang, Wei | Deng, Yue-Ting | Chen, Shi-Dong | Feng, Jian-Feng | Cheng, Wei | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes. Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases. Methods: We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD …diagnosis from the UK Biobank. Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95% CI [1.34, 1.45], p  = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95% CI [1.13, 1.24], p  = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR < 0.05). Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations. Show more

Keywords: Alzheimer’s disease, genetic pleiotropy, PheWAS, polygenic risk score

DOI: 10.3233/JAD-220740

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 437-447, 2023