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

Authors: Panzarella, Vera | Mauceri, Rodolfo | Baschi, Roberta | Maniscalco, Laura | Campisi, Giuseppina | Monastero, Roberto

Article Type: Research Article

Abstract: Background: The relationship between Alzheimer’s disease (AD) and periodontitis has been recently investigated with heterogenous results. Objective: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in rural community in Sicily, Italy. Methods: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment (aMCI), and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality …of life (OHR-QoL) were evaluated. Results: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than for aMCI (p  = 0.009) and controls (p  = 0.001). Furthermore, the “M” component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p  < 0.001) and controls (p  < 0.001). A Poisson regression model revealed that age (p  < 0.001), male gender (p  = 0.001), and AD (p  = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p  = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p  = 0.004). OHR-QoL scores did not differ among the groups. Conclusion: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum . These data remain to be confirmed in larger population-based cohorts. Show more

Keywords: Alzheimer’s disease, cognitive impairment, epidemiology, oral health, periodontitis, tooth loss

DOI: 10.3233/JAD-200385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Raji, Cyrus A. | Meysami, Somayeh | Merrill, David A. | Porter, Verna R. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer’s disease (AD). Objective: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. Methods: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen’s D effect sizes were calculated for statistically significant structures. Partial …correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. Results: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p  < 0.05) was observed in brainstem (t  = 2.33, p  = 0.02, Cohen’s D  = 0.71) and ventral diencephalon (t  = 3.01, p  = 0.004, Cohen’s D  = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp  = 0 .  37, p  = 0.01), thalamus (rp  = 0.31, p  = 0.04), ventral diencephalon (rp  = 0.50, p  = 0.001), and pallidum (rp  = 0.38, p  = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp  = 0.17, p  = 0.26). No brain volumes were larger in monolinguals. Conclusion: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD. Show more

Keywords: Alzheimer’s disease, bilingual, brain structure, Neuroreader

DOI: 10.3233/JAD-200200

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Traini, Enea | Carotenuto, Anna | Fasanaro, Angiola Maria | Amenta, Francesco

Article Type: Research Article

Abstract: Background: Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus. Objective: The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury. Methods: 56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to …donepezil + placebo (D + P) or donepezil + choline alphoscerate (D + CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques. Results: The D + P group (n  = 27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D + CA group (n  = 29) the gray matter atrophy was less pronounced compared to the D + P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests. Conclusion: Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance. Show more

Keywords: Alzheimer’s disease, association, brain atrophy, cerebrovascular injury, choline alphoscerate, donepezil

DOI: 10.3233/JAD-190623

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Sherman, Dale S. | Durbin, Kelly A. | Ross, David M.

Article Type: Research Article

Abstract: Background: Meta-analysis examining the efficacy of cognitive interventions on neuropsychological outcomes have suggested interventions that focus on memory may actually provide greater benefit against the cognitive declines associated with mild cognitive impairment (MCI). However, it remains unclear if memory-based training would be more effective at addressing the cognitive deficits associated with MCI than multidomain forms of intervention. Objective: A meta-analytic review and subgroup analysis was conducted to examine the effects of cognitive training in individuals diagnosed with MCI and to compare the efficacy of memory-based training with multidomain interventions. Methods: A total of 32 randomized controlled …trials met inclusion criteria for the meta-analysis, which included 9 studies on memory-focused training and 17 studies on multidomain interventions. Results: We found significant, large effects for memory-focused training (Hedges’ g observed = 0.947; 95% CI [–1.668, 3.562]; Z  = 2.517; p  = 0.012) and significant, moderate effects for multidomain interventions (Hedges’ g observed = 0.420; 95% CI [–0.4491, 1.2891]; Z  = 3.525; p  < 0.001). A subgroup analysis found significant point estimates for memory-based forms of training and multidomain interventions, with memory-based forms of content yielding significantly greater summary effects than multidomain interventions (SMD Z  = 2.162; p  = 0.031, two-tailed; all outcomes). There was no difference between effect sizes when comparing outcomes limited to its respective domain. Conclusion: Overall, these findings suggest that, while both interventions were beneficial, treatment interventions that were strictly memory-based were more effective at improving cognition in individuals diagnosed with MCI than interventions that targeted multiple cognitive domains. Show more

Keywords: Cognitive dysfunction, cognitive remediation, meta-analysis, neuropsychology, rehabilitation

DOI: 10.3233/JAD-200261

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2020

Authors: Cho, Soo Hyun | Choe, Yeong Sim | Kim, Young Ju | Kim, Hee Jin | Jang, Hyemin | Kim, Yeshin | Kim, Si Eun | Kim, Seung Joo | Kim, Jun Pyo | Jung, Young Hee | Kim, Byeong C. | Lockhart, Samuel N. | Farrar, Gill | Na, Duk L. | Moon, Seung Hwan | Seo, Sang Won

Article Type: Research Article

Abstract: Background: 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies. Objective: We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions. Methods: Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and …FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons). Results: The cortical SUVR (R2  = 0.97) and striatal SUVR (R2  = 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p  = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p  < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons). Conclusion: Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo . Show more

Keywords: Alzheimer’s disease, amyloid imaging, 18F-florbetaben, 18F-flutemetamol, head to head

DOI: 10.3233/JAD-200079

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Rabipour, Sheida | Rajagopal, Sricharana | Yu, Elsa | Pasvanis, Stamatoula | Lafaille-Magnan, Marie-Elyse | Breitner, John | PREVENT-AD Research Group | Rajah, M. Natasha

