Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau ...pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using
F-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer's disease.
Summary Background Anorexia nervosa is characterised by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder. Deep ...brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results. We aimed to assess the safety of DBS to modulate the activity of limbic circuits and to examine how this might affect the clinical features of anorexia nervosa. Methods We did a phase 1, prospective trial of subcallosal cingulate DBS in six patients with chronic, severe, and treatment-refractory anorexia nervosa. Eligible patients were aged 20–60 years, had been diagnosed with restricting or binge-purging anorexia nervosa, and showed evidence of chronicity or treatment resistance. Patients underwent medical optimisation preoperatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation. Patients were followed up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit. Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals. This trial is registered with ClinicalTrials.gov , number NCT01476540. Findings DBS was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious. Other related adverse events were panic attack during surgery, nausea, air embolus, and pain. After 9 months, three of the six patients had achieved and maintained a BMI greater than their historical baselines. DBS was associated with improvements in mood, anxiety, affective regulation, and anorexia nervosa-related obsessions and compulsions in four patients and with improvements in quality of life in three patients after 6 months of stimulation. These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder. Interpretation Subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory anorexia nervosa. Funding Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.
Structural, functional, and molecular imaging studies in late-life depressed patients have implicated changes in neural circuits associated with mood symptoms and cognitive deficits, molecular ...mechanisms including oxidative stress and mitochondrial dysfunction and neurochemical changes and, in some studies, Alzheimer’s Dementia (AD) pathology (Manning and Steffens, 2018; Mathias etal., 2017; Hirao and Smith, 2014). Krause-Sorio and colleagues reported the results of the subgroup of individuals in the clinical trial who underwent positron emission tomography (PET) scans with a radiotracer for AD pathology (18 F-FDDNP) to determine the relationship between AD pathology and the mood and cognitive responses to treatment (Krause-Sorio etal., 2020). Several pilot studies of combined citalopram and memantine treatment in late-life geriatric depressed patients with cognitive impairment and in patients with AD showed improvement in mood and cognition (Pelton etal., 2016; Zhou etal., 2019).
Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and ...dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.
To develop an instrument based on ISTAART-AA MBI criteria.
Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.
We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.
The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.
Objective
Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep ...brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits.
Methods
We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low‐resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments.
Results
DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain's default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer's Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events.
Interpretation
There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation. Ann Neurol 2010
To identify clusters of patients with incident mild cognitive impairment (MCI) based on their neuropsychiatric symptoms (NPS) and to examine the risk of progression to dementia based on these ...clusters.
In this cohort study with a median of 2 years of follow-up from the National Alzheimer's Coordinating Center, 540 patients with MCI at least 60 years old with complete data and follow-up were studied. Latent class analysis was used to identify clusters of patients based on their NPS, and Cox proportional hazards models were used to examine risk of progression to dementia based on clusters. Incident MCI was defined as a participant having MCI at a current visit but having been cognitively normal at his or her previous (yearly) visit. The Neuropsychiatric Inventory Questionnaire assessed the presence of 12 neuropsychiatric behavioral domains.
Three clusters were identified: a severe cluster (agitation, anxiety, apathy, nighttime behaviors, inhibition), an affective cluster (depression, anxiety, irritability, nighttime behaviors), and an asymptomatic cluster. The prevalence of each class was 56% for the asymptomatic class followed by the affective class (37%) and finally the severe class (7%). Compared with the asymptomatic class, the severe class had more than twice the hazard of progression to dementia (2.69; 95% CI: 1.12-2.70) and the affective class had over 1.5 times the hazard of progression to dementia (1.79; 95% CI: 1.12-2.70).
Among persons with incident MCI, patterns of NPS may increase the likelihood of progression to dementia. Implications for early detection and treatment are discussed.
Abstract Neuropsychiatric symptoms (NPS) are common in dementia and in predementia syndromes such as mild cognitive impairment (MCI). NPS in MCI confer a greater risk for conversion to dementia in ...comparison to MCI patients without NPS. NPS in older adults with normal cognition also confers a greater risk of cognitive decline in comparison to older adults without NPS. Mild behavioral impairment (MBI) has been proposed as a diagnostic construct aimed to identify patients with an increased risk of developing dementia, but who may or may not have cognitive symptoms. We propose criteria that include MCI in the MBI framework, in contrast to prior definitions of MBI. Although MBI and MCI can co-occur, we suggest that they are different and that both portend a higher risk of dementia. These MBI criteria extend the previous literature in this area and will serve as a template for validation of the MBI construct from epidemiologic, neurobiological, treatment, and prevention perspectives.
Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed ...neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.
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