Strengthening of Existing Episodic Memories Through Non-invasive Stimulation of Prefrontal Cortex in Older Adults with Subjective Memory Complaints

Episodic memory is critical to daily life functioning. This type of declarative memory declines with age and is the earliest cognitive function to be compromised in Alzheimer’s disease (AD). Subjective memory complaints are commonly reported by older adults and have been considered a risk factor for developing AD. The possibilities for prevention of memory disorders in older adults have increased substantially in recent years. Previous studies have shown that anodal transcranial Direct Current Stimulation (tDCS) applied over the left lateral prefrontal cortex (PFC) after a contextual reminder strengthened existing verbal episodic memories, conceivably through reconsolidation, in elderly people. In this study, we hypothesized that anodal tDCS applied over the left lateral PFC after a contextual reminder would improve delayed memory retrieval relative to placebo (sham) stimulation in elderly individuals with SMC. Twenty-two subjects learned a list of words. Twenty-four hour later, tDCS (anodal or placebo) was applied over the left lateral PFC after a contextual reminder. Memory retrieval was tested 48h and 30 days later. These findings showed that anodal tDCS over the left lateral PFC strengthened existing episodic memories, a behavioral effect documented by improved recognition up to 30 days, relative to placebo stimulation. This study suggests that tDCS after a contextual reminder can induce long-lasting beneficial effects by facilitating the consolidation processes and opens up the possibility to design specific non-invasive interventions aimed at preventing memory decline in this at-risk population

Behavioral and Neurophysiological Effects of Transdermal Rotigotine in Atypical Parkinsonism

Effective therapies for the so-called atypical parkinsonian syndrome (APS) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) are not available. Dopamine agonists (DA) are not often used in APS because of inefficacy and in a minority of case, their side effects, like dyskinesias, impairment of extrapyramidal symptoms or the appearance of psychosis, and REM sleep behavioral disorders (RBD). Transdermal rotigotine (RTG) is a non-ergot dopamine agonist indicated for use in early and advanced Parkinson’s disease with a good tolerability and safety. Moreover, its action on a wide range of dopamine receptors, D1, D2, D3, unlike other DA, could make it a good option in APS, where a massive dopamine cell loss is documented. In this pilot, observational open-label study we evaluate the efficacy and tolerability of RTG in patients affected by APS. Thirty-two subjects with diagnosis of APS were treated with transdermal RTG. APS diagnosis was: MSA parkinsonian type (MSA-P), MSA cerebellar type (MSA-C), PSP, and CBS. Patients were evaluated by UPDRS-III, neuropsychiatric inventory, mini mental state examination at baseline, and after 6, 12, and 18 months. The titration schedule was maintained very flexible, searching the major clinical effect and the minor possible adverse events (AEs) at each visit. AEs were recorded. APS patients treated with RTG show an overall decrease of UPDRS-III scores without increasing behavioral disturbances. Only three patients were dropped out of the study. Main AEs were hypotension, nausea, vomiting, drowsiness, and tachycardia. The electroencephalographic recording power spectra analysis shows a decrease of theta and an increase of low alpha power. In conclusion, transdermal RTG seems to be effective and well tolerated in APS patients

Comparison of the effects of transdermal and oral rivastigmine on cognitive function and EEG markers in patients with Alzheimer’s disease

Background: Alzheimer's disease (AD) is the most common cause of dementia in older patients. Rivastigmine (RV, Exelon®, Novartis), a reversible cholinesterase inhibitor, improves clinical manifestations of AD and may enhance ACh-modulated electroencephalogram (EEG) alpha frequency. This pilot study aimed to determine the effects of two formulations of RV (transdermal patch [TV-RDP] and oral capsules [TV-CP]) on alpha frequency, in particular the posterior dominant rhythm, and cognitive function (assessed by the Mini-Mental State Examination [MMSE]) in patients with AD.Methods: Subjects with AD were assigned to receive either RV-TDP 10 cm2 or RV-CP 12 mg/day. All patients underwent EEG recordings at the beginning and end of the 18-month study period using P3, P4, O1 and O2 electrodes, each at high (10.5–13.0 Hz) and low (8.0–10.5 Hz) frequency. MMSE scores were determined at the start of the study (T0) and at three successive 6-month intervals (T1, T2 and T3).Results: RV-TDP administration (n=10) maintained cognitive function as evidenced by stable MMSE scores from baseline to 18 months (21.07 ± 2.4 to 21.2 ± 3.1) compared with a decrease in MMSE score with RV-CP (n=10) over 18 months (18.3 ± 3.6 to 13.6 ± 5.06 [adjusted for covariates p=0.006]). MMSE scores were significantly different between treatment groups from 6 months (p=0.04). RV-TDP also increased the spectral power of alpha waves in the posterior region measured with electrode P3 in a significantly great percentage of patients than TV-CP from baseline to 18 months; 80% versus 30%, respectively (p=0.025 [χ2 test]).Conclusion: RV-TDP was associated with a greater proportion of patients with increased posterior region alpha wave spectral power and significantly higher cognitive function at 18 months, compared with RV-CP treatment. Our findings suggest that RV-TDP provides an effective long-term management option in patients with AD compared with oral RV-CP. This study is a pilot, open-label study with

Anatomical Substrate and Scalp EEG Markers are Correlated in Subjects with Cognitive Impairment and Alzheimer's Disease

