Exercise-induced cortical disinhibition mediates the relationship between fitness and memory in older adults.

Regular exercise benefits learning and memory in older adults, but the neural mechanisms mediating these effects remain unclear. Evidence in young adults indicates that acute exercise creates a favourable environment for synaptic plasticity by enhancing cortical disinhibition. As such, we investigated whether plasticity-related disinhibition mediated the relationship between cardiorespiratory fitness and memory function in healthy older adults (n = 16, mean age = 66.06). Participants completed a graded maximal exercise test and assessments of visual and verbal memory, followed by two counterbalanced sessions involving 20 min of either high-intensity interval training exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired-pulse transcranial magnetic stimulation. In line with our hypotheses, we observed a positive correlation between cardiorespiratory fitness and verbal memory, which was mediated by plasticity-related cortical disinhibition. Our novel finding implicates cortical disinhibition as a mechanism through which the effects of acute bouts of exercise may translate to improved memory in older adults. This finding extends current understanding of the physiological mechanisms underlying the positive influence of cardiorespiratory fitness for memory function in older adults, and further highlights the importance of promoting exercise engagement to maintain cognitive health in later life. KEY POINTS: There are well established benefits of regular exercise for memory function in older adults, but the mechanisms are unclear. Cortical disinhibition is important for laying down new memories, and is enhanced following acute exercise in young adults, suggesting it is a potential mechanism underlying these benefits in ageing. Older adults completed a fitness test and assessments of memory, followed by two sessions involving either 20 min of exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired-pulse transcranial magnetic stimulation. Cardiorespiratory fitness was positively associated with memory performance. Higher fitness was associated with enhanced cortical disinhibition following acute exercise. Cortical disinhibition completely mediated the relationship between fitness and memory. This novel finding provides a mechanistic account for the positive influence of cardiorespiratory fitness on memory in later life, and emphasises the importance of regular exercise for cognitive health in older populations.

High-intensity acute exercise impacts motor learning in healthy older adults.

Healthy aging is associated with changes in motor sequence learning, with some studies indicating decline in motor skill learning in older age. Acute cardiorespiratory exercise has emerged as a potential intervention to improve motor learning, however research in healthy older adults is limited. The current study investigated the impact of high-intensity interval exercise (HIIT) on a subsequent sequential motor learning task. Twenty-four older adults (aged 55-75 years) completed either 20-minutes of cycling, or an equivalent period of active rest before practicing a sequential force grip task. Skill learning was assessed during acquisition and at a 6-hour retention test. In contrast to expectation, exercise was associated with reduced accuracy during skill acquisition compared to rest, particularly for the oldest participants. However, improvements in motor skill were retained in the exercise condition, while a reduction in skill was observed following rest. Our findings indicate that high-intensity exercise conducted immediately prior to learning a novel motor skill may have a negative impact on motor performance during learning in older adults. We also demonstrated that exercise may facilitate early offline consolidation of a motor skill within this population, which has implications for motor rehabilitation.

Ageing attenuates exercise-enhanced motor cortical plasticity.

Cardiorespiratory exercise is known to modulate motor cortical plasticity in young adults, but the influence of ageing on this relationship is unknown. Here, we compared the effects of a single session of cardiorespiratory exercise on motor cortical plasticity in young and older adults. We acquired measures of cortical excitatory and inhibitory activity of the primary motor cortex using transcranial magnetic stimulation (TMS) from 20 young (mean ± SD = 25.30 ± 4.00 years, 14 females) and 20 older (mean ± SD = 64.10 ± 6.50 years, 11 females) healthy adults. Single- and paired-pulse TMS measurements were collected before and after a 20 min bout of high-intensity interval cycling exercise or an equivalent period of rest, and again after intermittent theta burst stimulation (iTBS). In both young (P = 0.027, Cohen's d = 0.87) and older adults (P = 0.006, Cohen's d = 0.85), there was an increase in glutamatergic excitation and a reduction in GABAergic inhibition from pre- to postexercise. However, in contrast to younger adults, older adults showed an attenuated plasticity response to iTBS following exercise (P = 0.011, Cohen's d = 0.85). These results demonstrate an age-dependent decline in cortical plasticity and indicate that a preceding bout of high-intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults. Our findings align with the hypothesis that the capacity for cortical plasticity is altered in older age. KEY POINTS: Exercise enhances motor cortical plasticity in young adults, but how ageing influences this effect is unknown. Here, we compared primary motor cortical plasticity responses in young and older adults before and after a bout of high-intensity interval exercise and again after a plasticity-inducing protocol, intermittent theta burst stimulation. In both young and older adults, exercise led to an increase in glutamatergic excitation and a reduction in GABAergic inhibition. Our key result was that older adults showed an attenuated plasticity response to theta burst stimulation following exercise, relative to younger adults. Our findings demonstrate an age-dependent decline in exercise-enhanced cortical plasticity and indicate that a preceding bout of high-intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults.

Post-Diagnostic Support for Behaviour Changes in Young-Onset Dementia in Australia.

