Instrumental, Neurophysiological, cognitive and Sleep InvestiGations into the High risk of neurodegeneraTion in Late Onset Epilepsy of Unknown aetiology: the INSIGHT-LOEU study.

Neuropsychiatric symptoms as early clinical indicators and functional biomarkers of cognitive decline in mild cognitive impairment and early Alzheimer's disease

Neuropsychiatric symptoms (NPS) have historically been considered secondary or late-stage features of Alzheimer's disease (AD), yet emerging evidence indicates that apathy, depression, anxiety, irritability, agitation, sleep disturbance, and psychosis frequently arise during prodromal phases, including mild cognitive impairment (MCI), and may precede measurable cognitive decline. This narrative review evaluates NPS as early clinical indicators and potential functional biomarkers of cognitive decline in MCI and early AD, emphasizing neurobiological mechanisms, prognostic significance, and translational relevance. A synthesis of epidemiological, longitudinal, neuroimaging, and biomarker studies published between 2012 and 2025 was conducted across major databases, integrating findings within the mild behavioral impairment (MBI) construct and the AT(N) biomarker framework. Across studies, NPS were found to affect approximately 43–80% of individuals with MCI and 75–90% with early AD, with lifetime prevalence approaching 97% across the disease course. Apathy, depression, anxiety, and irritability are particularly common in early stages and independently predict accelerated cognitive and functional decline, increased caregiver burden, and earlier institutionalization. NPS are associated with early tau pathology, neurotransmitter system dysfunction, and fronto-limbic network degeneration. Disparities in symptom burden, diagnostic access, and clinical outcomes are evident across racial, ethnic, sex-related, and cultural groups. Recognizing NPS as core features of early AD supports their integration into MBI- and AT(N)-informed diagnostic and intervention models to enhance early detection, personalize care, and reduce health inequities.

Cognitive and Biomarker Signatures of Late-Onset Temporal Lobe Epilepsy

Background and Objectives Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD). Methods This Italian cross-sectional cohort study included LO-TLE patients with normal CSF β-amyloid (Aβ) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups. Results The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory (t(53) = −7.79, pFDR < 0.001), short-term memory (t(53) = −2.94, pFDR = 0.007), language (t(53) = 4.12, pFDR < 0.001), and executive functions (t(53) = −3.76, pFDR < 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better (t(53) = 4.21, pFDR < 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic Aβ and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition (rs = 0.585, pFDR = 0.032) and short-term memory (rs = 0.588, pFDR = 0.032), whereas no associations emerged in MCI-AD. Discussion LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.

Sleep and Neurodegeneration.

OBJECTIVE This article discusses the relationship between sleep and neurodegenerative disorders. LATEST DEVELOPMENTS Sleep disorders disrupt neurotransmitters, facilitating the progression of neurodegenerative changes. Sleep impairment promotes amyloid-β aggregation, propagating memory impairment in neurodegenerative disorders. The use of biomarkers for early diagnosis of neurodegenerative disorders may include sleep features. Sleep apnea is associated with an increased risk of Parkinson disease. ESSENTIAL POINTS Sleep disorders, such as obstructive sleep apnea, are five times more likely in people with Alzheimer disease. Notably, individuals with genetic factors, including carriers of APOE4, are found to have decreased overall regulation of regions within the brain that control sleep. External factors that increase the risk of dementia include long-term use of antihistamines. The risk of mild cognitive impairment is reduced with the intake of 200 mg/d of caffeine, which aligns the circadian activity of suprachiasmatic nucleus cells. People diagnosed with idiopathic rapid eye movement (REM) sleep behavior disorders have more than a 90% risk of developing an α-synucleinopathy at 14 years follow-up.

Multimodal characterization of cortical hyperexcitability as a driver of cognitive decline in neurocognitive disorders: study protocol for the LENDÜLET Neurocognitive Research Project

Introduction Cognitive impairment is a major source of disability in neurodegenerative conditions, and it is also highly prevalent in autism spectrum disorder and attention-deficit/hyperactivity disorder. Across these conditions, subclinical epileptiform activity and resting-state functional hyperactivity have been repeatedly described, suggesting a shared state of cortical hyperexcitability. The LENDÜLET Neurocognitive Research Project aims to determine the incidence and multimodal characteristics of cortical hyperexcitability in multiple patient populations and to elucidate how hyperexcitability relates to cognitive performance, large-scale network connectivity, sleep-dependent memory consolidation, and tau/amyloid burden. Methods In a prospective, multimodal observational study, we are recruiting 75 participants per group (patients with mild cognitive impairment, patients with autism spectrum disorder, patients with attention deficit/hyperactivity disorder, and healthy controls; total N = 300) at the National Institute of Psychiatry and Addictology (Budapest, Hungary). All participants are undergoing a harmonized diagnostic protocol including detailed neuropsychological assessment, structural MRI, resting-state functional MRI, and 24-h ambulatory electroencephalography. Patients with neurodegenerative conditions will additionally undergo CSF sampling. Individuals who exhibit markers of cortical hyperexcitability will be invited to an in-ward mechanistic substudy (3-day video-electroencephalography monitoring with repeated neuropsychological paradigms, overnight sleep recordings, and spindle analysis, and serial blood sampling to characterize circadian dynamics of tau and amyloid. Anticipated results Primary outcome is the incidence and distribution of cortical hyperexcitability in each diagnostic group relative to controls. Secondary outcomes include relationships between hyperexcitability and (a) structural atrophy and white matter integrity; (b) functional connectivity within and between default mode, salience, and attention networks; (c) cerebrospinal and plasma tau/amyloid levels; and (e) domain-specific cognitive performance. The current paper describes the study design, while the results are not reported. Discussion This study will provide the first systematic, multimodal assessment of cortical hyperexcitability across multiple neurocognitive disorders with shared vulnerability to epilepsy and cognitive decline. The resulting biomarker panel may support risk stratification, inform clinical trial design for anti-hyperexcitability interventions, and ultimately enable individualized prevention strategies for cognitive decline.

Clinical, genetic, and neuropathologic correlates of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC): A systematic review and meta-analysis.

From function to structure: Cortical thickness correlates of olfactory dysfunction across cognitively normal, mild cognitive impairment and Parkinson's disease.

Decreased olfactory function occurs in over half of individuals aged 65-80 years, and in 62-80% of those over 80 years of age. Hyposmia is an early symptom and a potential marker for a number of neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD), and can predict the conversion from Mild Cognitive Impairment (MCI) to AD. Building on our previously published resting-state fMRI findings on olfactory network functional connectivity [10], this study examined the same 74 participants categorized as Cognitively Normal (CN), MCI, or PD with cognitive impairment (PD-CogImp) using the Brief Smell Identification Test (B-SIT®). Automated measurements of cortical thickness (CT) and volume for 34 bilateral cortical regions were obtained using FreeSurfer v7.3.2. A moderation analysis based on multiple linear regression was performed to investigate the relationship between B-SIT® scores and cortical measures, controlling for age, education, sex, APOE genotype, and estimated total intracranial volume (eTIV). A significant interaction effect of clinical diagnosis on the olfaction-cortical thickness relationship was identified in 3 out of 68 regions of interest (ROIs): the cuneus bilaterally and the right pericalcarine gyrus, all showing large effect sizes (η2 > 0.14). CN individuals showed a significant positive association between B-SIT® and CT in these regions, whereas MCI and PD-CogImp groups showed a negative trend. Cortical volume models yielded no significant findings after correction for multiple comparisons. These results highlight distinct diagnostic group-specific patterns in the olfaction-brain structure relationship, with implications for understanding early pathological aging and neurodegeneration.