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Introduction: Alzheimer's disease, a progressive neurodegenerative disorder, is marked by beta-amyloid plaque accumulation and cognitive decline. The limited efficacy and significant side effects of anti-amyloid monoclonal antibody therapies have prompted exploration into innovative treatments like focused ultrasound therapy. Focused ultrasound shows promise as a non-invasive technique for disrupting the blood-brain barrier, potentially enhancing drug delivery directly to the brain and improving the penetration of existing therapeutic agents. Methods: This systematic review was conducted using PubMed and Embase databases, focusing on studies published in the last ten years that examined the use of low-intensity focused ultrasound for blood-brain barrier disruption in Alzheimer's disease. The search strategy encompassed terms related to Alzheimer's disease, focused ultrasound, and the blood-brain barrier. Studies were selected based on predefined inclusion and exclusion criteria. The quality of included studies was assessed using the Oxford Centre for Evidence-Based Medicine Levels of Evidence framework. Results: Twelve studies were analyzed, the results of which suggested that low intensity focused ultrasound when combined with microbubbles may safely and transiently disrupt the blood-brain barrier. These studies, primarily early-phase and observational, highlight the potential feasibility of focused ultrasound in facilitating drug delivery to the brain for the treatment of Alzheimer's disease. Notably, one study reported positive impacts on cognitive tests, suggesting potential direct therapeutic effects of focused ultrasound beyond blood-brain barrier disruption. Conclusion: The results of the included studies indicate the use of focused ultrasound in Alzheimer's disease treatment might be safe and effective in transiently opening the blood-brain barrier. Although current evidence is promising, further research is needed to establish generalizability. Future studies should also aim to further elucidate the mechanisms of action of low-intensity focused ultrasound as well as microbubbles for blood-brain barrier opening and explore potential clinical benefits beyond blood-brain barrier opening such as impacts on cognitive outcomes. Future studies should also aim for greater participant diversity to ensure findings are applicable across the full spectrum of Alzheimer's disease patients.
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BACKGROUND/AIMS: Cognitive impairment is prevalent in older inpatients but may be unrecognized. Screening to identify cognitive deficits is therefore important to optimize care. The 10-point Abbreviated Mental Test Score (AMTS) is widely used in acute hospital settings but its reliability for mild versus more severe cognitive impairment is unknown. We therefore studied the AMTS versus the 30-point Montreal Cognitive Assessment (MoCA) in older (≥75 years) inpatients. METHODS: The AMTS and MoCA were administered to consecutive hospitalized patients at ≥72 h after admission in a prospective observational study. MoCA testing time was recorded. Reliability of the AMTS for the reference standard defined as mild (MoCA <26) or moderate/severe (MoCA <18) cognitive impairment was assessed using the area under the receiver-operating curve (AUC). Sensitivity, specificity, positive and negative predictive values of low AMTS (<8) for cognitive impairment were determined. RESULTS: Among 205 patients (mean/SD age = 84.9/6.3 years, 96 (46.8%) male, 74 (36.1%) dementia/delirium), mean/SD AMTS was 7.2/2.3, and mean/SD MoCA was 16.1/6.2 with mean/SD testing time = 17.9/7.2 min. 96/205 (46.8%) had low AMTS whereas 174/185 (94%) had low MoCA: 74/185 (40.0%) had mild and 100 (54.0%) had moderate/severe impairment. Moderate/severe cognitive impairment was more prevalent in the low versus the normal AMTS group: 74/83 (90%) versus 25/102 (25%, p < 0.0001). AUC of the AMTS for mild and moderate/severe impairment were 0.86 (95% CI = 0.80-0.93) and 0.88 (0.82-0.93), respectively. Specificity of AMTS <8 for both mild and moderate/severe cognitive impairment was high (100%, 71.5-100, and 92.7%, 84.8-97.3) but sensitivity was lower (44.8%, 37.0-52.8, and 72.8%, 62.6-81.6, respectively). The negative predictive value of AMTS <8 was therefore low for mild impairment (10.9%, 5.6-18.7) but much higher for moderate/severe impairment (75.2%, 65.7-83.3). All MoCA subtests discriminated between low and normal AMTS groups (all p < 0.0001, except p = 0.002 for repetition) but deficits in delayed recall, verbal fluency and visuo-executive function were prevalent even in the normal AMTS group. CONCLUSION: The AMTS is highly specific but relatively insensitive for cognitive impairment: a quarter of those with normal AMTS had moderate/severe impairment on the MoCA with widespread deficits. The AMTS cannot therefore be used as a "rule-out" test, and more detailed cognitive assessment will be required in selected patients.
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BACKGROUND AND PURPOSE: Cognitive assessment is recommended after stroke but there are few data on the applicability of short cognitive tests to the full spectrum of patients. We therefore determined the rates, causes, and associates of untestability in a population-based study of all transient ischemic attack (TIA) and stroke. METHODS: Patients with TIA or stroke prospectively recruited (2002-2007) into the Oxford Vascular Study had ≥1 short cognitive test (mini-mental state examination, telephone interview of cognitive status, Montreal cognitive assessment, and abbreviated mental test score) at baseline and on follow-up to 5 years. RESULTS: Among 1097 consecutive assessed survivors (mean: age/SD, 74.8/12.1 years; 378 TIA), numbers testable with a short cognitive test at baseline, 1, 6, 12, and 60 months were 835/1097 (76%), 778/947 (82%), 756/857 (88%), 692/792 (87%), and 472/567 (83%). Eighty-eight percent (331/378) of assessed patients with TIA were testable at baseline compared with only 46% (133/290) of major stroke (P<0.001). Untestability was also associated with older age, premorbid dependency, death on follow-up, and with both pre- and postevent dementia (all P<0.01). Untestability (and problems with testing) were commonly caused by acute stroke effects at baseline (153/262 [58%]: dysphasia/anarthria/hemiparesis=84 [32%], drowsiness=58 [22%], and acute confusion=11 [4%]), whereas sensory deficits caused relatively more problems with testing at later time points (24/63 [38%] at 5 years). CONCLUSIONS: Substantial numbers of patients with TIA and stroke are untestable with short cognitive tests. Future studies should report data on untestable patients and those with problems with testing in whom the likelihood of dementia is high.