scholarly journals Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications

2003 ◽  
Vol 32 (2) ◽  
pp. 200-204 ◽  
Author(s):  
C. Holmes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Functional Decline ◽  
Therapeutic Implications

Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer’s Disease Brain Extract in Mouse Brains

2021 ◽  
Vol 79 (4) ◽  
pp. 1701-1711
Author(s):  
Tetsuo Hayashi ◽  
Shotaro Shimonaka ◽  
Montasir Elahi ◽  
Shin-Ei Matsumoto ◽  
Koichi Ishiguro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Brain ◽  
Functional Decline ◽  
Brain Regions ◽  
Insoluble Fraction ◽  
Brain Extract ◽  
Post Injection ◽  
Learning Deficits

Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

scholarly journals Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Peter Wostyn ◽  
Debby Van Dam ◽  
Kurt Audenaert ◽  
Peter Paul De Deyn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Senile Plaques ◽  
Protective Effects ◽  
Caffeine Consumption ◽  
Neuroprotective Effects ◽  
Csf Production

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

Music as an Aid to Learn New Verbal Information in Alzheimer's Disease

2012 ◽  
Vol 29 (5) ◽  
pp. 521-531 ◽  
Author(s):  
Aline Moussard ◽  
Emmanuel Bigand ◽  
Sylvie Belleville ◽  
Isabelle Peretz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Implications ◽  
Verbal Recall ◽  
Initial Learning ◽  
Two Factors ◽  
Long Term Retention ◽  
Retention Intervals

the goal of this study is to assess whether new lyrics are better learned and memorized when presented in a spoken or sung form. In normal young adults, mixed results have been reported, with studies showing a positive, a negative, or a null effect of singing on verbal recall. Several factors can account for this limited aid of music. First, the familiarity of the melody might play a role. Second, successive learning sessions and long-term retention intervals may be necessary. These two factors are considered here in a case study of a participant who suffers from mild Alzheimer's disease. As expected, initial learning of new lyrics showed better performance for the spoken condition over the sung version unless the lyrics are learned on a familiar melody. After repeated learning episodes, learning sung lyrics – even on an unfamiliar melody – led to better retention of words. Thus, music may provide a more robust aid for consolidation in memory than spoken lyrics alone. The therapeutic implications of these results are discussed.

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

2019 ◽  
Vol 215 (5) ◽  
pp. 668-674 ◽  
Author(s):  
Orestes V. Forlenza ◽  
Márcia Radanovic ◽  
Leda L. Talib ◽  
Wagner F. Gattaz
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Lithium Treatment ◽  
Functional Decline ◽  
Amnestic Mild Cognitive Impairment ◽  
Community Dwelling

BackgroundExperimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia.AimsTo determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease.MethodA total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25–0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale – cognitive subscale) and functional (Clinical Dementia Rating – Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0–48 months).ResultsParticipants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1−42) after 36 months.ConclusionsLong-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI–Alzheimer's disease continuum.Declaration of interestNone.

Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer’s Disease: A Phase 2, Open-Label Extension Study

2018 ◽  
Vol 15 (13) ◽  
pp. 1231-1243 ◽  
Author(s):  
Stephen Salloway ◽  
Gad A. Marshall ◽  
Ming Lu ◽  
H. Robert Brashear
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Decline ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Delayed Treatment ◽  
Significant Difference ◽  
Open Label Extension

Background: Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer’s disease (AD). Objective: This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of bapineuzumab in patients with the mild-to-moderate AD. Methods: Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE. Three groups were assessed: bapineuzumab or placebo SC, and bapineuzumab (IV) in OLE (bapi SC/bapi IV); bapineuzumab (IV) in Study 201 and OLE (bapi/bapi); and placebo in Study 201 and bapineuzumab IV in OLE (placebo/bapi). Results: Of 194 patients enrolled, 158 withdrew from OLE; primarily due to withdrawal by subject (n=85) and AE (n=30). Mean (SD) bapineuzumab exposure was 2.9 (1.90) years. There were no significant differences for efficacy endpoints (AD Assessment Scale–cognitive subscale [ADAS-Cog], Disability Assessment for Dementia [DAD] and MMSE scores) between the bapi/bapi and placebo/bapi groups. Most patients (94.8%, 184/194) reported ≥1 treatment-emergent adverse events (TEAEs) in OLE. Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) occurred in 22 (11.3%) patients. The most common TEAEs (>20% patients) were fall, agitation and urinary tract infection with similar incidences between bapi/bapi and placebo/bapi groups. Conclusion: No significant difference was seen in cognitive and functional decline between early and delayed treatment groups. No new safety concerns emerged. ARIA-E incidence was higher in patients first exposed to bapineuzumab in OLE versus previously exposed. No clear pattern of etiology contributed to death events.

scholarly journals APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Zonghua Li ◽  
Francis Shue ◽  
Na Zhao ◽  
Mitsuru Shinohara ◽  
Guojun Bu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protective Effect ◽  
Late Onset ◽  
Amyloid Β ◽  
Systemic Effect ◽  
Protective Mechanism ◽  
Therapeutic Implications ◽  
Apoe Ε4 ◽  
Increased Risk

AbstractInvestigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

Familial Patterns of Risk in Very Late-Onset Alzheimer's Disease

2003 ◽  
Author(s):  
J. M. Silverman ◽  
C. J. Smith ◽  
D. B. Marin ◽  
R. C. Mohs ◽  
C. B. Propper
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Familial Patterns
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