Journal of Alzheimer's Disease Reports - Volume 2, issue 1

Authors: Ralph, Stephen J. | Espinet, Anthony J.

Article Type: Research Article

Abstract: It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these …studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta-analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients. Show more

Keywords: Antipsychotic agents, causes of death, clinical governance, dementia, deprescriptions, excess mortality, health care reform, meta-analysis, psychotropic drugs, review, risk

DOI: 10.3233/ADR-170042

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 1-26, 2018

Authors: Dolfe, Lisa | Tambaro, Simone | Tigro, Helene | Del Campo, Marta | Hoozemans, Jeroen J.M. | Wiehager, Birgitta | Graff, Caroline | Winblad, Bengt | Ankarcrona, Maria | Kaldmäe, Margit | Teunissen, Charlotte E. | Rönnbäck, Annica | Johansson, Jan | Presto, Jenny

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia and there is no successful treatment available. Evidence suggests that fibril formation of the amyloid β-peptide (Aβ) is a major underlying cause of AD, and treatment strategies that reduce the toxic effects of Aβ amyloid are sought for. The BRICHOS domain is found in several proteins, including Bri2 (also called integral membrane protein 2B (ITM2B)), mutants of which are associated with amyloid and neurodegeneration, and Bri3 (ITM2C). We have used mouse hippocampal neurons and brain tissues from mice and humans and show Bri3 deposits dispersed on AD plaques. In contrast …to what has been shown for Bri2, Bri3 immunoreactivity is decreased in AD brain homogenates compared to controls. Both Bri2 and Bri3 BRICHOS domains interact with Aβ40 and Aβ42 present in neurons and reduce Aβ42 amyloid fibril formation in vitro , but Bri3 BRICHOS is less efficient. These results indicate that Bri2 and Bri3 BRICHOS have different roles in relation to Aβ aggregation. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid β-peptide, BRICHOS, chaperone

DOI: 10.3233/ADR-170051

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 27-39, 2018

Authors: Lee, Wonseok | Lee, Sang Won | Lee, Gyudo | Yoon, Dae Sung

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides can be aggregated into β-sheet rich fibrils or plaques and deposited on the extracellular matrix of brain tissues, which is a hallmark of Alzheimer’s disease. Several drug candidates have been designed to retard the progression of the neurodegenerative disorder or to eliminate toxic Aβ aggregates. Recently, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) has emerged as a promising drug candidates for elimination of toxic Aβ aggregates. However, the effect of EPPS on the degradation of Aβ aggregates such as fibrils has not yet been fully elucidated. In this article, we investigate the EPPS-driven degradative behavior of Aβ aggregates at the …molecular level by using high-resolution atomic force microscopy. We synthesized Aβ fibrils and observed degradation of fibrils following treatment with various concentrations (1–50 mM) of EPPS for various time periods. We found that degradation of Aβ fibrils by EPPS increased as a function of concentration and treatment duration. Intriguingly, we also found regeneration of Aβ aggregates with larger sizes than original aggregates at high concentrations (10 and 50 mM) of EPPS. This might be attributed to a shorter lag phase that facilitates reformation of Aβ aggregates in the absence of clearance system. Show more

Keywords: Aβ aggregates, Alzheimer’s disease, amyloid-β, atomic force microscopy, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS), fibril degradation

DOI: 10.3233/ADR-170024

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 41-49, 2018

Authors: Villalba, Noel Lorenzo | Laboulbene, Stephane | Merzouki, Tawoufik | Méndez Bailon, Manuel | Kechida, Melek | Sigonney, Vanessa | Tabue Teguo, Maturin

Article Type: Research Article

Abstract: A 66-year-old woman presented with slowly progressive cognitive decline. MRI showed bi-frontotemporal atrophy, but the 14.3.3 protein was not present in cerebrospinal fluid. Electroencephalogram was irrelevant. Interview with relatives led doctors to search for a genetic cause and confirmed the diagnosis of Gerstmann–Sträussler–Scheinker syndrome.

Keywords: Cognitive decline, Gerstmann–Sträussler–Scheinker syndrome, prion protein

DOI: 10.3233/ADR-170050

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 51-53, 2018

Authors: Cruz-Aguilar, Manuel Alejandro | Ramírez-Salado, Ignacio | Guevara, Miguel Angel | Hernández-González, Marisela | Benitez-King, Gloria

Article Type: Research Article

Abstract: There is evidence demonstrating that 5-mg of fast-release melatonin significantly reduces nocturnal sleep onset in patients with mild-to-moderate Alzheimer’s disease (AD). However, the physiological mechanism that could promote sleep installation by melatonin in patients with AD is still poorly understood. The present pilot study was designed to analyze the effects of melatonin on cortical activity during the sleep onset period (SOP) in eight mild-to-moderate AD patients treated with 5-mg of fast-release melatonin. Electroencephalographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4, and O1-O2. The relative power (RP), interhemispheric, intrahemispheric, and fronto-posterior correlations of six electroencephalographic bands were calculated and …compared between two conditions: placebo and melatonin. Results show that at F7-T3, F3-F4, and C3-A1, melatonin induced an increase of the RP of the delta band. Likewise, in F7-T3, melatonin induced a decrease of the RP in the alpha1 band. Similarly, results show a lower interhemispheric correlation between the F7-T3 and F8-T4 derivations in the alpha1 band compared to the placebo condition. We conclude that the short sleep onset related to melatonin intake in AD patients was associated with a lower RP of the alpha1, a higher RP of the delta band (mainly in the left hemisphere) and a decreased interhemispheric EEG coupling in the alpha1 band. The possible role of the GABAergic neurotransmission as well as of the cascade of neurochemical events that melatonin triggers on sleep onset are discussed. Show more

Keywords: Alzheimer’s disease, EEG correlation, electroencephalography, melatonin, relative power, sleep onset, suprachiasmatic nucleus

DOI: 10.3233/ADR-170019

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 55-65, 2018

Authors: de Bellis, Alberto | de Bellis, Massimo | Aloe, Luigi

Article Type: Research Article

Abstract: Background: Nerve growth factor (NGF) is known for playing a critical protective role on a number of brain neurons in mammals, including humans. NGF can be delivered to the CNS via nasal route and has a neuroprotective action in case of neurodegenerative diseases. Objective: The aim of this study is to investigate for the first time whether purified NGF can play a neuroprotective role on human brain neurons affected by neurodegenerative diseases when administered via nasal route. Methods: Two female patients, both affected by frontotemporal dementia (FTD) associated with corticobasal syndrome (CBS) at different stages of …disease progression, received a daily intranasal NGF spray for one year. Clinical/neurological aspects were observed over time. The follow-up study was performed using 18 FDG PET. Results: This case study seems to demonstrate that IN-NGF slows down the common decline caused by FTD/CBS. Conclusions: These findings suggest the potential neuroprotective role of IN-NGF administered in case of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, intranasal delivery, nerve growth factor, neurodegenerative diseases, neuroprotection, non-invasive

DOI: 10.3233/ADR-180055

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 67-77, 2018

Authors: Mazi, Aise Rumeysa | Arzuman, Aysegul Sumeyye | Gurel, Busra | Sahin, Betul | Tuzuner, Mete Bora | Ozansoy, Mehmet | Baykal, Ahmet Tarik

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial …AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro . We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable. Show more

Keywords: Alzheimer’s disease, cerebellum, cortex, hippocampus, neonatal neurodegeneration, proteomics

DOI: 10.3233/ADR-170049

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 79-91, 2018

Authors: Younan, Ben

Article Type: Research Article

Abstract: Older adults engaging in regular physical activity can help create a buffer toward cognitive decline. The main aim of this study was to assess the effects of physical activity and cognitive functioning on a sample of young-old and old-old physically active adults and young-old and old-old sedentary adults. Cognitive functioning was examined using the digit span test, Wisconsin card sorting task. The National Task Group-Early Detection Screen for Dementia measure was used explore the relationship between scores and physical activity and sedentary adults. Findings from the study showed partial support for physical activity has a positive relationship with cognitive functioning. …The results found Young-old adults did better on the DST than all other groups regardless of being sedentary or physically active. Young-old physically active adults, however, did better on the DST latency measure than sedentary adults while old-old physically active adults did worse on the DST latency measure compared with old-old sedentary adults. The results also found that Physically active adults had a better score on the NTG-EDSD measure compared to the sedentary adults. Findings showed no significant differences for the WCST. Future research exploring the relationship between physical activity and cognitive functioning should do so by having more control over the extraneous variables. Show more

Keywords: Alzheimer’s disease, cognitive decline, old-old, older adults, physically active, young-old

DOI: 10.3233/ADR-180053

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 93-101, 2018

Authors: Picher, Ángel J. | Hernández, Félix | Budeus, Bettina | Soriano, Eduardo | Avila, Jesús

Article Type: Review Article

Abstract: Genetic factors may be involved in the onset of neurodegenerative diseases like Alzheimer’s disease. In the case of the familial type, the disease is due to an inherited mutation at specific sites in three genes. Also, there are some genetic risk factors that facilitate the development of sporadic Alzheimer’s disease. All of these genetic analyses were performed using blood samples as a source of DNA. However, the presence of somatic mutations in the brain can be identified only using brain samples. In this review, we comment on a method that correctly identifies single nucleotide variations in the human brain and …that can be used to validate high-through sequencing techniques. This method involves selective enrichment of the DNA population bearing the nucleotide variations, thereby facilitating posterior validation of the data by Sanger’s sequencing. Show more

Keywords: Brain somatic mutations, DNA sequencing, neurodegeneration

DOI: 10.3233/ADR-170039

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 103-109, 2018

Authors: Lehrer, Steven | Rheinstein, Peter H.

Article Type: Research Article

Abstract: Background: Studies of Alzheimer’s disease suggest that neuroinflammation or deranged brain wound healing may be a cause of some cases. But a placebo controlled study showed no effect at all on Alzheimer’s disease of low dose oral prednisone after one year. Introducing the steroid directly into the hippocampus and rhinencephalon via the nose, as happens in hay fever subjects, could be more effective. Objective: In the present study, we analyzed FDA MedWatch data for intranasal fluticasone propionate (Flonase) to determine the frequency of Alzheimer’s disease as an adverse event reported after use of the medication. Methods: …Machine-readable data from MedWatch, including adverse drug reaction reports from manufacturers, are part of a public database. We used the online tool eHealthMe to query the database. Results: By September 20, 2017, 35,221 people reported side effects to MedWatch after taking Flonase. Among them, 9 people (0.03%) had Dementia Alzheimer’s type. By October 3, 2017, 185,636 people reported side effects after taking Lipitor. Among them, 243 people (0.13%) had Dementia Alzheimer’s type. The lower incidence of Alzheimer’s dementia in the Flonase group compared to the Lipitor group was significant (p  <  0.001, Fisher exact test, two tailed). Conclusion: Long term use of oral non-steroidal anti-inflammatory drugs (NSAIDs) is linked with reduced risk of developing Alzheimer’s disease. Data from MedWatch suggest that fluticasone propionate administered intranasally might have a similar preventive effect to ibuprofen. Perhaps combining ibuprofen and Flonase could be therapeutic. Further studies would be desirable. Show more

Keywords: Alzheimer’s disease, brain, dementia, intranasal, steroids

DOI: 10.3233/ADR-170033

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 111-115, 2018