Article Type: Research Article

Abstract: Background: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer’s disease (AD). Older adults with the apolipoprotein E ɛ 4 (+APOE4 ) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. Objective: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent’s conversion to AD. Methods: Volunteers were scanned as they encoded …and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (–APOE4 ). We also examined group differences in the correlation between event-related brain activity and memory performance. Results: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. Conclusion: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E polymorphism, associative learning, brain-behavior relationships, episodic memory, familial history, task-related functional MRI

DOI: 10.3233/JAD-191292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2020

Authors: Picillo, Marina | Vitale, Emilia | Rendina, Antonella | Donizetti, Aldo | Aliperti, Vincenza | Tepedino, Maria Francesca | Dati, Giovanna | Ginevrino, Monia | Valente, Enza Maria | Barone, Paolo

Article Type: Research Article

Abstract: Background: Mutations in the GRN gene are causative for an autosomal dominant form of frontotemporal dementia. Objective/Methods: The objective of the present study is to describe clinical and molecular features of three siblings harboring the GRN deletion NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15) identified with next generation sequencing. Results: Our patients demonstrated heterogeneous clinical phenotypes, such as progressive supranuclear palsy-like in the proband and the behavioral variant of frontotemporal dementia in the two affected siblings. Progranulin haploinsufficiency was revealed by both gene expression and protein analyses. Conclusion: The pathogenicity of the novel GRN deletion c.295_308del …TGCCCACGGGGCTT is confirmed by both functional analysis and segregation in three affected siblings. Show more

Keywords: Dementia, gene, genetics, parkinsonism, progranulin, progressive supranuclear palsy

DOI: 10.3233/JAD-200151

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Benhamron, Sandrine | Nitzan, Keren | Valitsky, Michael | Lax, Neta | Karussis, Dimitrios | Kassis, Ibrahim | Rosenmann, Hanna

Article Type: Research Article

Abstract: Background: The high complexity of neurodegenerative diseases, including Alzheimer’s disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. Objective: To test the efficacy of ‘cerebrospinal fluid (CSF) exchange therapy’ in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). Methods: We …treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. Results: We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5–10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2–3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. Conclusion: These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases. Show more

Keywords: Alzheimer’s disease, artificial CSF, CSF exchange therapy, mesenchymal stem cells, mesenchymal stem cell secretions, mice

DOI: 10.3233/JAD-191219

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Dehhaghi, Mona | Kazemi Shariat Panahi, Hamed | Braidy, Nady | Guillemin, Gilles J.

Article Type: Research Article

Abstract: Background: The accumulation of extracellular plaques containing amyloid-β protein (Aβ ) in the brain is one of the main pathological hallmarks of Alzheimer’s disease (AD). Aβ peptide can promote the production of highly volatile free radicals and reactive oxygen species (ROS) that can induce oxidative damage to neurons and astrocytes. At present, numerous studies have investigated the neuroprotective and glioprotective effects of natural products derived from plants, animals, and microorganisms. Objective: We investigated the glioprotective effect of secondary metabolites obtained from Herpetosiphon sp. HM 1988 against Aβ 40 -induced toxicity in human primary astrocytes. …Methods: The protective effect of bacterial secondary metabolites against Aβ 40 -induced inducible nitric oxide synthase (iNOS) activity was evaluated using the citrulline assay. To confirm the iNOS activity, nitrite production was assessed using the fluorometric Griess diazotization assay. Intracellular NAD+ depletion and lactate dehydrogenase (LDH) release in human primary astrocytes were also examined using well-established spectrophotometric assays. Results: Our results indicate that Aβ 40 can induce elevation in iNOS and LDH activities, nitrite production, and cellular energy depletion. Importantly, extract of Herpetosiphon sp. HM 1988 decreased iNOS activity, nitrite production, and LDH release. In addition, metabolites of the strain were able to restore cellular energy deficits through inhibition of NAD+ depletion mediated by Aβ 40 . Conclusion: These findings suggest that Herpetosiphon metabolites may represent a promising, novel source for the prevention of Aβ toxicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , Herpetosiphon , inducible nitric oxide synthase, natural products, oxidative stress

DOI: 10.3233/JAD-200116

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Umegaki, Hiroyuki | Bonfiglio, Viviana | Komiya, Hitoshi | Watanabe, Kazuhisa | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Cognitive impairment is linked to decreased quality of life (QOL), but few studies have investigated the impact of comorbid sarcopenia. Objective: The aim of this study was to elucidate the association of sarcopenia with QOL in patients with early dementia and mild cognitive impairment. Methods: Individuals with a Clinical Dementia Rating of 0.5 or 1 and a Mini-Mental State Examination score of 20–30 underwent a battery of neuropsychological assessments administered by a group of well-trained clinical psychologists. The EQ-5D was completed by both the patients and their main caregivers. EQ-5D utility and visual analog scale …scores were measured. Sarcopenia was defined according to the criteria published in the 2019 consensus update by the Asian Working Group for Sarcopenia. Results: Patients with sarcopenia had significantly lower scores on the Digit Symbol Substitution Test and Trail Making Test Part A. There was a significant negative association between sarcopenia and both self- and proxy-rated EQ-5D utility scores independent of potential confounding factors. However, there was no association between QOL visual analog scale scores and sarcopenia. Conclusion: Given that sarcopenia is often found in individuals with cognitive impairment, early detection by timely screening and effective intervention may help to maintain or improve QOL in this population. However, this study could not determine whether reduced QOL is a direct consequence of sarcopenia. Show more

Keywords: Cognitive dysfunction, gait speed, grip, sarcopenia

DOI: 10.3233/JAD-200169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020