Rapid Cognitive Decline Research Articles (Page 1)

Neuropsychiatric symptom trajectories across cognitive spectrums of Alzheimer's disease: Joint probabilities with cognitive and functional decline.

Cognitive decline commonly co-occurs with dynamic physical and mental health changes in older adults. While early-life adversity has been linked to various later-life health outcomes, its relationship with cognitive function considering different health trajectories remains unclear. To identify distinct clusters of physical-mental-cognitive health trajectories among Chinese older adults and to examine the association between childhood adversities and cognitive function across these trajectories. Using data from the China Health and Retirement Longitudinal Study (2011-2020), we included 6178 adults aged ≥60years. Latent Class Growth Modeling was used to identify trajectory patterns of functional limitations, depressive symptoms, and cognitive function. Mixed linear models examined associations between childhood adversities and cognitive function overall and across different identified trajectory patterns. Four distinct trajectory classes were identified: healthy individuals (59.8%), rapid cognitive decline with gradual physical-mental decline (16.5%), mild cognitive decline with physical-mental improvement (14.4%), and moderate cognitive decline with rapid physical and moderate mental decline (9.4%). Experience of multiple childhood adversities was significantly associated with lower cognitive function (β=-0.36, 95% CI [-0.58, -0.14]), independent of adulthood factors and consistent across various trajectory patterns. Among individuals showing rapid cognitive decline with gradual physical-mental deterioration, experiencing two childhood adversities predicted lower cognitive function (β=-0.88, 95% CI [-1.62, -0.14]). Childhood adversities are associated with cognitive impairment regardless of physical-mental-cognitive health trajectories in older Chinese adults. These findings highlight the long-term impact of early-life experiences on cognitive health in later life.

Longitudinal trajectories of neuropsychological functions of MCI subtypes in population-based cohort of older adults.

Background: Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and universally fatal neurodegenerative disorder caused by the accumulation of misfolded prion proteins. Early-stage diagnosis is often delayed due to its initially non-specific presentation and broad differential diagnosis. Case Presentation: We describe a 75-year-old male who presented with new-onset dizziness and a pressure-like headache. Neurological examination revealed subtle left-sided ataxia, mild anomic aphasia, and possible left-leg neglect. Initial investigations, including non-contrast cranial CT and carotid angiography, were unremarkable. Cognitive screening using the Montreal Cognitive Assessment (MoCA) scored 17/30. Persistent neurological deficits prompted further evaluation, including lumbar puncture, electroencephalography, and magnetic resonance imaging of the brain. CSF analysis showed a mildly elevated white cell count and was positive for 14-3-3 protein. Although RT-QuIC testing was uninterpretable due to CSF blood contamination, markedly elevated total tau (>1765 pg/mL) with normal phosphorylated tau (pTau181) supported a diagnosis of prion disease. MRI demonstrated asymmetric cortical diffusion restriction and characteristic cortical ribboning. EEG revealed a diffuse encephalopathic pattern without periodic discharges. With the rapid evolution of cognitive dysfunction, cerebellar ataxia, and extrapyramidal signs, the clinical, radiological, and biochemical findings fulfilled diagnostic criteria for probable sporadic CJD. Conclusion: This case underscores the importance of a multimodal diagnostic approach in suspected CJD. In the absence of definitive RT-QuIC results or characteristic EEG changes, early recognition of MRI patterns and CSF biomarkers remains pivotal for timely diagnosis, appropriate counseling, and care planning.

