Journal of Alzheimer's Disease - Volume 89, issue 1

Authors: Liu, Qianqian | Liu, Hui | Zhang, Sizhe | Yang, Qijie | Shen, Lu | Jiao, Bin

Article Type: Research Article

Abstract: Background: Several studies have shown increased levels of cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) in patients with Alzheimer’s disease (AD). However, results have been inconsistent thus far. Objective: We conducted meta-analyses summarizing the associations of CSF SNAP-25 levels with AD to assess the utility of SNAP-25 as a novel biomarker for AD. Methods: We conducted a meta-analysis of differences in CSF SNAP-25 levels in patients with AD or mild cognitive impairment (MCI) and in cognitively healthy controls (HC). We calculated pooled correlation coefficients comparing SNAP-25 levels and total tau (T-tau) or hyperphosphorylated tau (P-tau) in …CSF. Results: Eight studies enrolling 1,162 individuals (423 AD, 275 MCI, 464 HC) were included for quantitative analysis. Patients with AD (ratio of means [RoM] = 1.50, 95% confidence interval [CI]: 1.30,1.74) and MCI (RoM = 1.45, 95% CI: 1.12,1.87) had increased levels of CSF SNAP-25 as compared to HC. The difference in CSF SNAP-25 levels when comparing AD and MCI (RoM = 1.05, 95% CI: 0.96,1.14) was not statistically significant but showed a trend toward significance. Statistically significant correlations were found when comparing CSF SNAP-25 with CSF T-tau (Spearman correlation coefficient, ρ =0.78; ρ =0.66; ρ =0.69, respectively) and P-tau (ρ =0.77; ρ =0.70; ρ =0.62, respectively) levels in patients with AD, MCI, and HC. Conclusion: Increased CSF SNAP-25 levels differentiated patients with AD or MCI from controls, suggesting the utility of this biomarker in the early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, CSF biomarkers, meta-analysis, mild cognitive impairment, synaptosomal-associated protein 25

DOI: 10.3233/JAD-215696

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 121-132, 2022

Authors: Pezzoli, Stefania | Manca, Riccardo | Cagnin, Annachiara | Venneri, Annalena

Article Type: Research Article

Abstract: Background: Hallucinations in Alzheimer’s disease (AD) have been linked to more severe cognitive and functional decline. However, research on visual hallucinations (VH), the most common type of hallucinations in AD, is limited. Objective: To investigate the cognitive and cerebral macrostructural and metabolic features associated with VH in AD. Methods: Twenty-four AD patients with VH, 24 with no VH (NVH), and 24 cognitively normal (CN) matched controls were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Differences in regional gray matter (GM) volumes and cognitive performance were investigated with whole brain voxel-based morphometry analyses of MRI …structural brain scans, and analyses of neuropsychological tests. Glucose metabolic changes were explored in a sub-sample of patients who had FDG-PET scans available. Results: More severe visuoconstructive and attentional deficits were found in AD VH compared with NVH. GM atrophy and hypometabolism were detected in occipital and temporal areas in VH patients in comparison with CN. On the other hand, NVH patients had atrophy and hypometabolism mainly in temporal areas. No differences in GM volume and glucose metabolism were found in the direct comparison between AD VH and NVH. Conclusion: In addition to the pattern of brain abnormalities typical of AD, occipital alterations were observed in patients with VH compared with CN. More severe visuoconstructive and attentional deficits were found in AD VH when directly compared with NVH, and might contribute to the emergence of VH in AD. Show more

Keywords: Alzheimer’s disease, attention, FDG-PET, MRI, neuropsychology, visual hallucinations, visuoconstruction

DOI: 10.3233/JAD-215107

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 133-149, 2022

Authors: Wezeman, Sandra L. | Uleman, Jeroen F. | Scarmeas, Nikolaos | Kosmidis, Mary H. | Dardiotis, Efthimios | Peeters, G.M.E.E. (Geeske) | Olde Rikkert, Marcel G.M.

Article Type: Research Article

Abstract: Background: Recent global meta-analyses show that 40% of dementia cases can be attributed to twelve modifiable risk factors. Objective: To investigate how health promotion strategies may differ in specific populations, this study estimated population attributable fractions (PAFs) of these risk factors for dementia in cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) in United States and Greek cohorts. Methods: We re-analyzed data from the National Alzheimer’s Coordinating Centre (NACC, n  = 16,147, mean age 75.2±6.9 years, 59.0% female) and the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD, n  = 1,141, mean age 72.9±5.0 years, …58.0% female). PAFs for the total samples and CN and MCI subgroups were calculated based on hazard ratios for the risk of dementia and risk factor prevalence in NACC (9 risk factors) and HELIAD (10 risk factors). Results: In NACC, 2,630 participants developed MCI (25.1%) and 3,333 developed dementia (20.7%) during a mean follow-up of 4.9±3.5 years. Weighted overall PAFs were 19.4% in the total sample, 15.9% in the CN subgroup, and 3.3% in the MCI subgroup. In HELIAD, 131 participants developed MCI (11.2%) and 68 developed dementia (5.9%) during an average follow-up of 3.1±0.86 years. Weighted overall PAFs were 65.5% in the total sample, 65.8% in the CN subgroup and 64.6% in the MCI subgroup. Conclusion: Translation of global meta-analysis data on modifiable risk factors should be carefully carried out per population. The PAFs of risk factors differ substantially across populations, directing health policy making to tailored risk factor modification plans. Show more

