Journal of Alzheimer's Disease - Volume 84, issue 1

Authors: Werber, Tom | Bata, Zsofia | Vaszine, Eniko Szabo | Berente, Dalida Borbala | Kamondi, Anita | Horvath, Andras Attila

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the leading cause of cognitive impairment in the elderly. Recent evidence suggests that preventive interventional trials could significantly reduce the risk for development of dementia. Periodontitis is the most common dental disease characterized by chronic inflammation and loss of alveolar bone and perialveolar attachment of teeth. Growing number of studies propose a potential link between periodontitis and neurodegeneration. In the first part of the paper, we overview case-control studies analyzing the prevalence of periodontitis among AD patients and healthy controls. Second, we survey observational libraries and cross-sectional studies investigating the risk of cognitive decline in patients …with periodontitis. Next, we describe the current view on the mechanism of periodontitis linked neural damage, highlighting bacterial invasion of neural tissue from dental plaques, and periodontitis induced systemic inflammation resulting in a neuroinflammatory process. Later, we summarize reports connecting the four most common periodontal pathogens to AD pathology. Finally, we provide a practical guide for further prevalence and interventional studies on the management of cognitively high-risk patients with and without periodontitis. In this section, we highlight strategies for risk control, patient information, dental evaluation, reporting protocol and dental procedures in the clinical management of patients with a risk for periodontitis and with diagnosed periodontitis. In conclusion, our review summarizes the current view on the association between AD and periodontitis and provides a research and intervention strategy for harmonized interventional trials and for further case-control or cross-sectional studies. Show more

Keywords: Alzheimer’s disease, dental health, intervention, neurodegeneration, neuroinflammation, periodontitis, prevention

DOI: 10.3233/JAD-210491

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 1-21, 2021

Authors: Sriwichaiin, Sirawit | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites …and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD. Show more

Keywords: Aging, Alzheimer’s disease, dementia, metabolomics

DOI: 10.3233/JAD-210737

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 23-50, 2021

Authors: Yu, Wenlei | Lu, Linjie | Ji, Xintong | Qian, Qiwei | Lin, Xiaohan | Wang, Huanhuan

Article Type: Review Article

Abstract: Chronic periodontitis caused by Porphyromonas gingivalis (P. gingivalis ) infection generally lasts for a lifetime. The long-term existence and development of P. gingivalis infection gradually aggravate the accumulation of inflammatory signals and toxic substances in the body. Recent evidence has revealed that P. gingivalis infection may be relevant to some central nervous system (CNS) diseases. The current work collects information and tries to explore the possible relationship between P. gingivalis infection and CNS diseases, including the interaction or pathways between peripheral infection and CNS injury, and the underlying neurotoxic mechanisms.

Keywords: Epigenetic regulation, nervous system damage (CNS), neuroinflammation, Porphyromonasgingivalis

DOI: 10.3233/JAD-215143

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 51-59, 2021

Authors: Allen, Herbert B.

Article Type: Research Article

Abstract: Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer’s disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible …for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed. Show more

Keywords: Amyloid-β, biofilm disperser, biofilms, hyperphosphorylated tau, penicillin, spirochetes, Toll-like receptor 2

DOI: 10.3233/JAD-210429

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 61-67, 2021

Authors: Farace, Paolo | Tamburin, Stefano

Article Type: Article Commentary

Abstract: Amyloid-β deposition is one of the neuropathological hallmarks of Alzheimer’s disease (AD), but pharmacological strategies toward its reduction are poorly effective. Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-β. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-β and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced …cognitive decline. However, selective irradiation of cortical amyloid-β plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-β deposition in AD since its preclinical stages. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, clinical trial, drug delivery, health technology, hippocampus, magnetic resonance guided focused ultrasound, radiation therapy, therapy

DOI: 10.3233/JAD-215041

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 69-72, 2021

Authors: González-Ortega, Guillermo | Llamas-Velasco, Sara | Arteche-López, Ana | Quesada-Espinosa, Juan Francisco | Puertas-Martín, Verónica | Gómez-Grande, Adolfo | López-Álvarez, Jorge | Saiz Díaz, Rosa Ana | Lezana-Rosales, José Miguel | Villarejo-Galende, Alberto | González de la Aleja, Jesús

Article Type: Short Communication

Abstract: The haploinsufficiency of the methyl-binding domain protein 5 (MBD5 ) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5 -neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients …with atypical early-onset dementia. Show more

Keywords: Early-onset dementia, gene, human phenotype ontology, MBD5-neurodevelopment disorders, methyl-binding domain protein 5 (MBD5), personality disorder, seizures

DOI: 10.3233/JAD-210648

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 73-78, 2021

Authors: Macpherson, Helen | McNaughton, Sarah A. | Lamb, Karen E. | Milte, Catherine M.

Article Type: Research Article

Abstract: Background: Higher quality diets may be related to lower dementia rates. Midlife is emerging as a critical life stage for a number of dementia risk factors. Objective: This study examines whether diet quality is related to brain structure during midlife, and if this differs by sex. Methods: This study used data from 19184 UK Biobank participants aged 40–65 years. Diet quality was assessed using three dietary indices including the Mediterranean Diet Score (MDS), Healthy Diet Score (HDS), and Recommended Food Score (RFS). MRI brain measures included total, grey, white and hippocampal volume. Linear regression examined associations …between diet quality and brain volume, controlling for potential confounders. Results: Better quality diet across all indices was significantly related to larger grey matter volume: MDS β= 429.7 (95%CI: 65.2, 794.2); HDS β= 700.1 (348.0, 1052.1); and RFS β= 317.1 (106.8, 527.3). Higher diet scores were associated with greater total volume: HDS β= 879.32 (286.13, 1472.50); RFS β= 563.37 (209.10, 917.65); and white matter volume: RFS β= 246.31 (20.56, 472.05), with the exception of Mediterranean diet adherence. Healthy eating guidelines and dietary variety associations with total and grey matter volume were more prominent in men. Conclusion: Findings suggest that diet quality is associated with brain structure during midlife, potentially decades prior to the onset of dementia. Show more

Keywords: Alzheimer’s disease, brain volume, dementia, healthy diet, Mediterranean diet

DOI: 10.3233/JAD-210705

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 79-90, 2021

Authors: Wong, Fennie Choy Chin | Saffari, Seyed Ehsan | Yatawara, Chathuri | Ng, Kok Pin | Kandiah, Nagaendran | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42 ) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between …BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales  = 36) = 73.80 years, SD  = 6.73; mean education years = 17.1, SD  = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p  = 0.008) and two-year change in Aβ1-42 (p  = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p  = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, cognition, memory, white matter hyperintensities

DOI: 10.3233/JAD-210333

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 91-101, 2021

Authors: Colato, Elisa | Chiotis, Konstantinos | Ferreira, Daniel | Mazrina, Mariam S. | Lemoine, Laetitia | Mohanty, Rosaleena | Westman, Eric | Nordberg, Agneta | Rodriguez-Vieitez, Elena

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD. Objective: We aimed to investigate the discriminative ability of 18 F-THK5317 and 18 F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition. Methods: Two cohorts, each including 29 participants (healthy controls [HC], prodromal AD, and AD dementia patients), underwent 18 F-THK5317 or 18 F-flortaucipir PET, T1-weighted MRI, and neuropsychological assessment. For each subject, we quantified regional 18 …F-THK5317 and 18 F-flortaucipir uptake within six bilateral and two composite regions of interest. We assessed global brain atrophy for each individual by quantifying the brain volume index, a measure of brain volume-to-cerebrospinal fluid ratio. We then quantified the discriminative ability of regional 18 F-THK5317, 18 F-flortaucipir, and brain volume index between diagnostic groups, and their associations with cognition in patients. Results: Both 18 F-THK5317 and 18 F-flortaucipir outperformed global brain atrophy in discriminating between HC and both prodromal AD and AD dementia groups. 18 F-THK5317 provided the highest discriminative ability between HC and prodromal AD groups. 18 F-flortaucipir performed best at discriminating between prodromal and dementia stages of AD. Across all patients, both tau tracers were predictive of RAVL learning, but only 18 F-flortaucipir predicted MMSE. Conclusion: Our results warrant further in vivo head-to-head and antemortem-postmortem evaluations. These validation studies are needed to select tracers with high clinical validity as biomarkers for early diagnosis, prognosis, and disease staging, which will facilitate their incorporation in clinical practice and therapeutic trials. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive dysfunction, dementia, positron emission tomography, tau protein

DOI: 10.3233/JAD-210614

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 103-117, 2021

Authors: Brugulat-Serrat, Anna | Cañas-Martínez, Alba | Canals-Gispert, Lidia | Marne, Paula | Gramunt, Nina | Milà-Alomà, Marta | Suárez-Calvet, Marc | Arenaza-Urquijo, Eider M. | Grau-Rivera, Oriol | González-de-Echávarri, José María | Minguillon, Carolina | Fauria, Karine | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Zetterberg, Henrik | Blennow, Kaj | Gispert, Juan Domingo | Molinuevo, José Luis | Sánchez-Benavides, Gonzalo | for the ALFA study

Article Type: Research Article

Abstract: Background: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer’s disease pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment. Objective: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV …in a sample of individuals aged 50–70 years with normal levels of amyloid-β and tau cerebrospinal fluid (CSF) biomarkers. Methods: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable. Results: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected. Conclusion: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cognition, memory, norms, sex

DOI: 10.3233/JAD-210640

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 119-128, 2021