Dementia is a syndromic diagnosis, encompassing various stage of severity and different anatomo-physiological substrates. The hippocampus is one of the first and most affected brain regions affected by both Alzheimer's disease (AD) and mild cognitive impairment (MCI). Moreover, chronic cerebrovascular disease (CVD) is one of the major risk factor for developing dementia. Recent studies have demonstrated different relationship between the anatomical substrate and scalp electroencephalography (EEG) markers. Indeed, modifications of EEG rhythmicity is not proportional to the hippocampal atrophy, whereas changes in EEG activity are directly proportional to the load of subcortical CVD. The computation of the EEG spectral power and the analysis of the functional coupling of brain areas, through linear coherence, are two of the most known processing methods in EEG research. Two specific EEG markers, theta/gamma and alpha3/alpha2 frequency ratio have been reliable associated to the atrophy of amygdalo–hippocampal complex. Moreover, theta/gamma ratio has been related to MCI conversion in dementia and alpha3/alpha2 ratio has been specifically related to MCI conversion in AD. The functional coupling of brain areas is also modulated by hippocampal atrophy. In the MCI subjects, hippocampal atrophy is linked to an increase of interhemispheric coherence seen on frontal and temporal regions whereas subcortical CVD is linked to a decrease of coherence in fronto-parietal regions. In the present study the most significant results of recent studies on correlation between scalp EEG, cognitive decline, and anatomical substrate have been reviewed, with particular attention to the relationships between EEG changes and hippocampal atrophy. The following review is not intended to provide a comprehensive summary of the literature. Rather it identifies and discusses selected studies that are designed to find the specific correlation between scalp EEG markers and anatomo-pathological substrate. The principal aim is to propose a plausible neurophysiological theoretical model of the cognitive decline as mirrored by both structural and functional tools of research

tDCS-Induced Memory Reconsolidation Effects: Analysis of Prominent Predicting Factors

BACKGROUND: Memory impairment is among one of the greatest cognitive complaints in midlife and in old age. Considering the importance of good memory functioning in everyday life, it is crucial to study interventions that can reduce the natural decline in this cognitive function. Transcranial Magnetic Stimulation (TMS) studies have demonstrated that the lateral prefrontal cortex (PFC) plays a causal role in enhancing episodic memory recall through reconsolidation. Using a similar paradigm with transcranial direct current stimulation (tDCS) over the left lateral PFC, facilitation effects were observed in delayed memory retrieval in older adults with subjective memory complaints (SMCs) and amnestic Mild Cognitive Impairment (aMCI). However, it remains unclear which potential factors (i.e., tDCS group, cognitive reserve, education level, diagnosis and encoding performance) directly and/or indirectly modulate the tDCS-induced memory reconsolidation effects. METHODS: We reanalyzed data acquired in our previous tDCS studies with 22 SMC and 18 aMCI participants from the perspective of predicting delayed memory retrieval performance. These studies included a learning session on Day 1, a reactivation by a contextual reminder followed by 15 min of tDCS session on Day 2 (24 h after Day 1), and two retrieval sessions (free recall and recognition) tested on Days 3 and 30 (48 h and 30 Days after Day 1). RESULTS: Univariate models showed that tDCS group (sham vs. active) significantly predicted memory recognition (but not free recall), evidenced by higher scores in the active tDCS group than in sham group, confirming our previous results. Encoding performance and diagnosis (SMC vs. aMCI) significantly predicted memory retrieval, suggesting higher performances in individuals with SMC than in those with aMCI. Regarding cognitive reserve, higher leisure time activity subscores significantly predicted better memory recognition. Finally, multiple models did not show any tDCS group × predictor interaction effects, indicating that the effects of the predictors on retrieval occurred irrespective of tDCS group. CONCLUSION: Our results shed light on predicting factors of episodic memory retrieval in this reconsolidation paradigm in individuals with SMC and aMCI. The findings suggest that multifactorial interventions program may be most promising to slow cognitive decline and delay the onset of dementia

A Window into the Heterogeneity of Human Cerebrospinal Fluid Aβ Peptides

The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβ assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβ peptides. Specifically, we focused our attention on the heterogeneity of the CSF Aβ world discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aβ assemblies, and (3) communication modes for Aβ peptides and their microenvironment targets. Finally, we suggest that Aβ peptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function

Advancing Italian Biomedical Information Extraction with Large Language Models: Methodological Insights and Multicenter Practical Application

The introduction of computerized medical records in hospitals has reduced burdensome operations like manual writing and information fetching. However, the data contained in medical records are still far underutilized, primarily because extracting them from unstructured textual medical records takes time and effort. Information Extraction, a subfield of Natural Language Processing, can help clinical practitioners overcome this limitation, using automated text-mining pipelines. In this work, we created the first Italian neuropsychiatric Named Entity Recognition dataset, PsyNIT, and used it to develop a Large Language Model for this task. Moreover, we conducted several experiments with three external independent datasets to implement an effective multicenter model, with overall F1-score 84.77%, Precision 83.16%, Recall 86.44%. The lessons learned are: (i) the crucial role of a consistent annotation process and (ii) a fine-tuning strategy that combines classical methods with a "few-shot" approach. This allowed us to establish methodological guidelines that pave the way for future implementations in this field and allow Italian hospitals to tap into important research opportunities

Presenilin 1 Protein Directly Interacts with Bcl-2

Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis

Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD