Christian Sandøe Musaeus

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable condition, but predicting shunt response remains challenging. Cerebrospinal fluid (CSF) biomarkers, including phosphorylated tau (p-tau181), have been suggested as potential predictors, although existing evidence is inconsistent. Methods: In this retrospective single-center study, we included 230 patients with probable or possible iNPH who underwent shunt surgery and had available CSF biomarker data for Amyloid beta42, total tau and phosphorylated tau 181. Patients were divided into two cohorts based on assay method (Innotest ^® and Elecsys ^® ). The primary outcome was improvement in gait score. Secondary outcomes included cognition, continence, and overall clinical response. Predictive performance of CSF p-tau181 was evaluated using logistic regression and receiver operating characteristic (ROC) analyses. Results: Mean CSF p-tau181 levels did not differ significantly between responders and non-responders in either cohort. In multivariable logistic regression analyses adjusted for age and sex, CSF p-tau181 was not associated with shunt response (Innotest ^® : OR 0.997 (0.972–1.024), p = 0.815; Elecsys ^® : OR 1.091 (0.910–1.419), p = 0.429). Findings were consistent across two CSF p-tau181 assay platforms, although the Elecsys ^® cohort was underpowered for calculating AUC with only 14 non-responders. Similar results were observed across secondary outcomes and after exclusion of patients with high CSF p-tau181 levels to reduce potential confounding by concomitant Alzheimer’s disease pathology. Conclusion: CSF p-tau181 does not demonstrate clinically meaningful predictive value for shunt response in patients with iNPH and cannot alone guide patient selection for shunt surgery. Future research should focus on multimodal approaches integrating clinical, radiological, and biochemical markers.

Cerebral amyloid angiopathy (CAA) is associated with transient focal neurological episodes (TFNEs), which are brief, stereotyped symptoms. As these may occur regularly, pharmacological treatment of TFNEs is needed but remains poorly investigated. To systematically evaluate the available evidence on the use of pharmacological treatment to reduce the frequency, severity, or duration of TFNEs in patients with CAA. A systematic literature search of PubMed and Embase was conducted. Eligible studies included observational studies, interventional trials, and case reports or series that assessed pharmacological interventions for TFNEs in patients with confirmed CAA. Nine case reports/series involving 13 patients met the inclusion criteria. The mean age was 75.15 years, with a predominance of sensory and motor TFNE symptoms. One EEG recording out of nine reported paroxysmal activity whereas the rest showed no epileptiform activity. Antiseizure medications (levetiracetam) were the most common treatment. Eleven patients experienced complete remission, and two had partial improvement. Most patients exhibited convexity subarachnoid hemorrhage or cortical superficial siderosis on imaging. Although symptomatic improvement following pharmacological treatment was commonly reported, the current evidence is limited to descriptive case reports without control groups. The unpredictable course of TFNEs and absence of long-term follow-up complicate treatment evaluation. Larger, controlled studies or observational studies are needed to establish effective and evidence-based treatment strategies for TFNEs in CAA.

Epileptiform discharges in Alzheimer’s disease (AD) and Lewy body dementia (DLB) may be associated with cognitive decline. Iron accumulation has been implicated in neurodegenerative processes; however, its relationship to epileptiform discharges remains unknown. In addition, the relationship between iron deposition, structural brain changes, and epileptiform discharges remains unclear. The objective is to investigate whether iron deposition and structural brain atrophy are associated with epileptiform discharges in patients with AD, DLB, and healthy controls (HCs). A total of 25 patients with AD, 10 patients with DLB, and 15 HCs were included in the analysis. The participants underwent MRI including quantitative susceptibility mapping (QSM) and structural T1-weighted imaging. We examined the four regions of interest, which are tied to iron deposition and AD pathology. Ear-EEG recordings were used to quantify spike frequency (epileptiform discharges/24 h). No significant group differences were found for susceptibility across regions. Susceptibility was not associated with spike frequency. Patients with AD exhibited significant hippocampal atrophy. Higher hippocampal volume was associated with lower spike rates in adjusted models. Susceptibility and hippocampal volume were associated, and in a multilinear model with age, hippocampal volume accounted for a larger proportion of the explained variance. This study found no evidence linking iron deposition to epileptiform discharges in AD or DLB. Instead, hippocampal atrophy appears more strongly associated with epileptiform discharges, which could indicate that the underlying pathological processes rather than iron are the primary driving factor for epileptiform discharges.