Keywords: Dementia, mild cognitive impairment, prevention, risk factors

DOI: 10.3233/JAD-215386

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 151-162, 2022

Authors: Fan, Yaohua | Liu, Wen | Chen, Si | Li, Mengzhu | Zhao, Lijun | Wu, Chunxiao | Liu, Helu | Zhu, Meiling

Article Type: Research Article

Abstract: Background: The relationship between serum folate status and cognitive functions is still controversial. Objective: To evaluate the association between serum tetrahydrofolate and cognitive functions. Methods: A total of 3,132 participants (60–80 years old) from the 2011–2014 NHANES were included in this cross-sectional study. The primary outcome measure was cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), …and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions. Results: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p  < 0.05). In GAM, the inflection points were 1.1, 2.8, and 2.8 nmol/L tetrahydrofolate, determined by a two-piece wise linear regression model of AF, DSST, and global cognitive score, respectively. Also, in GAM, there were no non-linear relationship between serum tetrahydrofolate and low cognitive functions, as determined by CERAD-WL or CERAD-DR. The results of subgroup analyses found that serum tetrahydrofolate levels and reduced cognitive functions as determined by AF had significant interactions for age and body mass index. The association between high serum tetrahydrofolate level and reduced cognitive functions as determined using DSST, CERAD-WL, CERAD-DR, or global cognitive score had no interaction with the associations between cognition and gender, or age, or so on. Conclusion: High serum tetrahydrofolate level is associated with significantly reduced cognitive function. Show more

Keywords: Analysis of non-linear relationship, cognitive functions, dementia, multiple logistic regression, NHANES, serum tetrahydrofolate

DOI: 10.3233/JAD-220058

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 163-179, 2022

Authors: Miotto, Eliane Correa | Brucki, Sonia Maria Dozzi | Cerqueira, Carlos T. | Bazán, Paulo R. | Silva, Geise Aline de Almeida | Martin, Maria da Graça M. | da Silveira, Paula Squarzoni | Faria, Daniele de Paula | Coutinho, Artur Martins | Buchpiguel, Carlos Alberto | Busatto Filho, Geraldo | Nitrini, Ricardo

Article Type: Research Article

Abstract: Background: Previous studies of hippocampal function and volume related to episodic memory deficits in patients with amnestic mild cognitive impairment (aMCI) have produced mixed results including increased or decreased activity and volume. However, most of them have not included biomarkers, such as amyloid-β (Aβ) deposition which is the hallmark for early identification of the Alzheimer’s disease continuum. Objective: We investigated the role of Aβ deposition, functional hippocampal activity and structural volume in aMCI patients and healthy elderly controls (HC) using a new functional MRI (fMRI) ecological episodic memory task. Methods: Forty-six older adults were included, among …them Aβ PET PIB positive (PIB+) aMCI (N = 17), Aβ PET PIB negative (PIB–) aMCI (N = 15), and HC (N = 14). Hippocampal volume and function were analyzed using Freesurfer v6.0 and FSL for news headlines episodic memory fMRI task, and logistic regression for group classification in conjunction with episodic memory task and traditional neuropsychological tests. Results: The aMCI PIB+ and PIB–patients showed significantly worse performance in relation to HC in most traditional neuropsychological tests and within group difference only on story recall and the ecological episodic memory fMRI task delayed recall. The classification model reached a significant accuracy (78%) and the classification pattern characterizing the PIB+ included decreased left hippocampal function and volume, increased right hippocampal function and volume, and worse episodic memory performance differing from PIB–which showed increased left hippocampus volume. Conclusion: The main findings showed differential neural correlates, hippocampal volume and function during episodic memory in aMCI patients with the presence of Aβ deposition. Show more

Keywords: Amyloid-beta, episodic memory, functional magnetic resonance, hippocampal volume, mild cognitive impairment

DOI: 10.3233/JAD-220100

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 181-192, 2022

Authors: Timsina, Jigyasha | Gomez-Fonseca, Duber | Wang, Lihua | Do, Anh | Western, Dan | Alvarez, Ignacio | Aguilar, Miquel | Pastor, Pau | Henson, Rachel L. | Herries, Elizabeth | Xiong, Chengjie | Schindler, Suzanne E. | Fagan, Anne M. | Bateman, Randall J. | Farlow, Martin | Morris, John C. | Perrin, Richard J. | Moulder, Krista | Hassenstab, Jason | Vöglein, Jonathan | Chhatwal, Jasmeer | Mori, Hiroshi | Sung, Yun Ju | Cruchaga, Carlos

Article Type: Research Article

Abstract: Background: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. Objective: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer’s disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. Methods: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine …measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson’s correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. Results: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r  > 0.9). sTREM2 had a fair correlation (r  > 0.6), whereas SNAP-25 showed weak correlation (r  = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. Conclusion: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. Show more

Keywords: Alzheimer’s disease, assays, cerebrospinal fluid biomarkers, correlation, SOMAscan

DOI: 10.3233/JAD-220399

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 193-207, 2022

Authors: Drenthen, Gerhard S. | Backes, Walter H. | Freeze, Whitney M. | Jacobs, Heidi I.L. | Verheggen, Inge C.M. | van Boxtel, Martin P.J. | Hoff, Erik I. | Verhey, Frans R. | Jansen, Jacobus F.A.

Article Type: Research Article

Abstract: Background: Though mediotemporal lobe volume changes are well-known features of Alzheimer’s disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN). Objective: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club. Methods: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n  = 37; mild cognitive impairment, n  = 41; …Alzheimer-type dementia, n  = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression. Results: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume. Conclusion: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy. Show more

Keywords: Cognition, cortex, hub, magnetic resonance imaging, memory, network analysis

DOI: 10.3233/JAD-220175

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 209-217, 2022

Authors: Song, Cheng | Li, Feng | Wang, Liu-Yu | Shi, Yu-Quan | Shen, Zhen-Hai

Article Type: Research Article

Abstract: Background: National and international experts have been attempting to find diagnostic tools for the early identification of symptoms to facilitate early identification and intervention of the disease. Objective: Detection of urine Alzheimer-associated neuronal thread protein (AD7c-NTP) and serum 25-hydroxyvitamin D (25(OH)D) in the diagnosis of Alzheimer’s disease (AD). Methods: Subjects aged >50 years who underwent a physical examination at the Taihu Sanatorium of Jiangsu Province, had no clinical evidence of AD-related issues, and had normal Mini-Mental State Exam and Montreal Cognitive Assessment scores were enrolled in the present study. There were 35 males and 15 females, …who were aged 51–91 years. Urine AD7c-NTP levels and serum 25(OH)D concentrations were measured. Results: The Pearson correlation analysis revealed that the urine AD7c-NTP levels in these subjects were negatively correlated with the serum 25(OH)D concentrations (r  = –0.460, p  < 0.001). Conclusion: Combined with previous studies, it was considered that cognitive function might be the only link for the correlation between AD7c-NTP and 25(OH)D. This finding might provide a starting point to investigate the potential value of the interaction between urine AD7c-NTP and serum 25(OH)D in chronic diseases. Further large-scale studies are needed to validate the results of the present study. Show more

Keywords: AD7c-NTP, Alzheimer’s disease, correlation analysis, serum 25-hydroxyvitamin D, urine Alzheimer-associated neuronal thread protein

DOI: 10.3233/JAD-220165

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 219-222, 2022

Authors: Baradaran, Hediyeh | Peloso, Gina M. | Polak, Joseph F. | Killiany, Ronald J. | Ghosh, Saptaparni | DeCarli, Charles S. | Thibault, Emma G. | Sperling, Reisa A. | Johnson, Keith A. | Beiser, Alexa | Romero, Jose R. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. Objective: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11 C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. Methods: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on …average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer’s disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. Results: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p  = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p  = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. Conclusion: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology. Show more

Keywords: Alzheimer’s disease, amyloid, carotid atherosclerosis, carotid ultrasound

DOI: 10.3233/JAD-215679

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 223-232, 2022

Authors: Kamath, Vidyulata | Senjem, Matthew L. | Spychalla, Anthony J. | Chen, Honglei | Palta, Priya | Mosley, Thomas H. | Windham, B. Gwen | Griswold, Michael | Knopman, David S. | Gottesman, Rebecca F. | Jack Jr, Clifford R. | Sharrett, A. Richey | Schneider, Andrea L.C.

Article Type: Research Article

Abstract: Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor …identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume (p  < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD. Show more

Keywords: Alzheimer’s disease, chemosensory, hyposmia, olfaction, smell

DOI: 10.3233/JAD-220228

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 233-245, 2022