scholarly journals Genetic Therapies for Alzheimer’s Disease: A Scoping Review

2021 ◽  
pp. 1-14
Author(s):  
Matthew J. Lennon ◽  
Grant Rigney ◽  
Vanessa Raymont ◽  
Perminder Sachdev
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Scoping Review ◽  
Genetic Therapy ◽  
Short Term ◽  
Exciting Opportunity ◽  
Alternative Approaches

Effective, disease modifying therapies for Alzheimer’s disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo, poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility.

Structural, Functional, and Molecular Neuroimaging Biomarkers for Alzheimer’s Disease

2013 ◽  
pp. 821-825
Author(s):  
James B. Brewer ◽  
Jorge Sepulcre ◽  
Keith A. Johnson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Brain Dysfunction ◽  
Imaging Biomarkers ◽  
Neurocognitive Evaluation ◽  
Neuroimaging Biomarkers

Advances in quantitative structural, functional, and molecular neuroimaging have provided new tools for objective, in vivo, assessment of critical aspects of Alzheimer’s disease and other neurodegenerative disorders. Measures of brain atrophy or brain dysfunction, coupled with measures of disease-linked pathology, might complement the history, physical and neurocognitive evaluation of patients and thereby improve predictive prognosis, especially at early stages of cognitive impairment where neurodegenerative etiology is less certain. Such imaging biomarkers are currently used in nearly all clinical trials of therapeutic agents for Alzheimer’s disease and are increasingly incorporated into clinical practice. In this chapter, imaging biomarkers are introduced and discussed to familiarize the reader with their potential research and clinical uses.

Short and Longer Term Effects of Musical Intervention in Severe Alzheimer's Disease

2012 ◽  
Vol 29 (5) ◽  
pp. 533-541 ◽  
Author(s):  
Sylvain Clément ◽  
Audrey Tonini ◽  
Fatiha Khatir ◽  
Loris Schiaratura ◽  
Séverine Samson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Facial Expressions ◽  
Emotional State ◽  
Present Finding ◽  
Well Being ◽  
Music Intervention ◽  
Short Term

in this study, we examined short and longer term effects of musical and cooking interventions on emotional well-being of severe Alzheimer's disease (AD) patients. These two pleasurable activities (i.e., listening to music, tasting sweets) that were collectively performed (i.e., playing music together, collaborative preparation of a cake) were compared in two groups of matched patients with AD (N = 14). Each intervention lasted four weeks (two sessions per week) and their effects were regularly assessed up to four weeks after the end of the intervention. We repeatedly evaluated the emotional state of both groups before, during, and after the intervention periods by analyzing discourse content and facial expressions from short filmed interviews as well as caregivers' judgments of mood. The results reveal short-term benefits of both music and cooking interventions on emotional state on all these measures, but long-term benefits were only evident after the music intervention. The present finding suggests that non-pharmacological approaches offer promising methods to improve the quality of life of patients with dementia and that music stimulation is particularly effective to produce long lasting effects on patients' emotional well-being.

scholarly journals SHORT-TERM PRACTICE EFFECTS AND AMYLOID DEPOSITION: PROVIDING INFORMATION ABOVE AND BEYOND BASELINE COGNITION

2017 ◽  
pp. 1-6
Author(s):  
K. Duff ◽  
D.B. Hammers ◽  
B.C.A. Dalley ◽  
K.R. Suhrie ◽  
T.J. Atkinson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Test Scores ◽  
Amyloid Deposition ◽  
Cognitive Testing ◽  
Practice Effects ◽  
Cognitive Test ◽  
Cognitive Tests ◽  
Short Term

Background: Practice effects, which are improvements in cognitive test scores due to repeated exposure to testing materials, may provide information about Alzheimer’s disease pathology, which could be useful for clinical trials enrichment. Objectives: The current study sought to add to the limited literature on short-term practice effects on cognitive tests and their relationship to amyloid deposition on neuroimaging. Participants: Twenty-seven, non-demented older adults (9 cognitively intact, 18 with mild cognitive impairment) received amyloid imaging with 18F-Flutemetamol, and two cognitive testing sessions across one week to determine practice effects. Results: A composite measure of 18F-Flutemetamol uptake correlated significantly with all seven cognitive tests scores on the baseline battery (r’s = -0.61 – 0.59, all p’s<0.05), with higher uptake indicating poorer cognition. Practice effects significantly added to the relationship (above and beyond the baseline associations) with 18F-Flutemetamol uptake on 4 of the 7 cognitive test scores (partial r’s = -0.45 – 0.44, p’s<0.05), with higher uptake indicating poorer practice effects. The odds ratio of being “amyloid positive” was 13.5 times higher in individuals with low practice effects compared to high practice effects. Conclusions: Short-term practice effects over one week may be predictive of progressive dementia and serve as an affordable screening tool to enrich samples for preventative clinical trials in Alzheimer’s disease.

scholarly journals Behavioral Improvements and its Molecular Mechanism of Ilex kudingcha C.J. Tseng on Animal Model of Alzheimer’s Disease

2020 ◽  
Vol 25 (3) ◽  
Author(s):  
Lap Thi Nguyen ◽  
Nguyen Huu Son ◽  
Tran Nguyen Hong ◽  
Nguyen Minh Khoi ◽  
Kinzo Matsumoto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Muscarinic Receptor ◽  
Short Term Memory ◽  
Long Term Memory ◽  
Short Term ◽  
Reference Drug ◽  
Term Memory ◽  
Model Of Alzheimer’S Disease

Alzheimer's disease (AD) is a common chronic neurodegenerative disease with well-defined pathophysiological mechanisms. Ilex kudingcha (IK) C.J. Tseng is commonly known as bitter tea or “Khom” tea in Vietnam. The present study was conducted to investigate the anti-dementia effect of IK using olfactory bulbectomized (OBX) mice. OBX mice were daily treated with IK extract (540 mg/kg) or reference drug, tacrine (2.5 mg/kg) 1 week before and continuously for 3 days after the OBX surgery. The object recognition test, modified Y maze test and fear conditioning test were employed to analyze non-spatial short-term, spatial short-term and long-term memories of the mice respectively. Administration of IK extract and tacrine attenuated these OBX-induced cognitive deficits in mice. The effects of IK and tacrine on spatial short-term memory impairment were reversed by scopolamine, a muscarinic receptor antagonist. The amyloid-beta (Aβ) production in adult transgenic Drosophila brain flies was also investigated by using Western blotting with APP-HA antibody. These results indicated that IK extract improves short-term and long-term memory disturbances in OBX mice and that muscarinic receptor may play a role on these actions. In addition, our result also showed that IK extract reduces the expression of amyloid precursor protein (APP) in brain of AD model using Drosophila melanogaster.

scholarly journals Neuroprotective and Anti-Inflammatory Effects of Low–Moderate Dose Ionizing Radiation in Models of Alzheimer’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3678 ◽  
Author(s):  
Sujin Kim ◽  
Yunkwon Nam ◽  
Chanyang Kim ◽  
Hyewon Lee ◽  
Seojin Hong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Ionizing Radiation ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Moderate Dose ◽  
Short Term ◽  
Anti Inflammatory ◽  
5Xfad Mice

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

Cholinesterase Inhibitors and Memantine

2008 ◽  
Author(s):  
Constantine G. Lyketsos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Imaging Study ◽  
Behavioral Symptoms ◽  
Cognitive Symptoms ◽  
Dementia Patients ◽  
Comparison Groups

Several lines of evidence suggest that acetylcholine (ACh) neurotransmission is important to the normal functioning of memory, and loss of ACh-producing cells in the basal forebrain (nucleus basalis) is a consistent finding in patients with Alzheimer’s disease and other dementias. The most successful approach to increasing ACh in vivo has been to develop drugs that reduce its degradation by the synaptic enzyme acetylcholinesterase (AChE). Four cholinesterase inhibitors are available to treat memory and other cognitive symptoms in dementia patients. They may also stabilize or prevent the onset of milder non-cognitive neuropsychiatric or behavioral symptoms, although their use as exclusive agents for the more severe forms of the latter is not recommended. A recent Consensus Panel has articulated sound clinical principles regarding the use of these drugs in the context of the broader treatment of Alzheimer’s dementia (Lyketsos et al., 2006). Tacrine, donepezil, rivastigmine, and galantamine have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. Tacrine should not ordinarily be used in light of the associated high risk of hepatotoxicity, its complex titration, and the availability of bettertolerated alternatives. The other three cholinesterase inhibitors seem similar in efficacy. All appear to modestly improve cognitive symptoms in 15% to 20% of patients, sometimes quite notably. In addition, they may either improve patient function and delay the emergence of behavioral symptoms or reduce the severity of the latter. The evidence does not support their use as single agents to treat more severe neuropsychiatric symptoms such as depression or delusions, although patients with apathy and visual hallucinations may respond. Any benefit of cholinesterase inhibitors to the long-term progression of dementia has not been shown conclusively. Some studies suggest that they may attenuate the long-term slope of cognitive or functional decline, but those studies have been flawed due to high levels of dropout and the use of historical untreated comparison groups. One brain imaging study, part of a clinical trial, has suggested that they may affect the size of the hippocampus or the integrity of hippocampal neurons. In the absence of replication or a better understanding of the imaging measures involved, these data are not conclusive.

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