Background: Cognitive testing is critical for screening, diagnosing, and monitoring neurocognitive disorders, but current tests are limited by long administration times and the need for trained personnel. Digital cognitive testing offers a convenient and highly repeatable alternative to track cognitive decline, which is essential for evaluating patient care and in clinical trials. To address these limitations, we developed a novel digital spatial working memory test called the D-Cog. Objective: This study aimed to assess the feasibility, validity, and diagnostic utility of the D-Cog in a clinical population. Methods: Patients with Alzheimer's disease (AD), Lewy body dementia (DLB), Parkinson's disease (PD), and cognitively normal controls (CN) were included. During clinical visits, a medical assistant administered the D-Cog test, presented as a “serious game” on an iPad. Results: The D-Cog showed high participant engagement, although engagement decreased with advancing cognitive impairment. A significant difference in the mean D-Cog score was observed between CN and both AD and DLB/PD groups (p < 0.003). Additionally, a significant correlation between the D-Cog score and the Mini-Mental State Examination was identified (r = 0.65, p < 0.001, 95% CI: 0.52–0.75). The D-Cog demonstrated good discrimination between groups, with AUCs of 0.96 (95% CI: 0.91–1.00) for AD versus healthy controls and 0.88 (95% CI: 0.75–0.97) for MCI versus healthy controls. Conclusions: The D-Cog is a feasible and valid digital cognitive test with potential clinical utility across neurocognitive disorders. Although engagement was lower in advanced dementia, these findings support further development and exploration of the D-Cog, particularly for potential in-home assessments.

Brain metabolism is reduced in patients with dementia disorders, as demonstrated by hypometabolism on 2-deoxy-2-[ ¹⁸ F]fluoroglucose ([ ¹⁸ F]FDG) positron emissions tomography. A contributing factor to the hypometabolism could be decreased cerebral blood flow (CBF) leading to a state of subtle hypoperfusion‐induced tissue hypoxia causing a reduced brain oxygen metabolism and consequently elevated brain lactate. In the current exploratory study, we investigated brain lactate, global and regional CBF, and global cerebral metabolic rate of oxygen (CMRO ₂ ) in patients with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLBs). We hypothesized that the patients demonstrate a state of tissue hypoxia with reduced CMRO ₂ and elevated brain lactate concentration. Participants included 24 AD patients, 10 DLB patients, and 15 healthy controls. MR spectroscopy measured lactate in the precuneus and occipital lobe. Global CBF and venous oxygen saturation (for CMRO2 calculation) were assessed using phase-contrast and susceptibility-based oximetry MRI, respectively. Regional CBF was measured with ASL-MRI. We observed no significant difference in either brain lactate or CMRO ₂ between groups. The regional CBF in precuneus was significantly lower in AD compared to HC; however, this hypoperfusion was not associated with a higher lactate concentration. The lack of a difference in CMRO ₂ or lactate concentration between patients and controls suggests that the hypometabolism observed in patients with AD and DLB may reflect structural neurodegeneration and not a state of tissue hypoxia. The local decrease of CBF in precuneus in patients with AD may be due to a lower CBF demand due to neurodegeneration.

Background: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer’s disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer’s disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus. Methods: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG. Results: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC. Conclusions: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD. Trial registration: The study is registered at clinicaltrials.gov (NCT04436341).

Background: In patients with Alzheimer’s disease (AD) without clinical seizures, up to half have epileptiform discharges in long‐term in‐patient electroencephalography (EEG) recordings. Long‐term in‐patient monitoring is obtrusive, and expensive as compared to out‐patient monitoring. No studies have so far investigated if long‐term out‐patient EEG monitoring is able to identify epileptiform discharges in AD. To investigate if epileptiform discharges as measured with ear‐EEG are more common in patients with AD compared to healthy elderly controls (HC). To understand the association with AD, we investigated the variability across multiple recordings.Method: In this longitudinal observational study, 24 patients with mild to moderate AD and 15 age‐matched HC were included in the analysis. Patients with AD underwent up to three ear‐EEG recordings, each lasting up to two days, within 6 months. The first recording was defined as the baseline recording.Result: At baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p‐value = 0.073). The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77‐5.01, p<0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear‐EEG recordings.Conclusion: Long‐term ear‐EEG monitoring detects epileptiform discharges in most patients with AD with a three‐fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD.