Journal of Alzheimer's Disease - Volume 71, issue 2

Authors: Maher, Barbara A.

Article Type: Review Article

Abstract: Fewer than 5% of Alzheimer’s disease (AD) cases are demonstrably directly inherited, indicating that environmental factors may be important in initiating and/or promoting the disease. Excess iron is toxic to cells; iron overload in the AD brain may aggressively accelerate AD. Magnetite nanoparticles, capable of catalyzing formation of reactive oxygen species, occur in AD plaques and tangles; they are thought to form in situ, from pathological iron dysfunction. A recent study has identified in frontal cortex samples the abundant presence of magnetite nanoparticles consistent with high-temperature formation; identifying therefore their external, not internal source. These magnetite particles range from ∼10 …to 150 nm in size, and are often associated with other, non-endogenous metals (including platinum, cadmium, cerium). Some display rounded crystal morphologies and fused surface textures, reflecting cooling and crystallization from an initially heated, iron-bearing source material. Precisely-matching magnetite ‘nanospheres’ occur abundantly in roadside air pollution, arising from vehicle combustion and, especially, frictional brake-wear. Airborne magnetite pollution particles < ∼200 nm in size can access the brain directly via the olfactory and/or trigeminal nerves, bypassing the blood-brain barrier. Given their toxicity, abundance in roadside air, and nanoscale dimensions, traffic-derived magnetite pollution nanoparticles may constitute a chronic and pernicious neurotoxicant, and hence an environmental risk factor for AD, for large population numbers globally. Olfactory nerve damage displays strong association with AD development. Reported links between AD and occupational magnetic fields (e.g., affecting welders, machinists) may instead reflect inhalation exposure to airborne magnetic nanoparticles. Show more

Keywords: Air pollution, Alzheimer’s disease, inhalation exposure, iron overload, magnetite nanoparticles, metal nanoparticles

DOI: 10.3233/JAD-190204

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 361-375, 2019

Authors: Mendez, Mario F.

Article Type: Review Article

Abstract: Despite the large number of elderly bilinguals at risk for Alzheimer’s disease (AD) and dementia worldwide, significant questions remain about the relationship between speaking more than one language and later cognitive decline. Bilingualism may impact on cognitive and neural reserve, time of onset of dementia symptoms and neuropathology, and linguistic competency in dementia. This review indicates increased cognitive reserve from executive (monitoring, selecting, inhibiting) control of two languages and increased neural reserve involving left frontal and related areas for language control. Many, but not all, studies indicate a delay in dementia symptom onset but worse hippocampal and mesiotemporal atrophy among …bilinguals versus monolinguals with AD. In contrast, bilinguals do worse on language measures, and bilinguals with AD or dementia have difficulty maintaining and monitoring their second language. Together, these studies suggest that early-acquired and proficient bilingualism increases reserve through frontal-predominant executive control, and these executive abilities compensate for early dementia symptoms, delaying their onset but not the neuropathology of their disease. Finally, as executive control decreases further with advancing dementia, there is increasing difficulty inhibiting the dominant first language and staying in the second language. These conclusions must be interpreted with caution, given the problems inherent in this type of research; however, they do recommend more work on the pre-dementia neuroprotective effects and the dementia-related language impairments of bilingualism. Show more

Keywords: Alzheimer’s disease, bilingualism, dementia, language

DOI: 10.3233/JAD-190397

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 377-388, 2019

Authors: Chandra, Sujyoti | Roy, Avik | Patel, Dhruv R. | Pahan, Kalipada

Article Type: Review Article

Abstract: Mounting evidence has identified that impaired amyloid-β (Aβ) clearance might contribute to Alzheimer’s disease (AD) pathology. The lysosome-autophagy network plays an important role in protein homeostasis and cell health by removing abnormal protein aggregates via intracellular degradation. Therefore, stimulation of cellular degradative machinery for efficient removal of Aβ has emerged as a growing field in AD research. However, mechanisms controlling such pathways and drugs to promote such mechanisms are poorly understood. Aspirin is a widely used drug throughout the world and recent studies have identified a new function of this drug. At low doses, aspirin stimulates lysosomal biogenesis and autophagy …to clear amyloid plaques in an animal model of AD. This review delineates such functions of aspirin and analyzes underlying mechanisms that involve peroxisome proliferator-activated receptor alpha (PPARα )-mediated transcription of transcription factor EB (TFEB), the master regulator of lysosomal biogenesis. Show more

Keywords: Alzheimer’s disease, amyloid plaques, autophagy, lysosomal biogenesis, PPARα, TFEB

DOI: 10.3233/JAD-190586

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 389-397, 2019

Authors: Attier-Zmudka, Jadwiga | Sérot, Jean-Marie

Article Type: Editorial

Abstract: After World War I and more particularly in June 1940, the prestige of French Marshal Philippe Pétain, considered as the winning general the battle of Verdun, was very high. He became President of Council while the French army was unable to stop the German offensives. But five years later he was sentenced to death for high treason. By rereading his bibliography from a medical perspective, it is possible to find multiple suggestive events and to affirm a posteriori Pétain suffered from a neurodegenerative disorder, whose first signs appeared in the 1930s, suggestive of Alzheimer’s disease, which had an impact …on French politics. The modern medical knowledge of this disease casts a new light on the behavior of Petain during the last war. Show more

Keywords: Alzheimer’s disease, dementia, neurocognitive syndrome, Pétain

DOI: 10.3233/JAD-190225

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 399-404, 2019

Authors: Abbate, Carlo | Trimarchi, Pietro D. | Inglese, Silvia | Damanti, Sarah | Dolci, Giulia A.M. | Ciccone, Simona | Rossi, Paolo D. | Mari, Daniela | Arosio, Beatrice | Bagarolo, Renzo | Giunco, Fabrizio | Cesari, Matteo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated. Objective: To explore the existence of focal RAD on the basis of existing literature. Methods: We performed a literature search …for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD. Results: Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome. Conclusion: Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition. Show more

Keywords: Alzheimer’s disease, cognitive manifestations, left right asymmetry, right Alzheimer’s disease, right hemisphere, syndromic diversity, variant of Alzheimer’s disease, visuospatial ORCID: 0000-0002-0368-3834

DOI: 10.3233/JAD-190338

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 405-420, 2019

Authors: Tarumi, Takashi | Rossetti, Heidi | Thomas, Binu P. | Harris, Thomas | Tseng, Benjamin Y. | Turner, Marcel | Wang, Ciwen | German, Zohre | Martin-Cook, Kristin | Stowe, Ann M. | Womack, Kyle B. | Mathews, Dana | Kerwin, Diana R. | Hynan, Linda | Diaz-Arrastia, Ramon | Lu, Hanzhang | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Background: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). Objective: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ ) plaque deposition in aMCI patients. Methods: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and …the Delis–Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition. Results: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. Conclusion: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group. Show more

Keywords: Aerobic exercise, amyloid deposition, brain volume, cardiovascular fitness, mild cognitive impairment

DOI: 10.3233/JAD-181175

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 421-433, 2019

Authors: Xiong, Li | Charidimou, Andreas | Pasi, Marco | Boulouis, Gregoire | Pongpitakmetha, Thanakit | Schirmer, Markus D. | Singh, Sanjula | Benson, Emily | Gurol, Edip M. | Rosand, Jonathan | Greenberg, Steven M. | Biffi, Alessandro | Viswanathan, Anand

Article Type: Research Article

Abstract: Background and Objective: Cerebral amyloid angiopathy (CAA) accounts for the majority of lobar intracerebral hemorrhage (ICH); however, the risk factors for dementia conversion after ICH occurrence in CAA patients are unknown, especially in the long-term period after ICH. Therefore, we aimed to unravel the predictors for late post-ICH dementia (6 months after ICH event) in probable CAA patients. Methods: From a large consecutive MRI prospective cohort of spontaneous ICH (2006–2017), we identified probable CAA patients (modified Boston criteria) without dementia 6 months post-ICH. Cognitive outcome during follow-up was determined based on the information from standardized clinical visit notes. …We used Cox regression analysis to investigate the association between baseline demographic characteristics, past medical history, MRI biomarkers, and late post-ICH dementia conversion (dementia occurred after 6 months). Results: Among 97 non-demented lobar ICH patients with probable CAA, 25 patients (25.8%) developed dementia during a median follow-up time of 2.5 years (IQR 1.5–3.8 years). Pre-existing mild cognitive impairment, increased white matter hyperintensities (WMH) burden, the presence of disseminated cortical superficial siderosis (cSS), and higher total small vessel disease score for CAA were all independent predictors for late dementia conversion. Conclusion: In probable CAA patients presenting with lobar ICH, high WMH burden and presence of disseminated cSS are useful neuroimaging biomarkers for dementia risk stratification. These findings have implications for clinical practice and future trial design. Show more

Keywords: Cerebral amyloid angiopathy, cerebral hemorrhage, cerebral small vessel disease, dementia

