Locus coeruleus integrity and neuropsychiatric symptoms in a cohort of early- and late-onset Alzheimer's disease.

INTRODUCTION: Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage. METHODS: One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations. RESULTS: EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers. DISCUSSION: Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD. HIGHLIGHTS: LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

Sex differences in early-onset Alzheimer's disease.

BACKGROUND AND PURPOSE: Sex is believed to drive heterogeneity in Alzheimer's disease (AD), although evidence in early-onset AD (EOAD; <65 years) is scarce. METHODS: We included 62 EOAD patients and 44 healthy controls (HCs) with core AD cerebrospinal fluid (CSF) biomarkers, neurofilament light chain levels, neuropsychological assessment, and 3-T magnetic resonance imaging. We measured cortical thickness (CTh) and hippocampal subfield volumes (HpS) using FreeSurfer. Adjusted linear models were used to analyze sex-differences and the relationship between atrophy and cognition. RESULTS: Compared to same-sex HCs, female EOAD subjects showed greater cognitive impairment and broader atrophy burden than male EOAD subjects. In a direct female-EOAD versus male-EOAD comparison, there were slight differences in temporal CTh, with no differences in cognition or HpS. CSF tau levels were higher in female EOAD than in male EOAD subjects. Greater atrophy was associated with worse cognition in female EOAD subjects. CONCLUSIONS: At diagnosis, there are sex differences in the pattern of cognitive impairment, atrophy burden, and CSF tau in EOAD, suggesting there is an influence of sex on pathology spreading and susceptibility to the disease in EOAD.

Hemichorea as Presentation of Acute Cortical Ischemic Stroke. Case Series and Review of the Literature.

Hemichorea and other hyperkinetic movement disorders are a rare presentation of stroke, usually secondary to deep infarctions affecting the basal ganglia and the thalamus. Chorea can also result from lesions limited to the cortex, as shown in recent reports. Still, the pathophysiology of this form of cortical stroke-related chorea remains unknown. We report 4 cases of acute ischemic cortical strokes presenting as hemichorea, with the infarction being limited to the parietal and insular cortex in perfusion computed tomography scans and magnetic resonance imaging. These cases suggest potential dysfunction of pathways connecting these cortical regions with the basal ganglia.

Beyond group classification: Probabilistic differential diagnosis of frontotemporal dementia and Alzheimer's disease with MRI and CSF biomarkers.

Neuroimaging and fluid biomarkers are used to differentiate frontotemporal dementia (FTD) from Alzheimer's disease (AD). We implemented a machine learning algorithm that provides individual probabilistic scores based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. We investigated whether combining MRI and CSF levels could improve the diagnosis confidence. 215 AD patients, 103 FTD patients, and 173 healthy controls (CTR) were studied. With MRI data, we obtained an accuracy of 82 % for AD vs. FTD. A total of 74 % of FTD and 73 % of AD participants have a high probability of accurate diagnosis. Adding CSF-NfL and 14-3-3 levels improved the accuracy and the number of patients in the confidence group for differentiating FTD from AD. We obtain individual diagnostic probabilities with high precision to address the problem of confidence in the diagnosis. We suggest when MRI, CSF, or the combination are necessary to improve the FTD and AD diagnosis. This algorithm holds promise towards clinical applications as support to clinical findings or in settings with limited access to expert diagnoses.

Impact of demographics and comorbid conditions on plasma biomarkers concentrations and their diagnostic accuracy in a memory clinic cohort.

Plasma biomarkers have emerged as promising tools for identifying amyloid beta (Aß) pathology. Before implementation in routine clinical practice, confounding factors modifying their concentration beyond neurodegenerative diseases should be identified. We studied the association of a comprehensive list of demographics, comorbidities, medication and laboratory parameters with plasma p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) on a prospective memory clinic cohort and studied their impact on diagnostic accuracy for discriminating CSF/amyloid PET-defined Aß status. Three hundred sixty patients (mean age 66.5 years, 55% females, 53% Aß positive) were included. Sex, age and Aß status-adjusted models showed that only estimated glomerular filtration rate (eGFR, standardized ß -0.115 [-0.192 to -0.035], p = 0.005) was associated with p-tau181 levels, although with a much smaller effect than Aß status (0.685 [0.607-0.763], p < 0.001). Age, sex, body mass index (BMI), Charlson comorbidity index (CCI) and eGFR significantly modified GFAP concentration. Age, blood volume (BV) and eGFR were associated with NfL levels. p-tau181 predicted Aß status with 87% sensitivity and specificity with no relevant increase in diagnostic performance by adding any of the confounding factors. Using two cut-offs, plasma p-tau181 could have spared 62% of amyloid-PET/CSF testing. Excluding patients with chronic kidney disease did not change the proposed cut-offs nor the diagnostic performance. In conclusion, in a memory clinic cohort, age, sex, eGFR, BMI, BV and CCI slightly modified plasma p-tau181, GFAP and NfL concentrations but their impact on the diagnostic accuracy of plasma biomarkers for Aß status discrimination was minimal.

Cognitive profile, neuroimaging and fluid biomarkers in post-acute COVID-19 syndrome.

We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

Sleep in Gerstmann-Straüssler-Scheinker disease.

BACKGROUND: Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. METHODS: We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. RESULTS: Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. CONCLUSIONS: In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.

Diagnostic Performance and Clinical Applicability of Blood-Based Biomarkers in a Prospective Memory Clinic Cohort.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. METHODS: All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. RESULTS: Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. DISCUSSION: Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

Assessment of Cognitive Symptoms in Brain Bank-Registered Control Subjects: Feasibility and Utility of a Telephone-Based Screening.

BACKGROUND: For neuroscience research, the study of brain tissue of neurologically unimpaired subjects is crucial to interpret findings in neurodegenerative diseases. Sub-optimal neurological follow-up and the presence of neuropathological lesions in supposedly asymptomatic subjects casts doubt as to whether these subjects present an undetected underlying neurodegenerative disease or are resilient to neurodegeneration. OBJECTIVE: We aimed to assess whether the control donors registered in the Neurological Tissue Bank-Hospital Clínic-IDIBAPS (NTB-HCI) are still free of cognitive symptoms at follow-up and to evaluate the feasibility and utility of a telephone-based screening. METHODS: All control subjects older than 65 years registered at the NTB-HCI database were selected for the study. After a structured telephone interview, those subjects already diagnosed with a neurological disease were excluded. Then, a cognitive screening was performed, including the telephone version of the Mini-Mental State Examination (t-MMSE) and the eight-item interview (AD-8) to the subject and to one informant (AD-8i). RESULTS: In total, 73.8% of the registered donors collaborated in the study. Only 21.4% had at least one of the three cognitive screening tools impaired, and 2.7% had a profile highly suggestive of cognitive impairment. AD-8i correlated moderately with t-MMSE. CONCLUSION: Telephone-based neurologic screening in control donors is feasible and was within the normal range in most of the subjects in our cohort. Albeit, the involvement of neurologists and periodic neurological screenings are desirable in a control subjects brain donor program, AD8-i could be used to screen the control's neurological status in the absence of accurate clinical data at the time of the death.

Clinically reversible ustekinumab-induced encephalopathy: case report and review of the literature.