BACKGROUND Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative condition caused by misfolded prion proteins. It most commonly presents with rapidly progressive dementia and neurological deterioration. While psychiatric symptoms are not unusual in the early stages of CJD, it is very uncommon for the disease to begin with manic features as the primary presentation. CASE REPORT We describe the case of a 65-year-old woman who initially developed symptoms consistent with mania. These included an elevated mood, emotional instability, and insomnia. Over time, her clinical condition worsened, and she began to experience hallucinations, along with a noticeable motor decline. Due to the atypical nature of her initial symptoms, she was first treated for viral encephalitis, which contributed to a delay in establishing the correct diagnosis. Subsequent investigations played a key role in clarifying the underlying pathology. Brain magnetic resonance imaging (MRI) revealed characteristic findings of CJD, including cortical ribboning and changes in the basal ganglia. Electroencephalography (EEG) showed periodic sharp-wave complexes, further supporting the diagnosis. Cerebrospinal fluid analysis tested positive for prion protein using real-time quaking-induced conversion (RT-QuIC), confirming a final diagnosis of sporadic CJD (sCJD). CONCLUSIONS Although rare, mania can be an early sign of CJD. This case illustrates the diagnostic challenges that arise when psychiatric symptoms dominate the initial clinical picture. It emphasizes the importance of maintaining a broad differential diagnosis when evaluating new-onset psychiatric symptoms in older adults, especially when these symptoms are accompanied by a rapid decline in cognition or motor function. Early consideration of CJD in such scenarios may help expedite diagnosis, avoid unnecessary treatments, and provide clarity for patients and families facing a progressive and life-limiting illness.

INTRODUCTIONPolygenic risk score (PRS) identifies individuals at high genetic risk for Alzheimer's disease (AD), but its utility in predicting cognitive trajectories and AD pathologies remains unclear. We optimized PRS (optPRS) for AD, investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.METHODSUsing genome‐wide association study (GWAS) summary statistics from a European population, we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell–derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p‐tau) levels.RESULTSOptPRS predicted AD dementia and Aβ positivity, independent of apolipoprotein E (APOE). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p‐tau levels.CONCLUSIONOptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug‐screening platform.HighlightsOptimized polygenic risk scores (optPRSs) improve the prediction of Alzheimer's disease (AD) dementia and amyloid beta positivity (Aβ+).High optPRS is associated with faster cognitive decline, particularly in Aβ+.Induced pluripotent stem cell (iPSC)–derived cerebral organoids from high optPRSs show high Aβ insolubility and phosphorylated tau (p‐tau).PRS genetic risk stratification provides insight into AD progression and pathology.

Depressive symptoms and cognitive function trajectories in frail middle-aged and older adults: A longitudinal analysis based on the CHARLS cohort (2011-2018).

Cognitive function, psychobehavioral symptoms, and MRI features in patients with non-demented Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies.

Behavioral Variant Frontotemporal Dementia as a Catalyst for Caregiver Stress Syndrome: A Neuropsychiatric and Sociopolitical Examination

IntroductionThe global burden of chronic kidney disease (CKD) in elderly patients is rising, presenting significant management challenges. These patients often experience rapid cognitive and physical decline following dialysis initiation, complicating treatment decisions. Given that age alone is an insufficient criterion for identifying candidates likely to benefit from dialysis, an optimal shared decision-making model should integrate clinical parameters related to comorbid conditions, as well as patient-centered factors such as individual values and treatment preferences. Traditional models, such as the REIN and Wick scores, use predefined linear relationships and are often based on Western populations, limiting their generalizability. Machine learning (ML) offers an innovative approach by identifying complex, nonlinear relationships in diverse datasets, potentially improving predictive accuracy.MethodsThis study aimed to develop ML models to predict six-month mortality in elderly patients initiating haemodialysis. We used data from a single-center cohort of 1,606 patients with advanced CKD, aged ≥65 years, who initiated haemodialysis at Changi General Hospital, Singapore, between January 2015 and October 2023. Specifically, random forest and balanced random forest models were developed and their predictive performance was compared with existing prognostic tools. Both models incorporated feature importance rankings determined by SHapley Additive exPlanations (SHAP).ResultsThe normal random forest model marginally outperformed the balanced random forest model, achieving an area under the receiver operating characteristic curve (ROC-AUC) of 0.83 (95% CI 0.775 – 0.874) versus 0.82 (95% CI: 0.772 – 0.873). Both models demonstrated superior performance and calibration compared to conventional tools.ConclusionThis study demonstrates that ML-based models may offer modest improvements in predicting six-month mortality in elderly patients with end-stage renal disease (ESRD). These tools could support, but not replace, shared decision-making by providing additional prognostic insights alongside clinical judgment.Clinical trial numberNot applicable.