DOI: 10.3233/JAD-190346

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 435-442, 2019

Authors: Quan, Qiankun | Qian, Yihua | Li, Xi | Li, Ming

Article Type: Research Article

Abstract: Cyclin-dependent kinase 5 (CDK5) in adipose tissue mediates peroxisome proliferator-activated receptor γ (PPARγ ) phosphorylation at Ser273 to inhibit its activity, causing PPARγ target gene expression changes. Among these, insulin-degrading enzyme (IDE) degrades amyloid-β peptide (Aβ), the core pathological product of Alzheimer’s disease (AD), whereas β-amyloid cleavage enzyme 1 (BACE1) hydrolyzes amyloid-β protein precursor (AβPP). Therefore, we speculated that CDK5 activity in the brain might participate in Aβ production, thereby functioning as a key molecule in AD pathogenesis. To confirm this hypothesis, we transduced primary rat hippocampal neurons using CDK5-expressing lentiviral vectors. CDK5 overexpression increased PPARγ Ser273 …phosphorylation, decreased IDE expression, increased BACE1 and AβPP expression, increased Aβ levels, and induced neuronal apoptosis. The CDK5 inhibitor roscovitine effectively reversed these CDK5 overexpression-mediated effects. Moreover, silencing of the Cdk5 gene via CDK5 shRNA-expressing lentiviral vectors in primary hippocampal neurons did not exert any protective effect against normal neuronal apoptosis, nor were significant effects observed on Aβ levels, PPARγ phosphorylation, or PPARγ target gene expression in the cells. However, Cdk5 gene silencing exhibited a neuroprotective effect in the Aβ-induced AD neuron model by effectively inhibiting the Aβ-induced neuronal apoptosis, PPARγ phosphorylation, PPARγ expression downregulation, and PPARγ target gene expression changes, and reducing Aβ levels. In conclusion, this study demonstrated that CDK5 played an important role in the pathogenesis of AD. Specifically, CDK5 participated in Aβ production by regulating PPARγ phosphorylation. Targeted therapy against CDK5 could effectively reduce and reverse the neurotoxic effects of Aβ and may represent a novel approach for AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid, cyclin-dependent kinase 5, peroxisome proliferator-activated receptors, phosphorylation

DOI: 10.3233/JAD-190026

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 443-460, 2019

Authors: Zhu, Wenhao | Huang, Hao | Yang, Shiqi | Luo, Xiang | Zhu, Wenzhen | Xu, Shabei | Meng, Qi | Zuo, Chengchao | Zhao, Kun | Liu, Hesheng | Liu, Yong | Wang, Wei

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) are common in older adults and are associated with cognitive decline. However, little is known about the functional changes underlying cognitive decline in WMH subjects. Objectives: To investigate whole-brain functional connectivity (FC) underpinnings of cognitive decline in WMH subjects using univariate and multivariate analyses. Methods: Twenty-three WMH subjects with mild cognitive impairment (WMH-MCI), 43 WMH subjects with no cognitive impairment (WMH-nCI), and 55 healthy controls underwent resting-state functional MRI scans. Whole-brain FC was calculated using the fine-grained human Brainnetome Atlas, followed by performance of between-group comparisons and FC-cognition correlation analysis. A …multivariate analysis using support vector machine (SVM) was performed to classify WMH-MCI and WMH-nCI subjects based on FC. Results: Both the WMH-MCI and WMH-nCI subjects exhibited characteristic impaired FC patterns. Markedly reduced FC involving subcortical nuclei and cortical hub regions of cognitive networks, especially the cingulate cortex, was identified in the WMH-MCI patients. In the WMH-MCI group, several connections involving the cingulate cortex were associated with cognitive decline. The exploratory mediation analyses indicated that FC alterations could partially explain the association between WMH and cognition. Furthermore, an SVM classifier based on FC distinguished WMH-MCI and WMH-nCI subjects with 78.8% accuracy. Connections that contributed most to the classification showed a similar distribution as the connections identified in the univariate analysis. Conclusions: This study provides a new window into the pathophysiology of cognitive impairment in WMH subjects and offer a novel and potential approach for early detection of the cognitive impairment in WMH subjects at the individual level. Show more

Keywords: Functional connectivity, mild cognitive impairment, resting-state functional MRI, support vector machine, white matter hyperintensities

DOI: 10.3233/JAD-190174

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 461-476, 2019

Authors: Showraki, Alireza | Murari, Geetanjali | Ismail, Zahinoor | Barfett, Joseph J. | Fornazzari, Luis | Munoz, David G. | Schweizer, Tom A. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objective: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. Methods: For this systematic review, four databases, PubMed (1946–2018), Cochrane (2005–2018), EMBASE (1947–2018), and PsycINFO (1806–2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) …at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. Results: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. Conclusion: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized “objective” approach for the evaluation of NPS. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, biomarkers, cerebrospinal fluid, neuropsychiatry, systematic review

DOI: 10.3233/JAD-190365

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 477-501, 2019