Cerebral multi-morbidity is common in older people with dementia, including people with dementia with Lewy bodies (DLB). We describe the first Australian-based, longitudinal observational biomarker study of DLB.

To investigate the frequency and influence of Alzheimer’s disease (AD) pathology (amyloid-β and tau) and cerebrovascular disease on clinical symptoms and disease outcome in DLB.

The study will recruit 100 people with mild to moderate probable DLB, who will undergo comprehensive clinical and cognitive assessments. Scales targeting DLB-specific clinical features (such as cognitive fluctuations and rapid eye movement sleep behaviour disorder) are administered. Biomarker protocols incorporate blood sampling (including ApoE genotyping and systemic inflammatory markers), molecular imaging (amyloid-β [18F-NAV 4694], tau [18F-MK6240], VMAT2 [18F-AV133] PET scans), 3-tesla magnetic resonance imaging and optional lumbar puncture. Clinical assessments are completed 6 - monthly and imaging 18-monthly. Participants are also invited to register for post-mortem brain tissue donation.

Thirty participants with probable DLB have been enrolled to date (mean age 75.4 years, range 64-82; 87% male). All participants have mild to moderate cognitive impairment (mean MMSE 25, range 17-30). Approximately 64% of the participants were amyloid-β positive. Study procedure tolerability has been excellent with no adverse events reported.

There is significant overlap of AD-related proteinopathies in people with DLB. Understanding the impact of multi-morbidity is essential in the development of effective treatment strategies. This study supports the feasibility of intensive, longitudinal biomarker studies in DLB in the Australian setting.

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.

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.

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.

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.

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.