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The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer’s disease (AD) dementia.
As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ −1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years.
Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81–.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40–2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status.
Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.
Northern Australia is a region where limited information exists on environments at the last glacial maximum (LGM). Girraween Lagoon is located on the central northern coast of Australia and is a site representative of regional tropical savanna woodlands. Girraween Lagoon remained a perennial waterbody throughout the LGM, and as a result retains a complete proxy record of last-glacial climate, vegetation and fire. This study combines independent palynological and geochemical analyses to demonstrate a dramatic reduction in both tree cover and woody richness, and an expansion of grassland, relative to current vegetation at the site. The process of tree decline was primarily controlled by the cool-dry glacial climate and CO2 effects, though more localised site characteristics restricted wetland-associated vegetation. Fire processes played less of a role in determining vegetation than during the Holocene and modern day, with reduced fire activity consistent with significantly lower biomass available to burn. Girraween Lagoon's unique and detailed palaeoecological record provides the opportunity to explore and assess modelling studies of vegetation distribution during the LGM, particularly where a number of different global vegetation and/or climate simulations are inconsistent for northern Australia, and at a range of resolutions.
Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms.
Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS).
In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy.
In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone.
Supported by funding from Intra-Cellular Therapies, Inc.
Jaswal & Akhtar's outstanding target article identifies the necessary social nature of the human mind, even in autism. We agree with the authors and present significant contributory origins of this autistic isolation in disruption of purposeful movement made social from infancy. Timing differences in expression can be misunderstood in embodied engagement, and social intention misread. Sensitive relations can repair this.
Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns.
To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE 4) allele.
Participants were 22 SMC carrying the APOE ɛ4 allele (ɛ4+; mean age 72.18 years) and 58 SMC non-carriers (ɛ4–; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored.
ɛ4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC–SMA connectivity.
The results provide the first evidence that ɛ4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity.
OBJECTIVES/SPECIFIC AIMS: Deep brain stimulation is currently being evaluated as an experimental therapy for various psychiatric disorders, as well as being investigated as a method for mapping emotional brain functions. This growing area of research requires sensitive measures to quantify effects of stimulation on emotional processing. The current study examined the effects of acute stimulation to 2 limbic regions—the subcallosal cingulate (SCC) and the amygdala—on bias in the perception and evaluation of emotional facial expressions. We hypothesized that transient electrical stimulation to the limbic system would produce acute reductions in negative bias, consistent with its antidepressant effects in patients with severe depression. METHODS/STUDY POPULATION: The current study uses a novel affective bias task, developed to rapidly and covertly quantify emotional state. Over 4–6 minutes, patients rate the intensity and valence of static images of emotional facial expressions. We examined effects of electrical brain stimulation in 2 groups: patients with treatment-refractory depression undergoing SCC DBS therapy, and epilepsy patients undergoing amygdala stimulation via stereo-EEG electrodes during inpatient intracranial monitoring. DBS patients completed the task under stimulation and sham conditions during monthly visits over the first 6 months of therapy, as well as daily during a 1 week, blinded period of DBS discontinuation at the 6-month time point. Epilepsy patients completed the task under stimulation and sham conditions at a single visit. Mixed linear models and paired-samples t-test were used to investigate effects of stimulation as well as depression scale scores on affective bias ratings. RESULTS/ANTICIPATED RESULTS: Four SCC DBS patients showed significant effects of stimulation (p<0.0001) and depressive state (p<0.0001) on affective bias scores across 6 months of chronic DBS therapy, where emotional faces were perceived as less sad with stimulation ON, as well as during visits in which patients were nondepressed (typically later in the treatment course). Furthermore, 2 DBS patients showed rapid negative shifts in bias following acute blinded discontinuation of chronic stimulation, an effect which persisted over the 1-week period of discontinuation (t29=−2.58, p=0.015), in the absence of any self-reported change in mood. Likewise, 6 epilepsy patients showed significant positive shifts in affective bias with acute amygdala stimulation (t5=−4.75, p=0.005). Current analyses are investigating electrophysiological, autonomic and facial motor correlates to affective bias in these patients. DISCUSSION/SIGNIFICANCE OF IMPACT: Affective bias has revealed rapid, significant changes with stimulation at 2 limbic targets—one a white matter hub and one a nuclear subcortical structure—suggesting the task’s utility as an emotional outcome measure in brain stimulation studies. These stimulation-sensitive measures may provide a new metric to track treatment response to deep brain stimulation therapy for affective disorders. Future studies will determine whether affective bias can predict neuropsychiatric complications in patients undergoing stimulation mapping of brain circuitry ahead of resection surgery for epilepsy.
The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36–54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months.
Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ– or Aβ+.
At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ– Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF.
While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.
Oxtotitlán Cave paintings have been considered among the earliest in Mesoamerica on stylistic grounds, but confirmation of this hypothesis through absolute dating has not been attempted until now. We describe the application of advanced radiocarbon strategies developed for situations such as caves with high carbon backgrounds. Using a low-temperature plasma oxidation system, we dated both the ancient paint and the biogenic rock coatings that cover the paint layers at Oxtotitlán. Our research has significantly expanded the time frame for the production of polychrome rock paintings encompassing the Early Formative and Late Formative/Early Classic periods, statistically spanning a long era from before ca. 1500 cal B.C. to cal A.D. 600.
Implementation intentions link triggers for self-harm with coping skills
and appear to create an automatic tendency to invoke coping responses
when faced with a triggering situation.
To test the effectiveness of implementation intentions in reducing
suicidal ideation and behaviour in a high-risk group.
Two hundred and twenty-six patients who had self-harmed were randomised
to: (a) forming implementation intentions with a ‘volitional help sheet’;
(b) self-generating implementation intentions without help; or (c)
thinking about triggers and coping, but not forming implementation
intentions. We measured self-reported suicidal ideation and behaviour,
threats of suicide and likelihood of future suicide attempt at baseline
and then again at the 3-month follow-up.
All suicide-related outcome measures were significantly lower at
follow-up among patients forming implementation intentions compared with
those in the control condition (ds>0.35). The
volitional help sheet resulted in fewer suicide threats
(d = 0.59) and lowered the likelihood of future
suicide attempts (d = 0.29) compared with patients who
self-generated implementation intentions.
Implementation intention-based interventions, particularly when supported
by a volitional help sheet, show promise in reducing future suicidal
ideation and behaviour.