Journal of Alzheimer's Disease - Volume 83, issue 3

Authors: Lazarova, Maria I. | Tsekova, Daniela S. | Tancheva, Lyubka P. | Kirilov, Kiril T. | Uzunova, Diamara N. | Vezenkov, Lyubomir T. | Tsvetanova, Elina R. | Alexandrova, Albena V. | Georgieva, Almira P. | Gavrilova, Petja T. | Dragomanova, Stela T. | Papazova, Maria G. | Handzhiyski, Yordan S. | Kalfin, Reni E.

Article Type: Research Article

Abstract: Background: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer’s disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). Objective: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. Methods: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance …was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. Results: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. Conclusion: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention. Show more

Keywords: Acetylcholine esterase, galantamine derivatives, inhibition, peptide

DOI: 10.3233/JAD-210577

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1211-1220, 2021

Authors: Matsuoka, Teruyuki | Ueno, Daisuke | Ismail, Zahinoor | Rubinstein, Ellen | Uchida, Hiroyuki | Mimura, Masaru | Narumoto, Jin

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated. Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging. Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between …MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p- value of 0.05, with false discovery rate correction, was considered significant. Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score. Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship. Show more

Keywords: Default mode network, fronto-parietal control network, functional magnetic resonance imaging, mild behavioral impairment, salience network

DOI: 10.3233/JAD-210628

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1221-1231, 2021

Authors: Esteban de Antonio, Ester | Pérez-Cordón, Alba | Gil, Silvia | Orellana, Adelina | Cano, Amanda | Alegret, Montserrat | Espinosa, Ana | Alarcón-Martín, Emilio | Valero, Sergi | Martínez, Joan | de Rojas, Itziar | Sotolongo-Grau, Óscar | Martín, Elvira | Vivas, Assumpta | Gomez-Chiari, Marta | Tejero, Miguel Ángel | Bernuz, Mireia | Tárraga, Lluis | Ruiz, Agustín | Marquié, Marta | Boada, Mercè | The BIOFACE study group

Collaborators: Abdelnour, Carla | Aguilera, Nuria | Alonso-Lana, Silvia | Calvet, Anna | Cañabate, Pilar | Cañada, Laia | Castillón, María José | Hernández, Isabel | López-Cuevas, Rogelio | Mauleón, Ana | Montrreal, Laura | Moreno, Mariola | Nogales, Ana Belén | Ortega, Gemma | Preckler, Silvia | Ramis, María Isabel | Roberto, Natalia | Rosende-Roca, Maitee | Sanabria, Ángela | Tartari, Juan Pablo | Vargas, Liliana

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the …different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, early onset Alzheimer’s disease, exosomes, mild cognitive impairment, presenile, proteomics

DOI: 10.3233/JAD-210254

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1233-1249, 2021

Authors: Schenning, Katie J. | Holden, Sarah | Davis, Brett A. | Mulford, Amelia | Nevonen, Kimberly A. | Quinn, Joseph F. | Raber, Jacob | Carbone, Lucia | Alkayed, Nabil J.

Article Type: Research Article

Abstract: Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4 , compared to APOE3 , and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 …or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer’s disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning. Show more

Keywords: Alzheimer’s disease, anesthesia, apolipoprotein E4, behavior, DNA methylation, ephrins, epigenomics, hippocampus, postoperative cognitive complications, surgery

DOI: 10.3233/JAD-210499

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1251-1268, 2021

Authors: Najar, Jenna | Aakre, Jeremiah A. | Vassilaki, Maria | Wetterberg, Hanna | Rydén, Lina | Zettergren, Anna | Skoog, Ingmar | Jack Jr, Clifford R. | Knopman, David S. | Petersen, Ronald C. | Kern, Silke | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: The modifying effect of sex on the relation between marital status and dementia has yet to be determined. Objective: To examine if sex modifies the association between marital status and incident dementia. Methods: Population-based samples from the Mayo Clinic Study of Aging (MCSA, N = 3,471) and the Gothenburg H70 Birth Cohort Study (H70-study, N = 913) were used. A multiplicative interaction term was used to analyze the modifying effect of sex on the relation between marital status (married versus not married) and incident dementia using Cox regression models. Further, risk of dementia by marital status was also evaluated …in models separated by sex. Results: In the MCSA, there was an interaction between marital status and sex in relation to dementia (p  = 0.015). In contrast, in the H70-study, no significant interaction was observed (p  = 0.28). Nevertheless, in both studies, not married men had increased risk of dementia compared to married men in models adjusted for age, education, and number of children (H70-study: 1.99; 1.06–3.76, MCSA: 1.43; 1.08–1.89). Associations remained similar after additional adjustment for depression, BMI, hypertension, dyslipidemia, and diabetes mellitus (H70-study: 2.00; 1.05–3.82, MCSA: 1.32; 0.99–1.76). Further, no significant association was observed between marital status and dementia in women (H70-study: 1.24; 0.82–1.89, MCSA: 0.82; 0.64–1.04). Conclusion: Sex had a modifying effect on the association between marital status and incident dementia. In analyses separated by sex, not married men had an increased risk of dementia compared to married men, while no significant association was observed between marital status and risk of dementia in women. Show more

Keywords: Dementia, epidemiology, marital status, risk factors, sex differences

DOI: 10.3233/JAD-210246

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1269-1279, 2021

Authors: Yang, Hyun Ju | Lee, Subin | Koh, Myeong Ju | Lee, Ho Kyu | Kim, Bong Soo | Kim, Ki Woong | Park, Joon Hyuk

Article Type: Research Article

Abstract: Background: Frailty, one of serious global health problems in the elderly, is a growing concern in patients with Alzheimer’s disease (AD) because of its high prevalence in AD and its impact on the prognosis. Objective: To investigate the quantitative association between white matter hyperintensities (WMH) and frailty in AD. Methods: A total of 144 outpatients were included. All subjects were evaluated by using Korean version of the CERAD assessment battery and diagnosed very mild to moderate AD. WMH volume was calculated using automated segmentation analysis from the 3D MRI image and further partitioned according to the …distance from the ventricular surface. Using the Korean Frailty Index, prefrailty was defined by the scores of 3 and 4 and frailty by the score of 5 and higher. Results: In total, 23.6%were frailty, 32.6%were pre-frailty, and 43.8%were classified as a robust group. The frailty group had higher WMH volume compared to the robust group (p  = 0.02), and these trends remained significant after linear regression analyses. According to the subclassification of WMH, using the robust group as a reference, total WMH (OR = 6.297, p  = 0.013, 95%CI = 1.463–27.114), juxtaventricular WMH (OR = 12.955, p  = 0.014, 95%CI = 1.687–99.509), and periventricular WMH (OR = 3.382, p  = 0.025, 95%CI = 1.163–9.8531) volumes were associated with frailty, but deep WMH volume was not. Conclusions: A quarter of patients with very mild to moderate AD is suffering from frailty. Our study provides the evidence of a cross-sectional relationship between WMH volume and frailty, and there is a difference in the association between the subclassification of WMH volume and frailty. Show more

Keywords: Alzheimer’s disease, frailty, magnetic resonance imaging, white matter hyperintensities

DOI: 10.3233/JAD-210494

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1281-1289, 2021

Authors: Tofiq, Avin | Zetterberg, Henrik | Blennow, Kaj | Basun, Hans | Cederholm, Tommy | Eriksdotter, Maria | Faxén-Irving, Gerd | Hjorth, Erik | Jernerén, Fredrik | Schultzberg, Marianne | Wahlund, Lars-Olof | Palmblad, Jan | Freund-Levi, Yvonne

Article Type: Research Article

Abstract: Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer’s disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). Methods: Thirty-three patients diagnosed with …AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score. Show more

Keywords: Chitinase-3-like protein 1, dementia, inflammation, mini-mental state examination, neurodegeneration, neurofilament light, YKL-40

DOI: 10.3233/JAD-210007

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1291-1301, 2021

Authors: Barthold, Douglas | Gibbons, Laura E. | Marcum, Zachary A. | Gray, Shelly L. | Dirk Keene, C. | Grabowski, Thomas J. | Postupna, Nadia | Larson, Eric B. | Crane, Paul K.

Article Type: Research Article

Abstract: Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD …score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ1–42 . Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ1–42 , but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD. Show more

Keywords: Alzheimer’s disease, dementia, diabetes treatments, neuropathology

DOI: 10.3233/JAD-210059

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1303-1312, 2021

Authors: Sorrentino, Federica | Arighi, Andrea | Serpente, Maria | Arosio, Beatrice | Arcaro, Marina | Visconte, Caterina | Rotondo, Emanuela | Vimercati, Roberto | Ferri, Evelyn | Fumagalli, Giorgio G. | Pietroboni, Anna M. | Carandini, Tiziana | Scarpini, Elio | Fenoglio, Chiara | Galimberti, Daniela

Article Type: Research Article

Abstract: Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2 ) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1–42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1 , NPC2 , and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) …low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p  > 0.05). Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population. Show more

Keywords: Amyloid, cerebrospinal fluid, NPC1, NPC2, Niemann-Pick Type C, psychiatric onset, variability

DOI: 10.3233/JAD-210453

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1313-1323, 2021

Authors: Rostalski, Hannah | Korhonen, Ville | Kuulasmaa, Teemu | Solje, Eino | Krüger, Johanna | Gen, Finn | Kaivola, Karri | Eide, Per Kristian | Lambert, Jean-Charles | Julkunen, Valtteri | Tienari, Pentti J. | Remes, Anne M. | Leinonen, Ville | Hiltunen, Mikko | Haapasalo, Annakaisa

Article Type: Research Article

Abstract: Background: C9orf72 repeat expansion (C9exp ) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exp requires elaborative methods. Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp . Methods: We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal …pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15–30) and full-length (> 60 repeats) C9exp carriers (n  = 41) to C9exp negative patients (< 15 repeats, n  = 801). Results: In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p  < 2×10–15 ), while the strongest association was found with rs139185008 (OR 39.4, p  < 5×10–18 ). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3×10–15 ) and motor neuron disease ALS (OR 5.19, 3×10–21 ). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p  = 9.0×10–8 ). Conclusion: Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland. Show more

Keywords: Amyotrophic lateral sclerosis, C9orf72, DNA repeat expansion, frontotemporal lobar degeneration, motor neuron disease, polymorphism, single nucleotide

DOI: 10.3233/JAD-210599

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1325-1332, 2021