INTRODUCTIONIncreasing evidence indicates that α‐synuclein (αSYN) oligomers are toxic. We sought to determine whether αSYN oligomers were associated with faster cognitive decline in prospectively‐followed patients with dementia with Lewy bodies (DLB).METHODSEight autopsy‐confirmed patients with DLB were selected based on rapid or slow cognitive decline determined by the rate of change of Mini‐Mental State Examination (MMSE) scores. Quantitative neuropathologic analysis of αSYN oligomers, Lewy‐related pathology, phosphorylated tau, and amyloid‐β was conducted in hippocampal subfields (CA1‐4 and subiculum) and the entorhinal cortex.RESULTSDLB with rapid cognitive decline showed greater CA1 αSYN oligomer burden (p = 0.029) and tau burden (p = 0.029) than DLB with slow decline. The groups showed comparable burden of Lewy‐related pathology and amyloid‐β pathology in the hippocampal formation and entorhinal cortex.DISCUSSIONHippocampal accumulation of αSYN oligomers and phosphorylated tau is associated with rapid cognitive decline in DLB. Therapeutic strategies targeting αSYN oligomers warrant further investigation.HighlightsProximity ligation assay (PLA) and digital pathology for oligomer quantification.Abundant α‐synuclein (αSYN) oligomers in CA1 of patients with dementia with Lewy bodies (DLB) with rapid decline.First human brain study linking αSYN oligomers to cognitive trajectory.Potential therapeutic implications of targeting αSYN oligomers in DLB.

Group-based trajectory modelling for cognitive changes in middle-aged and older adults: A systematic review.

We present the case of a 74-year-old woman with behavioral variant frontotemporal dementia (bvFTD) linked to a pathogenic TANK-binding kinase 1 (TBK1) mutation (c.1349_1352del; p.Ile450Lysfs*15). During clinical workup, the patient underwent comprehensive biomarker analysis, including tau positron emission tomography (PET) and cerebrospinal fluid (CSF) seed amplification assay (SAA) for α-synuclein (αSyn). While CSF biomarkers for Alzheimer's disease were normal, the αSyn SAA was clearly positive, indicating misfolded αSyn aggregates. Tau PET revealed increased [18F]PI-2620 uptake in the basal ganglia. Genetic testing confirmed autosomal dominant TBK1-associated FTD. The patient's condition deteriorated over the following year, with rapid cognitive decline and the emergence of cortical signs. Post-mortem neuropathological analysis confirmed multiple proteinopathies: FTLD-TDP43 (subtype A), Lewy body disease (limbic type, Braak stage 5), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), and primary age-related tauopathy (PART). This is the first reported TBK1-FTD case with in vivo detection of αSyn pathology via SAA and in vivo monitoring of tau pathology. The case expands the clinical and neuropathological spectrum of TBK1-associated FTD. Our findings support a broader interpretation of TBK1-associated neurodegeneration and highlight the importance of multimodal diagnostic approaches that integrate molecular, genetic, imaging, and neuropathological tools. This case also underscores the utility of αSyn SAA and tau PET in detecting co-pathologies that may otherwise remain clinically silent and illustrates the need for further studies exploring the molecular cross-talk between TBK1, tau, and αSyn pathologies.

Sleep fragmentation is common in older adults and is associated with cognitive impairment and dementia, as well as key histopathological correlates of dementia, including small vessel disease and cerebral infarcts. Vascular and blood–brain barrier dysfunction are thought to contribute to cognitive decline and dementia. Pericytes, a key vascular cell type, may play a key role.In model organisms, sleep disruption is associated with pericyte dysfunction and blood–brain barrier breakdown. Recent advances in single-nucleus RNA sequencing (snRNAseq) technology have identified two transcriptionally distinct subtypes of pericytes: extracellular matrix protein-expressing M-pericytes and solute carrier-expressing T-pericytes. However, the relationship between sleep, pericyte biology and cognition in humans remains unclear.We tested the hypothesis that differences in the composition of brain pericyte subpopulations, as inferred from marker gene expression, may link sleep fragmentation and cognitive decline. We leveraged two published human brain snRNAseq datasets to identify specific marker genes for M- and T-type pericytes. We then used post-mortem bulk RNAseq data from the dorsolateral prefrontal cortex (n = 1092) and lateral orbitofrontal cortex (n = 495) to quantify expression of these marker genes in older adults in two longitudinal cohort studies: the Religious Orders Study and Rush Memory and Aging Project. We derived trajectories of global cognitive function from participants’ ante-mortem annual cognitive assessments, while sleep fragmentation was derived from ante-mortem wrist-actigraphy recordings from a subset of 572 participants. We used multivariate linear regression to relate pericyte marker gene expression to sleep fragmentation and cognitive decline in the decade preceding death.In the dorsolateral prefrontal cortex, greater average sleep fragmentation was associated with greater expression of M-pericyte marker genes [estimate = +3.65 × 10−1, standard error (SE) = 1.61 × 10−1, P = 0.024] but not T-pericyte marker genes. Dorsolateral prefrontal cortex expression of M-pericyte (estimate = −8.30 × 10−3, SE = 3.37 × 10−3, P = 0.014) but not T-pericyte marker genes was associated with more rapid cognitive decline in the 10 years prior to death. In the lateral orbitofrontal cortex, greater sleep fragmentation was also associated with greater composite M-pericyte gene expression (estimate = + 4.48 × 10−1, SE = 1.92 × 10−1, P = 0.02), which in turn was associated with faster cognitive decline in the decade preceding death (estimate = −1.30 × 10−2, SE = 4.55 × 10−3, P = 0.0044).These findings identify a potential role of M-pericytes in linking sleep fragmentation and cognitive trajectories in older adults. Additionally, our findings highlight the importance of vascular mechanisms in linking disrupted sleep to dementia.

This case study investigates the impact of Lyme neuroborreliosis (LNB) on cognitive and executive functions in a 60- year-old pilot. Using purposive sampling, the participant’s executive function was assessed with the Delis-Kaplan Executive Function System (D-KEFS), and memory was evaluated with the Wechsler Memory Scale (WMS). A quantitative approach employing paired with t-tests compared to cognitive performance before and after LNB diagnosis. Results showed a significant decline in memory function post-LNB (t (3) = 3.055, p = 0.028). Executive function also declined, particularly in visual scanning and inhibition, although these changes were not statistically significant (t (2) = 2.079, p = 0.087). These findings suggest that LNB may contribute to cognitive deterioration, especially in memory domains. The rapid cognitive decline observed within six months from superior to below-average performance highlights the aggressive progression of Lyme neuroborreliosis on cognitive function especially in memory. This swift deterioration underscores the urgent need for early and comprehensive cognitive assessments to enable timely intervention and support. Given the study limitation of a single participant and no control group, further research with larger samples is necessary. Comprehensive cognitive assessments are recommended for individuals with LNB to facilitate timely intervention and support.

BackgroundAlzheimer disease (AD) clinical progression is highly heterogeneous, making its prediction essential for the development of effective therapies. The advancement of cognitive decline in AD is tightly linked to the spread of pathological tau protein aggregates in the brain, through tau seeding properties.MethodsWe developed a cellular biosensor to measure tau seeding activity from cerebrospinal fluid (CSF) and human brain lysates. Longitudinal analysis of cognitive function was correlated with biosensor response.ResultsIndividuals with CSF exhibiting high or intermediate seeding activity experienced more rapid cognitive decline compared to those with low seeding. High tau seeding was associated with total and phosphorylated tau biomarkers in AD. The biosensor also predicts the potential of human AD brain lysates to induce tau aggregation upon experimental transmission in animal models.ConclusionsThese results suggest that seeding activity might be a relevant biomarker to forecast AD pathogenicity and clinical progression.

Impact of Y chromosome loss on the risk of Parkinson's disease and progression.

