Dennis Velakoulis

Description:Objective: There has been growing interest in the role of biofluid biomarkers to aid the diagnosis of dementia in older people. However, less attention has been given to younger people who have dementia (young-onset dementia), who frequently experience misdiagnoses of primary psychiatric disorders diagnostic delay and challenges accessing appropriate care. Results: We describe 12 studies from the previous 2 years of which the majority have investigated the role of neurofilament light chain protein (NfL) in blood and cerebrospinal fluid in distinguishing young-onset dementia from primary psychiatric disorders. Synaptic and astrocytic biomarkers were also investigated. Sample sizes ranged from n = 46 to n = 999 and studies were mostly from Australia and the Netherlands. Conclusions: The major finding from this review was that NfL has very high sensitivity and specificity in differentiating a range of young-onset dementias (Alzheimer's dementia, behavioural-variant frontotemporal dementia) from PPD (schizophrenia, bipolar affective and major depressive disorders). NfL is easily accessible via the blood, so there is significant potential that a blood test could be available to make this dichotomisation. Further research is required to support clinical translation such as changes of NfL with disease progression and standardising analytic techniques.

Description:Background: Recent advances now allow detection of brain-specific proteins in blood, including neurofilament light chain (NfL), a marker of axonal pathology, and glial fibrillary acidic protein (GFAP), indicative of astrocytic activation. Given the evidence of astroglial pathology and neuronal dysfunction in bipolar disorder, and ongoing debates on neuroprogression, we investigated plasma NfL and GFAP levels in affected individuals. Methods: This study analysed plasma NfL and GFAP measured in 216 individuals using Simoa. We used bootstrapped general linear models (GLM) to compare plasma NfL and GFAP levels between people with bipolar depression (n = 120) and healthy controls (n = 96), adjusting for age, sex, and weight. We examined associations between these biomarkers and clinical variables while adjusting for multiple comparisons. For sensitivity analyses, predictors were evaluated using Bayesian model averaging (BMA). Results: Plasma GFAP (β = 0.21 [0.07, 0.35], p = 0.006) and NfL (β = 0.06 [0.01, 0.10], p = 0.028) were elevated in people with bipolar depression. Illness duration was positively associated with NfL (r = 2.97, p = 0.002), and further supported by BMA analysis (posterior inclusion probability, PIP = 0.85). Age of onset was positively associated with GFAP (r = 0.246 p = 0.041), which was also supported by BMA analysis (PIP = 0.67). Conclusions: These findings indicate increased plasma NfL and GFAP levels in bipolar disorder. Our findings support the neuroprogression hypothesis, where prolonged illness duration contributes to neuroaxonal damage. Elevated GFAP in those with later onset suggests a role for neuroinflammation, potentially linked to increased cardiovascular and metabolic comorbidities.

Description:Background: Apathy and affective neuropsychiatric symptoms (NPS) are prevalent in Alzheimer's disease (AD), yet their neurobiological cause is still unclear. We examined associations between plasma neurofilament light chain (NfL) and tau pathology (p-tau181) with apathy and affective symptoms in mild cognitive impairment (MCI) and AD dementia. Methods: This longitudinal study analyzed data from 781 participants with MCI and AD dementia enrolled in ADNI, with annual blood samples collected over 4 years. NPS were assessed via the Neuropsychiatric Interview (NPI), and biomarker trajectories were analyzed using mixed-effects models. Results: Elevated plasma NfL levels were associated with apathy, anxiety and depression in MCI and AD dementia, with apathy linked to a significantly higher rate of NfL increase, indicating accelerated neurodegeneration. Conclusions: Apathy and affective symptoms may indicate greater neurodegenerative burden in AD independent of tau-related pathology. Apathy was associated with a steeper rise in plasma NfL, suggesting a more aggressive disease progression. Apathy and affective neuropsychiatric symptoms (NPS) are highly prevalent in clinical Alzheimer's disease (AD).The presence of apathy, depression or anxiety was associated with higher plasma levels of neurofilament light chain (NfL).Apathy was associated with an accelerated increase in plasma NfL levels over time.Apathy and affective NPS were not associated with p-tau181 levels in plasma.

Description:Background: Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals <65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses. Methods: Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer's disease (n = 18), non-Alzheimer's disease neurodegeneration (n = 23) or primary psychiatric disorders (n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181, apolipoprotein E genotype and late-onset Alzheimer's disease polygenic risk scores were determined. Information-theoretic model selection identified discriminatory factors. Results: Neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181 levels were elevated in early-onset Alzheimer's disease compared with other diagnostic categories. A multi-omic model selection identified that a combination of cognitive and blood biomarkers, but not the polygenic risk score, discriminated between early-onset Alzheimer's disease and primary psychiatric disorders (area under the curve ⩾ 0.975, 95% confidence interval: 0.825-1.000). Phosphorylated-tau 181 alone significantly discriminated between early-onset Alzheimer's disease and non-Alzheimer's disease neurodegeneration causes (area under the curve = 0.950, 95% confidence interval: 0.877-1.00). Conclusions: Discriminating between early-onset Alzheimer's disease, non-Alzheimer's disease neurodegeneration and primary psychiatric disorders causes of young-onset neurocognitive symptoms is possible by combining cognitive profiles with blood biomarkers. These results support utilizing blood biomarkers for the work-up of young-onset neurocognitive symptoms and highlight the need for the development of a young-onset Alzheimer's disease-specific polygenic risk score.