Ustekinumab, a monoclonal antibody against interleukin (IL)-12 and IL-23 approved for the treatment of Crohn's disease, has shown to be an effective therapy with a favourable safety profile. Clinical trials and real-world studies have reported very few neurological adverse events, including posterior reversible encephalopathy syndrome, idiopathic intracranial hypertension and headache. We describe the case of a 48-year-old man with Crohn's disease who initiated treatment with ustekinumab on top of ongoing treatment with methotrexate 25 mg/week who presented with an acute-onset encephalopathy that rapidly evolved to severe tetraparesis and akinetic mutism, associated with extensive leukoencephalopathy and restricted diffusion on brain magnetic resonance imaging (MRI), 1 month after the second dose of ustekinumab. Comprehensive in-patient diagnostic testing ruled out vascular, demyelinating, metabolic, tumoral and infectious etiologies. Brain biopsy showed patchy infiltrates of foamy histiocytes with perivascular distribution, associated with edema, diffuse astrocytic gliosis and focal perivascular axonal destruction without demyelination, and ustekinumab-induced neurotoxicity was suspected. After drug discontinuation, the patient presented a complete clinical recovery despite the persistence of leukoencephalopathy. In conclusion, in an era in which biological therapies are continually evolving and expanding, knowledge about the potential neurotoxicity of these new therapies and their management becomes crucial. Although ustekinumab-induced encephalopathy is uncommon, the recognition of this potentially serious side effect is important because prompt withdrawal is associated with a favourable outcome. Whether methotrexate played an additional contributing role is currently unknown, but it is a factor that should be considered.

Evolution of Clinical-Pathological Correlations in Early-Onset Alzheimer's Disease Over a 25-Year Period in an Academic Brain Bank.

BACKGROUND: Early onset Alzheimer's disease (EOAD) represents a diagnostic challenge and is associated with a high diagnostic delay and misdiagnosis. OBJECTIVE: To describe clinical and pathological data from a pathologically confirmed EOAD cohort and evaluate evolving trends in clinical-pathological correlation accuracy. METHODS: Retrospective review of clinical and neuropathological data of pathologically confirmed EOAD patients (age at onset [AAO] < 60). Comparison between two periods: 1994- 2009 and 2010- 2018. RESULTS: Eighty brain donors were included. Mean AAO, age at death, and diagnostic delay was 55, 66, and 3 years, respectively. Twenty-nine percent had a nonamnestic presentation. Sixteen percent were given a non-AD initial clinical diagnosis (initial misdiagnosis) and 14% received a final misdiagnosis. Nonamnestic presentation patients received more misdiagnoses than amnestic presentation ones (39% versus 7% and 39% versus 3.5%, on initial and final misdiagnosis, respectively). When comparing both time periods, a trend towards a higher diagnostic accuracy in the 2010- 2018 period was observed, mainly on initial misdiagnosis in nonamnestic presentation patients (53% versus 13%, p = 0.069). Diagnostic delay was similar between both periods. Cerebral amyloid angiopathy (96%) and Lewy body co-pathology (55%) were very frequent, while limbic-predominant age-related TDP-43 encephalopathy pathologic changes were only present in 12.5%. CONCLUSION: In the last decade, there has been a trend towards improved diagnostic accuracy in EOAD, which might be explained by improved diagnostic criteria, increasing experience on EOAD and the beginning of the use of biomarkers, although diagnostic delay remains similar. Concomitant neuropathology was very frequent despite the relatively young age of brain donors.

Spinal cord hemodynamic infarction after vertebral artery endovascular trapping despite preserved flow in the anterior spinal artery.

Context: Spinal cord infarction is a rare condition that develops as a result of insufficient vascular perfusion, sometimes related to procedures involving the aorta and vertebral arteries.Findings: We present the case of a 66-year-old woman who developed weakness on all four extremities and thermalgesic sensory deficit following an elective endovascular embolization of an incidentally diagnosed aneurysm in the posterior circulation. The procedure involved the cathetherization of both vertebral arteries, but was unremarkable and the flow into the anterior spinal artery was preserved. Radiological findings highly suggested a spinal cord infarction. She was started on corticosteroids and showed a significant neurological improvement.Clinical relevance: The present case illustrates that spinal cord infarction is a typical - but uncommon - complication that has to be suspected after vertebral artery endovascular procedures. It can result from hypoperfusion of smaller branches that irrigate the cervical spinal cord, and patients can make remarkable recoveries despite severe initial deficits.