Cognitive Reserve (CR) represents the brain’s ability to maintain function despite neurodegenerative pathology, with synaptic plasticity playing a crucial role in this adaptability. While high CR individuals often experience delayed onset of Alzheimer’s disease (AD) symptoms, they tend to exhibit rapid cognitive decline once pathology surpasses compensatory mechanisms. This paradox underscores the importance of understanding the relationship between CR and synaptic plasticity. In this review, we explore the biological underpinnings of CR, the role of synaptic plasticity in cognitive resilience, and the adaptive versus maladaptive consequences of neuroplasticity in AD. Additionally, we highlight challenges in CR research, such as its measurement and the need for longitudinal studies, and propose future research directions to enhance therapeutic strategies aimed at strengthening CR mechanisms.

Transmissible spongiform encephalopathies are uncommon neurodegenerative diseases caused by misfolded prion protein deposition. Creutzfeldt-Jakob disease (CJD), the commonest human spongiform encephalopathy, has an average survival of 5 months. Common presenting symptoms are rapid cognitive decline, psychiatric disturbances, cerebellar ataxia, visual deficits, and movement disorders including myoclonus and parkinsonism. CJD may also present in atypical and nonspecific ways, hampering diagnosis. We present 3 pathologically verified cases with unusual onset and a review of recent literature on early clinical features of CJD. MRI and CSF biomarkers are generally less sensitive in patients with atypical presentations, and in such cases the disease course may be longer than in typical CJD.

Aims: Creutzfeldt–Jakob Disease (CJD) is a rare, fatal neurodegenerative disorder caused by prion proteins, leading to progressive brain damage. CJD has sporadic, variant, genetic, and iatrogenic forms, with sporadic being the most common, affecting 1–2 people per million annually. It typically presents with rapid cognitive decline, motor dysfunction, and personality changes, with no effective treatment available.Methods: A 59-year-old physically fit, male with no past medical history presented to A&E with a two-week history of behavioural changes, aggression, left facial droop, disorientation, poor coordination, and mild dysarthria. He had repetitive speech and his GCS on admission was 14/15.Stroke was suspected and CT scan showed hypoattenuation of the right frontal lobe. Contrast MRI showed multifocal areas of gyriform diffusion restriction affecting bilateral cerebral hemispheres. Initial differential diagnoses were stroke, vasogenic oedema, old brain injury, post-ictal changes, encephalitis. EEG and initial blood tests were normal. CSF analysis revealed elevated proteins, normal glucose and lactate and no oligoclonal bands. CSF virology and cultures were negative. A protein assay from specialist services in Edinburgh confirmed a diagnosis of sporadic CJD.The patient was discharged to a care home with clonazepam and a plan to introduce low-dose quetiapine if needed. Upon transfer, he became increasingly agitated, displaying verbal and physical aggression towards staff and residents, wandering and damaging property. His sleep was poor, and his aggression unpredictable, escalating late in the evening. The care home implemented a low-stimulus environment with one-to-one care and covert medication administration. Initially treated with quetiapine and benzodiazepines, his aggression persisted, prompting introduction of haloperidol, which resulted in some reduction in aggression. He was later transferred to an inpatient ward.On the ward, his dysphasia worsened, but he had no further behavioural challenges. He received regular physiotherapy, occupational therapy and specialised nursing care. Parkinsonism symptoms prompted the discontinuation of haloperidol, which was later reinstated at a lower dose due to return of restlessness. Quetiapine was gradually tapered off. At discharge, he was compliant with medication, required assistance with feeding and personal care, had severe dysphasia and some ataxia.Results: This case demonstrates the atypical presentation of CJD with neuropsychiatric symptoms at onset, rather than the usual neurological signs. The patient’s agitation and aggression required careful pharmacological adjustments and highlighted challenges in managing CJD’s neuropsychiatric symptoms.Conclusion: This case highlights the importance of considering CJD in the differential diagnosis for patients with rapid-onset neuropsychiatric disturbances. Early recognition and symptomatic management, although not curative, can improve the patient’s quality of life during the disease’s progression.