Journal of Alzheimer's Disease - Volume 63, issue 3

Authors: Proserpio, Paola | Arnaldi, Dario | Nobili, Flavio | Nobili, Lino

Article Type: Review Article

Abstract: Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer’s disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship …between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms. Show more

Keywords: Aging, circadian process, homeostatic process, melatonin, sleep

DOI: 10.3233/JAD-180041

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 871-886, 2018

Authors: Abu-Rumeileh, Samir | Capellari, Sabina | Parchi, Piero

Article Type: Review Article

Abstract: Rapidly progressive Alzheimer’s disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the …neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathological, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinical, pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathological data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group. Show more

Keywords: Amyloid-β, biomarkers, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, human prions, tau protein

DOI: 10.3233/JAD-171181

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 887-897, 2018

Authors: Cortés, Nicole | Andrade, Víctor | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: Alzheimer‘s disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms …(BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact. Show more

Keywords: Alzheimer’s disease, apathy, asymptomatic stages, behavioral disorders, neuroimmunomodulation, neuroinflammation, neuropsychiatric symptoms

DOI: 10.3233/JAD-180005

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 899-910, 2018

Authors: Shi, Yan | Fang, Ying-Yan | Wei, Yu-Ping | Jiang, Qian | Zeng, Peng | Tang, Na | Lu, Youming | Tian, Qing

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, …melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage. Show more

Keywords: Alzheimer’s disease, amyloid-β, melatonin, melatonin receptors, synapse

DOI: 10.3233/JAD-171178

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 911-926, 2018

Authors: Arispe, Nelson | De Maio, Antonio

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major contemporary and escalating malady in which amyloid-β (Aβ) peptides are the most likely causative agent. Aβ peptides spontaneously tend to aggregate in extracellular fluids following a progression from a monomeric state, through intermediate forms, ending in amyloid fibers and plaques. It is generally accepted now that the neurotoxic agents leading to cellular death, memory loss, and other AD characteristics are the Aβ intermediate aggregated states. However, Aβ peptides are continuously produced, released into the extracellular space, and rapidly cleared from healthy brains. Coincidentally, members of the heat shock proteins (hsp) family are present in …the extracellular medium of healthy cells and body fluids, opening the possibility that hsps and Aβ could meet and interact in the extracellular milieu of the brain. In this perspective and reflection article, we place our investigation showing that the presence of Hsp70s mitigate the formation of low molecular weight Aβ peptide oligomers resulting in a reduction of cellular toxicity, in context of the current understanding of the disease. We propose that it may be an inverse relationship between the presence of Hsp70, the stage of Aβ oligomers, neurotoxicity, and the incidence of AD, particularly since the expression and circulating levels of hsp decrease with aging. Combining these observations, we propose that changes in the dynamics of Hsp70s and Aβ concentrations in the circulating brain fluids during aging defines the control of the formation of Aβ toxic aggregates, thus determining the conditions for neuron degeneration and the incidence of AD. Show more

Keywords: Aging, Alzheimer’s disease, heat shock proteins, neurotoxicity, protein oligomerization

DOI: 10.3233/JAD-180161

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 927-934, 2018

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Editorial

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. Laboratory research and longitudinal clinical studies have helped to reveal various information about the disease but the exact causal process is not known yet. Patterns from alteration of neurochemicals (e.g., glutathione depletion, etc.), hippocampal atrophy, and brain effective connectivity loss as well as associated behavioral changes have generated important characteristic features. These imaging-based readouts and neuropsychological outcomes along with supervised clinical review are critical for developing a comprehensive artificial intelligence strategy for early predictive AD diagnosis and therapeutic development.

Keywords: Alzheimer’s disease, artificial Intelligence, glutathione depletion, hippocampal atrophy, oxidative stress, pattern recognition

DOI: 10.3233/JAD-180063

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 935-939, 2018

Authors: Mendez, Mario F. | Moheb, Negar | Desarzant, Randy E. | Teng, Edmond H.

Article Type: Research Article

Abstract: Background: Many patients with early-onset Alzheimer’s disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. Methods: We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer’s disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers. Results: We identified 18 (9M/9F) (6.5%) EOAD patients with progressive …acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia (“anarithmetia”) not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann’s syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. Conclusions: Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann’s syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD. Show more

Keywords: Acalculia, Alzheimer’s disease, apraxia, Gerstmann’s syndrome, parietal variant

DOI: 10.3233/JAD-180024

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 941-948, 2018

Authors: Zlatar, Zvinka Z. | Muniz, Martha C. | Espinoza, Sarah G. | Gratianne, Roberto | Gollan, Tamar H. | Galasko, Douglas | Salmon, David P.

Article Type: Research Article

Abstract: Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manifest differently in Hispanic older adults. We examined if SCD is associated with objective cognitive performance or with depression symptoms in 145 Hispanic individuals ages 60 or older referred by community health clinics for screening of cognitive complaints. All participants lived near the U.S.-Mexico border, spoke Spanish only, …or were Spanish-English bilingual. Memory-only and global cognitive composites were created from scores on Spanish versions of several neuropsychological tests. The Geriatric Depression Scale (GDS) and a five-item SCD questionnaire developed by our group were also completed. Multiple regression analyses showed no significant associations between SCD and memory or global cognitive composite scores after adjusting for age, sex, education, and GDS score. In contrast, there was a significant association between GDS and SCD after adjusting for age, sex, education, global and memory composite scores. Findings suggest that SCD does not accurately reflect current cognitive status in older Hispanics who present to their primary care physician with cognitive complaints. Clinicians should interpret SCD in this population within the context of information about symptoms of depression. Longitudinal research is needed in older Hispanics to better characterize SCD in this population and to determine if it can predict future cognitive decline. Show more

Keywords: Aging, cognition, depression, Hispanic Americans, subjective cognitive decline

DOI: 10.3233/JAD-170865

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 949-956, 2018

Authors: Matsuoka, Teruyuki | Imai, Ayu | Fujimoto, Hiroshi | Kato, Yuka | Shibata, Keisuke | Nakamura, Kaeko | Yokota, Hajime | Yamada, Kei | Narumoto, Jin

Article Type: Research Article

Abstract: Background: Sleep disturbance may affect the development of Alzheimer’s disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified. Objective: To examine the factors associated with sleep disturbance in AD. Methods: A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed …using SPM8 and VBM8. A two-sample t -test was used to compare patients with AD with (n  = 19) and without (n  = 44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p -value of 0.001 at the voxel level and a corrected p -value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t -tests. Results: In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups. Conclusion: Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD. Show more

Keywords: Alzheimer’s disease, pineal gland, precuneus, sleep disturbance, white matter hyperintensity

DOI: 10.3233/JAD-171169

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 957-964, 2018

Authors: Zumkehr, Joannee | Rodriguez-Ortiz, Carlos J. | Medeiros, Rodrigo | Kitazawa, Masashi

Article Type: Research Article

Abstract: Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer’s disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post-transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1β, TNF-α , or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1β and TNF-α , but not IL-6, …significantly increased GLT-1 steady-state levels (p ≤0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1β treatment (p ≤0.05). Co-treatment of microRNA-181a mimic in IL-1β-treated primary astrocytes and neurons effectively blocked the IL-1β-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD. Show more

Keywords: Alzheimer’s disease, cytokines, GLT-1, glutamate excitotoxicity, microRNA

DOI: 10.3233/JAD-170828

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 965-975, 2018