Behaviour changes (BCs) are common in young-onset dementia (YOD). Access to knowledgeable and age-appropriate support services is needed to assist with the appropriate management of BCs. We sought to investigate the types of YOD-related BCs that most commonly require support, the formal services being accessed for support, and the experiences of those seeking support in Australia. We employed a cross-sectional online questionnaire for individuals living with YOD as well as individuals providing informal or formal care for someone with YOD. Thirty-six questionnaire responses were recorded. Of the total sample, 83% reported YOD-related BCs requiring support, the most common being appetite/eating changes, followed by agitation/aggression and apathy/indifference. Seventy-six percent of these individuals had attempted to seek support from a formal service, with Dementia Australia, Dementia Support Australia, and general practitioners most commonly approached. Responses suggested that the support access pathway is suboptimal, with a lack of clarity about what services to approach for support and long wait times. Furthermore, 28% of participants had not gained access to support utilizing non-pharmacological strategies. Individuals who need support for YOD-related BCs demonstrated a high rate of help-seeking from formal support services; however, the support access pathway is slow, is difficult to navigate, and does not result in the best-practice management of BCs. Formal services resourced to provide efficient support with the implementation of behavioural strategies are needed, along with clear, accessible guidelines on the pathway to access them.

Acute exercise as a modifier of neocortical plasticity and aperiodic activity in the visual cortex.

Long-term potentiation (LTP) is a form of neuroplasticity commonly implicated in mechanistic models of learning and memory. Acute exercise can boost LTP in the motor cortex, and is associated with a shift in excitation/inhibition (E:I) balance, but whether this extends to other regions such as the visual cortex is unknown. We investigated the effect of a preceding bout of exercise on LTP induction and the E:I balance in the visual cortex using electroencephalography (EEG). Young adults (N = 20, mean age = 24.20) engaged in 20 min of high-intensity interval training (HIIT) exercise and rest across two counterbalanced sessions. LTP was induced using a high frequency presentation of a visual stimulus; a "visual tetanus". Established EEG markers of visual LTP, the N1b and P2 component of the visual evoked potential, and an EEG-derived measure of the E:I balance, the aperiodic exponent, were measured before and after the visual tetanus. As expected, there was a potentiation of the N1b following the visual tetanus, with specificity to the tetanised stimulus, and a non-specific potentiation of the P2. These effects were not sensitive to a preceding bout of exercise. However, the E:I balance showed a late shift towards inhibition following the visual tetanus. A preceding bout of exercise resulted in specificity of this E:I balance shift to the tetanised stimulus, that was not seen following rest. This novel finding suggests a possible exercise-induced tuning of the visual cortex to stimulus details following LTP induction.

Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from non-progressors.

BACKGROUND: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. METHODS: Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). RESULTS: Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. CONCLUSION: This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.

Music and Psychology & Social Connections Program: Protocol for a Novel Intervention for Dyads Affected by Younger-Onset Dementia.

Psychosocial interventions targeting the specific needs of people affected by younger-onset dementia are lacking. Younger-onset dementia refers to dementia where symptom onset occurs at less than 65 years old. Because of its occurrence in middle age, the impact on spouses is particularly marked and dyadic-based interventions are recommended. Music And Psychology & Social Connections (MAPS) is a novel online intervention, informed by the theory of adaptive coping by Bannon et al. (2021) for dyads affected by younger-onset dementia. MAPS combines therapeutic songwriting, cognitive behaviour therapy, and a private social networking group that focuses on the dyads. This will be a randomised controlled trial with a waitlist control. The primary aims are to assess whether MAPS improves depressive, anxiety, and stress symptoms in caregivers, with secondary aims to assess whether MAPS improves depressive symptoms in people with younger-onset dementia. The trial also aims to assess dyadic social connectedness; caregiver coping skills; and neuropsychiatric symptoms in people with younger-onset dementia. We will recruit 60 dyads to participate in a group-based weekly online program for 8 weeks facilitated by a credentialed music therapist and psychologist. Sessions 1 and 8 will include both caregivers and people with younger-onset dementia and Sessions 2-7 will involve separate group sessions for caregivers and those with dementia. There will be focus groups for qualitative feedback. Due to its online administration, MAPS has the potential to reach many dyads affected by younger-onset dementia.

Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings.

INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.

Multi-professional-delivered enhanced supportive care improves quality of life for patients with incurable cancer.

BACKGROUND:: Enhanced supportive care (ESC) promotes the earlier implementation of supportive care within cancer care. While earlier supportive care has been demonstrated to improve patient outcomes, the model of delivery is variable. The Clatterbridge Cancer Centre has developed a multi-professional delivered model with clinical nurse specialists providing ongoing patient review and care. METHOD:: A retrospective single-system design was used to assess longitudinal changes in Integrated Palliative Care Outcome Scale (IPOS) scores as indicators of quality of life. For other outcomes, a retrospective case control analysis was undertaken. RESULTS:: Statistically significant improvements in all IPOS scores were observed for patients attending ESC. Compared to controls, quantitative outcomes included prolonged survival and reduced chemotherapy-related mortality. Multi-professional delivered ESC successfully improves quality of life and outcomes.