Astrocytic-derived vascular remodeling factors are independently associated with blood brain barrier permeability in Alzheimer's disease.

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo, a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls. CSF levels of VEGF and ET-1 positively correlated with MMP-9 but negatively with MMP-2, suggesting a complex vascular remodeling process occurring in AD. Only MMP-2 levels were significantly associated with CSF AD biomarkers. Conversely, higher MMP-2 (ß = 0.411, p < 0.001), ET-1 levels (ß = 0.344, p < 0.001) and VEGF (ß = 0.221, p = 0.022), were associated with higher BBB permeability. Astrocytic-derived vascular remodeling factors are altered in AD, disclosing the failure of important protective mechanisms which proceed independently alongside AD pathology.

Transcranial direct current stimulation combined with speech therapy in Fragile X syndrome patients: a pilot study.

Background: Fragile X syndrome (FXS) is the leading cause of genetic intellectual disability. Among the neurobehavioral dysfunctions in FXS individuals, language development and literacy are compromised. Recent evidence hypothesized that the disruption of excitatory glutamatergic and GABAergic inhibitory neurotransmission balance might be responsible for impairment in cognitive function. In this study, we evaluated for the first time, the safety, tolerability, and efficacy of anodal prefrontal transcranial direct current stimulation (tDCS) combined with standard speech therapy to enhance language function in FXS patients. Methods: In total, 16 adult FXS patients were enrolled. Participants underwent 45 min of anodic tDCS combined with speech therapy for 5 weeks (3 times per week). Language function was evaluated using the Test for Reception of Grammar-Version 2 (TROG-2) and subtests of the Italian Language Examination (Esame del Linguaggio - II, EDL-II). Right and left dorsolateral prefrontal cortex transcranial magnetic stimulation and concurrent electroencephalography (TMS-EEG) recordings were collected at baseline and after the treatment to evaluate cortical reactivity and connectivity changes. Results: After 5 weeks of combined therapy, we observed a significant improvement in the writing (7.5%), reading (20.3%), repetition (13.3%), and TROG-2 (10.2%) tests. Parallelly with clinical change, TMS-EEG results showed a significant difference in TMS-evoked potential amplitude over the left frontal cortex after treatment (-0.73 ± 0.87 µV) compared to baseline (0.18 ± 0.84 µV). Conclusion: Our study provides novel evidence that left anodal prefrontal tDCS combined with standard speech therapy could be effective in enhancing language function in FXS patients, mainly by inducing a rebalance of the dysfunctional prefrontal cortical excitability.

Different associations between amyloid-ßeta 42, amyloid-ßeta 40, and amyloid-ßeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer's disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study.

BACKGROUND: Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aß)42 to detect amyloid pathology, the Aß42/Aß40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aß42 and amyR have different meanings and whether Aß40 represents more than an Aß42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aß42 and amyR to detect AD pathology in terms of p-tau/Aß42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET). METHODS: CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aß42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAß42 + /amyR - = 46) and pathological amyR (CSFAß42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aß42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls. RESULTS: CSF Aß40 levels were the lowest in A - T - and in CSFAß42 + /amyR - , higher in CSFAß42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aß40 and p-tau in A - T - (ß = 0.58; p < 0.001), CSFAß42 + /amyR - (ß = 0.47; p < 0.001), and CSFAß42 + /amyR + patients (ß = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aß40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aß40: + 4.5 z-score). CSFAß42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aß42 than CSFAß42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aß42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAß42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAß42 + /amyR + , like in A + T + . CONCLUSIONS: Pathological p-tau/Aß42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aß42 levels alone. AmyR positivity, associated with higher Aß40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Frontotemporal Dementia, Where Do We Stand? A Narrative Review.

Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.

Association of Choroid Plexus Volume With Serum Biomarkers, Clinical Features, and Disease Severity in Patients With Frontotemporal Lobar Degeneration Spectrum.

BACKGROUND AND OBJECTIVES: Choroid plexus (ChP) is emerging as a key brain structure in the pathophysiology of neurodegenerative disorders. In this observational study, we investigated ChP volume in a large cohort of patients with frontotemporal lobar degeneration (FTLD) spectrum to explore a possible link between ChP volume and other disease-specific biomarkers. METHODS: Participants included patients meeting clinical criteria for a probable syndrome in the FTLD spectrum. Structural brain MRI imaging, serum neurofilament light (NfL), serum phosphorylated-Tau181 (p-Tau181), and cognitive and behavioral data were collected. MRI ChP volumes were obtained from an ad-hoc segmentation model based on a Gaussian Mixture Models algorithm. RESULTS: Three-hundred and sixteen patients within FTLD spectrum were included in this study, specifically 135 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD), 75 primary progressive aphasia, 46 progressive supranuclear palsy, and 60 corticobasal syndrome. In addition, 82 age-matched healthy participants were recruited as controls (HCs). ChP volume was significantly larger in patients with FTLD compared with HC, across the clinical subtype. Moreover, we found a significant difference in ChP volume between HC and patients stratified for disease-severity based on CDR plus NACC FTLD, including patients at very early stage of the disease. Interestingly, ChP volume correlated with serum NfL, cognitive/behavioral deficits, and with patterns of cortical atrophy. Finally, ChP volume seemed to discriminate HC from patients with FTLD better than other previously identified brain structure volumes. DISCUSSION: Considering the clinical, pathologic, and genetic heterogeneity of the disease, ChP could represent a potential biomarker across the FTLD spectrum, especially at the early stage of disease. Further longitudinal studies are needed to establish its role in disease onset and progression. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that choroid plexus volume, as measured on MRI scan, can assist in differentiating patients with FTLD from healthy controls and in characterizing disease severity.

TMS-EEG perturbation biomarkers for Alzheimer's disease patients classification.

The combination of TMS and EEG has the potential to capture relevant features of Alzheimer's disease (AD) pathophysiology. We used a machine learning framework to explore time-domain features characterizing AD patients compared to age-matched healthy controls (HC). More than 150 time-domain features including some related to local and distributed evoked activity were extracted from TMS-EEG data and fed into a Random Forest (RF) classifier using a leave-one-subject out validation approach. The best classification accuracy, sensitivity, specificity and F1 score were of 92.95%, 96.15%, 87.94% and 92.03% respectively when using a balanced dataset of features computed globally across the brain. The feature importance and statistical analysis revealed that the maximum amplitude of the post-TMS signal, its Hjorth complexity and the amplitude of the TEP calculated in the window 45-80 ms after the TMS-pulse were the most relevant features differentiating AD patients from HC. TMS-EEG metrics can be used as a non-invasive tool to further understand the AD pathophysiology and possibly contribute to patients' classification as well as longitudinal disease tracking.

Cerebrospinal Fluid sTREM-2, GFAP, and ß-S100 in Symptomatic Sporadic Alzheimer's Disease: Microglial, Astrocytic, and APOE Contributions Along the Alzheimer's Disease Continuum.

BACKGROUND: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer's disease (AD), since amyloid-ß (Aß) deposition, tau pathology, and neuroinflammation influence each other. OBJECTIVE: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype. METHODS: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; ß-S100) from 71 patients with AD (23 A+T-,48 A+T+; 38 APOEɛ3, 33 APOEɛ4) and 30 healthy controls (HC). With multivariate analyses we investigated associations between glial biomarkers, Aß42, and p-tau in all subgroups. RESULTS: CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T- [1.355 (0.213)] than in HC [1.042 (0.198); both p < 0.001]; GFAP and ß-S100 were comparable across groups. Considering all patients, sTREM-2 positively associated with Aß42 (p = 0.04) and p-tau (=0.016), with the first being present only in the A+T- subgroup (p = 0.023). GFAP positively associated with Aß42 in all patients (p = 0.020) and in the A+T+ subgroup (p = 0.04). Stratifying by APOE, a positive association of sTREM-2 and p-tau was confirmed selectively in carriers of ɛ4 (p = 0.018). Finally, sTREM-2 positively correlated with ß-S100 in all subgroups, and with GFAP in A+T+ (p = 0.042). CONCLUSION: Our results confirm the increase of CSF sTREM-2 in AD, which associates with reduced amyloidopathy in A+T- patients. Moreover, microglial activation seems to increase CSF tau levels in carriers of APOEɛ4, is associated with astrocytic reactivity (GFAP) in A+T+, and likely leads the acquisition of a more neurotoxic astrocytic phenotype (ß-S100).

Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum.

BACKGROUND AND PURPOSE: The locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes. METHODS: The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-ß-hydroxylase (DßH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (Aß)1-42 (A) and p-tau (T) in AD pathological changes (A+ T-) and AD (A+ T+) subgroups, as well as in 15 control subjects (A- T-). RESULTS: The ADc group had lower CSF levels of DAT and TH but increased DßH levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but comparable with controls in the A+ T- subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aß1-42 (R2  = 0.25) and between DDC and p-tau (R2  = 0.33). Finally, TH correlated with interleukin (IL)-10 levels (p = 0.0008) and DßH with IL-1ß (p = 0.03), IL-4 (p = 0.02), granulocyte colony-stimulating factor (p = 0.007), and IL-17 (p = 0.01). CONCLUSIONS: Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology.

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome.

OBJECTIVE: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. METHODS: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. RESULTS: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. CONCLUSIONS: Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. SIGNIFICANCE: This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

OBJECTIVE: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. METHODS: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). RESULTS: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aß42 . INTERPRETATION: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex.

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (θtACS) or gamma (γtACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with γtACS but not with θtACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions.

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer's disease. Alzheimer's disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer's disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer's disease. Fifty Alzheimer's disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale-Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale-Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer's disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer's disease patients.

Characterizing TMS-EEG perturbation indexes using signal energy: initial study on Alzheimer's Disease classification.

Transcranial Magnetic Stimulation (TMS) combined with EEG recordings (TMS-EEG) has shown great potential in the study of the brain and in particular of Alzheimer's Disease (AD). In this study, we propose an automatic method of determining the duration of TMS-induced perturbation of the EEG signal as a potential metric reflecting the brain's functional alterations. A preliminary study is conducted in patients with Alzheimer's disease (AD). Three metrics for characterizing the strength and duration of TMS-evoked EEG (TEP) activity are proposed and their potential in identifying AD patients from healthy controls was investigated. A dataset of TMS-EEG recordings from 17 AD and 17 healthy controls (HC) was used in our analysis. A Random Forest classification algorithm was trained on the extracted TEP metrics and its performance is evaluated in a leave-one-subject-out cross-validation. The created model showed promising results in identifying AD patients from HC with an accuracy, sensitivity and specificity of 69.32%, 72.23% and 66.41%, respectively. Clinical relevance- Three preliminary metrics were proposed to quantify the strength and duration of the response to TMS on EEG data. The proposed metrics were successfully used to identify Alzheimer's disease patients from healthy controls. These results proved the potential of this approach which will provide additional diagnostic value.

Preliminary study on the impact of EEG density on TMS-EEG classification in Alzheimer's disease.

Transcranial magnetic stimulation co-registered with electroencephalographic (TMS-EEG) has previously proven a helpful tool in the study of Alzheimer's disease (AD). In this work, we investigate the use of TMS-evoked EEG responses to classify AD patients from healthy controls (HC). By using a dataset containing 17AD and 17HC, we extract various time domain features from individual TMS responses and average them over a low, medium and high density EEG electrode set. Within a leave-one-subject-out validation scenario, the best classification performance for AD vs. HC was obtained using a high-density electrode with a Random Forest classifier. The accuracy, sensitivity and specificity were of 92.7%, 96.58% and 88.82% respectively. Clinical relevance- TMS-EEG responses were successfully used to identify Alzheimer's disease patients from healthy controls.

Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders.

Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients' studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Isolated Amyloid-ß Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients.

BACKGROUND: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. OBJECTIVE: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. METHODS: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-ß (Aß) deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. RESULTS: A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p < 0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE -0.5±2.12 versus -6.05±4.95; post-hocp = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p > 0.05). CONCLUSION: Our results suggest that APOE4 in patients with isolated Aß pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Diabetes mellitus contributes to higher cerebrospinal fluid tau levels selectively in Alzheimer's disease patients with the APOE4 genotype.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using ß amyloid (A: Aß1-42 ) and phosphorylated tau (T: p-tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. METHODS: For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. RESULTS: A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T- patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t-tau) levels compared to non-DM patients (DM: 919.4 ± 444 vs. non-DM: 773.1 ± 348.2; p = 0.04), but similar p-tau (p = 0.72) and Aß1-42  levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t-tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49-398.1; p = 0.01), but not in APOE E4- (p = 0.53). CONCLUSIONS: The present study shows a clear dependency of CSF t-tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4-related and non-related disease, with key implications for AD pathophysiology and treatment.

Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias.

Mitochondrial dysfunction is pivotal in the development of neurodegenerative dementias, causing cellular death alongside disease-specific pathogenic cascades. Holding cerebrospinal fluid (CSF) lactates as an indirect measure of brain metabolic activity, we first compared CSF lactate levels from patients with Alzheimer's disease (AD)-stratified according to the ATN system and epsilon genotype-frontotemporal dementia (FTD) and dementia with Lewy body (DLB) to findings from healthy controls. With respect to controls, we detected lower CSF lactates in patients with AD and FTD but comparable levels in patients with DLB. Second, a correlation analysis between CSF lactates and biomarkers of neurodegeneration identified an inverse correlation between lactates and levels of t-tau and p-tau only in the Alzheimer's continuum. The reduction of CSF lactate correlates to the advent of tauopathy and cellular death in AD, implying that Aß pathology alone is not sufficient to induce neuronal metabolic impairment. The metabolic impairment in FTD patients has a similar explanation, as it is likely due to fast neuronal degeneration in the disease. The absence of CSF lactate reduction in patients with DLB may be related to the prevalent subcortical localization of the pathology.

Cognitive reserve and Alzheimer's biological continuum: clues for prediction and prevention of dementia.

Cognitive reserve is originally an epidemiological concept that encompasses individual abilities to cope with changes. It is considered the result of a balance between processes of cellular damage and repair, and its description raised much interest in predicting and preventing cognitive decline in aging and Alzheimer's disease (AD). In this study, we discussed the concept of cognitive reserve considering the recent definition of AD as a biological continuum and suggest that the protection of cognitive reserve may result from efficient synaptic plasticity mechanisms. Despite pathological changes of AD appearing very early during life, long before the onset of cognitive symptoms, different variables act together to keep repair mechanisms effective guaranteeing successful aging if environmental enrichment is maintained.