Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Grober, Ellen | Qi, Qi | Kuo, Lynn | Hassenstab, Jason | Perrin, Richard J. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To identify clinical measures that predict pathology, we evaluated the relationships of the picture version of the Free and Cued Selective Reminding Test (pFCSRT + IR), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to Braak stage. Methods: 315 cases from the clinicopathologic series at the Knight Alzheimer’s Disease Research Center were classified according to Braak stage. Boxplots of each predictor were compared to identify the earliest stage at which decline …was observed and ordinal logistic regression was used to predict Braak stage. Results: Looking at the assessment closest to death, free recall scores were lower in individuals at Braak stage III versus Braak stages 0 and I (combined) while MMSE and CDR scores for individuals did not differ from Braak stages 0/I until Braak stage IV. The sum of free recall and total recall scores independently predicted Braak stage and had higher predictive validity than MMSE and CDR-SB in models including all three. Conclusion: pFCSRT + IR + IR scores may be more sensitive to early pathological changes than either the CDR-SB or the MMSE. Show more

Keywords: Alzheimer’s disease, braak stage, clinical dementia rating scale –sum of boxes, free and cued selective reminding test, mini-mental state exam, neuropathology

DOI: 10.3233/JAD-200980

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Cuervo-Zanatta, Daniel | Garcia-Mena, Jaime | Perez-Cruz, Claudia

Article Type: Research Article

Abstract: Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work …was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD. Show more

Keywords: Anxiety, APP/PS1 mice, dysbiosis, high-throughput DNA sequencing, short-chain fatty acids, spatial memory, wildtype littermates

DOI: 10.3233/JAD-201367

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Nakano, Masaki | Mitsuishi, Yachiyo | Liu, Lei | Watanabe, Naoki | Hibino, Emi | Hata, Saori | Saito, Takashi | Saido, Takaomi C. | Murayama, Shigeo | Kasuga, Kensaku | Ikeuchi, Takeshi | Suzuki, Toshiharu | Nishimura, Masaki

Article Type: Research Article

Abstract: Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis …in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, ILEI, neurotransmitter receptor, synapse

DOI: 10.3233/JAD-201174

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Plotzker, Alan S. | Henson, Rachel L. | Fagan, Anne M. | Morris, John C. | Day, Gregory S.

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging …(MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31–513). Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p  = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p  = 0.04), or lower CSF Aβ 40 at presentation (rho = –0.83; p  = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p  = 0.03) or higher late ARIA-E scores (rho = 0.70; p  = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p  = 0.66). Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness. Show more

Keywords: Alzheimer’s disease, amyloid-beta related angiitis, biomarkers, cerebral amyloid angiopathy, inflammation, treatment outcome

DOI: 10.3233/JAD-201299

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Ibanez, Agustin | Parra, Mario A | Butlerfor, Christopher | for The Latin America and the Caribbean Consortium on Dementia (LAC-CD)

Article Type: Research Article

Abstract: In comparison with other regions, dementia prevalence in Latin America is growing rapidly, along with the consequent clinical, social, and economic burden upon patients and their families. The combination of fragile health care systems, large social inequalities, and isolated clinical and research initiatives makes the coordination of efforts imperative. The Latin America and the Caribbean Consortium on Dementia (LAC-CD) is a regional organization overseeing and promoting clinical and research activities on dementia. Here, we first provide an overview of the consortium, highlighting the antecedents and current mission. Then, we present the consortium’s regional research, including the multi-partner consortium to expand …dementia research in Latin America (ReDLat), which aims to identify the unique genetic, social, and economic factors that drive Alzheimer’s and frontotemporal dementia presentation in LAC relative to the US. We describe an extension of ReDLat which aims to develop affordable markers of disease subtype and severity using high density EEG. We introduce current initiatives promoting regional diagnosis, visibility, and capacity, including the forthcoming launch of the Latin American Brain Health Institute (BrainLat). We discuss LAC-CD-led advances in brain health diplomacy, including an assessment of responses to the impact of COVID-19 on people with dementia and examining the knowledge of public policies among experts in the region. Finally, we present the current knowledge-to-action framework, which paves the way for a future regional action plan. Coordinated actions are crucial to forging strong regional bonds, supporting the implementation of regional dementia plans, improving health systems, and expanding research collaborations across Latin America. Show more

Keywords: Dementia, genetics, implementation science, LAC-CD, Latin America, neurodegeneration, neuroimaging, regional health, social determinants of health, socioeconomic status

DOI: 10.3233/JAD-201384

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Grober, Ellen | Qi, Qi | Kuo, Lynn | Hassenstab, Jason | Perrin, Richard J. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). Methods: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the …Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. Results: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. Conclusion: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage. Show more

Keywords: Alzheimer’s disease, braak stage, clinical dementia rating scale –sum of boxes, free and cued selective reminding test, neuropathology

DOI: 10.3233/JAD-200946

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Lim, Yen Ying | Pase, Matthew P. | Buckley, Rachel F. | Yassi, Nawaf | Bransby, Lisa | Fowler, Christopher | Laws, Simon M. | Masters, Colin L. | Maruff, Paul

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ɛ 4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ɛ 4 heterozygotes; 50 ɛ 4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective …cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ 4 heterozygotes; 31 ɛ 4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ɛ 4 homozygotes compared with ɛ 4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ 4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ 4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ɛ 4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ 4 homozygosity increases with older age. APOE ɛ 4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, early detection, memory

DOI: 10.3233/JAD-201281

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Sragovich, Shlomo | Gershovits, Michael | Lam, Jacqueline C.K. | Li, Victor O.K. | Gozes, Illana

Article Type: Research Article

Abstract: Background: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer’s disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. Objective: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. Methods: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, …PTSD) was performed. Results: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. Conclusion: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design. Show more

Keywords: Alzheimer’s disease, autism, blood biomarkers, cognition, post-traumatic stress disorder

DOI: 10.3233/JAD-201158

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: There is a need for more reliable diagnostic tools for the early detection of Alzheimer’s disease (AD). This can be a challenge due to a number of factors and logistics making machine learning a viable option. Objective: In this paper, we present on a Support Vector Machine Leave-One-Out Recursive Feature Elimination and Cross Validation (SVM-RFE-LOO) algorithm for use in the early detection of AD and show how the SVM-RFE-LOO method can be used for both classification and prediction of AD. Methods: Data were analyzed on n  = 300 participants (n  = 150 AD; n  = 150 cognitively normal …controls). Serum samples were assayed via a multi-plex biomarker assay platform using electrochemiluminescence (ECL). Results: The SVM-RFE-LOO method reduced the number of features in the model from 21 to 16 biomarkers and achieved an area under the curve (AUC) of 0.980 with a sensitivity of 94.0% and a specificity of 93.3%. When the classification and prediction performance of SVM-RFE-LOO was compared to that of SVM and SVM-RFE, we found similar performance across the models; however, the SVM-RFE-LOO method utilized fewer markers. Conclusion: We found that 1) the SVM-RFE-LOO is suitable for analyzing noisy high-throughput proteomic data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance. Our recursive feature elimination model can serve as a general model for biomarker discovery in other diseases. Show more

Keywords: Alzheimer’s disease, blood biomarkers, machine learning, recursive feature elimination, support vector machine

DOI: 10.3233/JAD-201254

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Costa, Ana Sofia | Pinho, João | Kučikienė, Domantė | Reich, Arno | Schulz, Jörg B. | Reetz, Kathrin

Article Type: Research Article

Abstract: Background: The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is frequent and relevant for patients with cognitive impairment. Objective: To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Methods: Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white …matter hyperintensities, perivascular spaces) characteristics. Results: Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1–42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95%CI] = 0.90–0.98, p  = 0.003), and Aβ1–40 (aOR = 0.98, 95% CI=0.97–0.99 p  = 0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95% CI = 1.21–11.15, p  = 0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. Conclusion: The presence of probable CAA in Aβ positive patients was associated with lower Aβ1–42 and Aβ1–40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window. Show more

Keywords: Alzheimer’s disease, brain perivascular spaces, cerebral amyloid angiopathy, cerebral small vessel disease, cognitive decline, longitudinal studies

DOI: 10.3233/JAD-201218

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021