Chronic Hyponatremia and Brain Structure and Function Before and After Treatment.

RATIONALE & OBJECTIVE: Hyponatremia is the most common electrolyte disorder and is associated with significant morbidity and mortality. This study investigated neurocognitive impairment, brain volume, and alterations in magnetic resonance imaging (MRI)-based measures of cerebral function in patients before and after treatment for hyponatremia. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients with presumed chronic hyponatremia without signs of hypo- or hypervolemia treated in the emergency department of a German tertiary-care hospital. EXPOSURE: Hyponatremia (ie, plasma sodium concentration [Na+]<125mmol/L) before and after treatment leading to [Na+]>130mmol/L. OUTCOMES: Standardized neuropsychological testing (Mini-Mental State Examination, DemTect, Trail Making Test A/B, Beck Depression Inventory, Timed Up and Go) and resting-state MRI were performed before and after treatment of hyponatremia to assess total brain and white and gray matter volumes as well as neuronal activity and its synchronization. ANALYTICAL APPROACH: Changes in outcomes after treatment for hyponatremia assessed using bootstrapped confidence intervals and Cohen d statistic. Associations between parameters were assessed using correlation analyses. RESULTS: During a 3.7-year period, 26 patients were enrolled. Complete data were available for 21 patients. Mean [Na+]s were 118.4mmol/L before treatment and 135.5mmol/L after treatment. Most measures of cognition improved significantly. Comparison of MRI studies showed a decrease in brain tissue volumes, neuronal activity, and synchronization across all gray matter after normalization of [Na+]. Volume effects were particularly prominent in the hippocampus. During hyponatremia, synchronization of neuronal activity was negatively correlated with [Na+] (r=-0.836; 95% CI, -0.979 to-0.446) and cognitive function (Mini-Mental State Examination, r=-0.523; 95% CI, -0.805 to-0.069; DemTect, r=-0.744; 95% CI, -0.951 to-0.385; and Trail Making Test A, r=0.692; 95% CI, 0.255-0.922). LIMITATIONS: Small sample size, insufficient quality of several MRI scans as a result of motion artifact. CONCLUSIONS: Resolution of hyponatremia was associated with improved cognition and reductions in brain volumes and neuronal activity. Impaired cognition during hyponatremia is closely linked to increased neuronal activity rather than to tissue volumes. Furthermore, the hippocampus appears to be particularly susceptible to hyponatremia, exhibiting pronounced changes in tissue volume. PLAIN-LANGUAGE SUMMARY: Hyponatremia is a common clinical problem, and patients often present with neurologic symptoms that are at least partially reversible. This study used neuropsychological testing and magnetic resonance imaging to examine patients during and after correction of hyponatremia. Treatment led to an improvement in patients' cognition as well as a decrease in their brain volumes, spontaneous neuronal activity, and synchronized neuronal activity between remote brain regions. Volume effects were particularly prominent in the hippocampus, an area of the brain that is important for the modulation of memory. During hyponatremia, patients with the lowest sodium concentrations had the highest levels of synchronized neuronal activity and the poorest cognitive test results.

The structure of cognitive strategies for wayfinding decisions.

Literature proposes five distinct cognitive strategies for wayfinding decisions at intersections. Our study investigates whether those strategies rely on a generalized decision-making process, on two frame-specific processes-one in an egocentric and the other in an allocentric spatial reference frame, and/or on five strategy-specific processes. Participants took six trips along a prescribed route through five virtual mazes, each designed for decision-making by a particular strategy. We found that wayfinding accuracy on trips through a given maze correlated significantly with the accuracy on trips through another maze that was designed for a different reference frame (rbetween-frames = 0.20). Correlations were not significantly higher if the other maze was designed for the same reference frame (rwithin-frames = 0.19). However, correlations between trips through the same maze were significantly higher than those between trips through different mazes that were designed for the same reference frame (rwithin-maze = 0.52). We conclude that wayfinding decisions were based on a generalized cognitive process, as well as on strategy-specific processes, while the role of frame-specific processes-if any-was relatively smaller. Thus, the well-established dichotomy of egocentric versus allocentric spatial representations did not translate into a similar, observable dichotomy of decision-making.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.

Alzheimer's Disease Plasma Biomarkers Distinguish Clinical Diagnostic Groups in Memory Clinic Patients.

INTRODUCTION: Several recent research studies show high performance of blood biomarkers to identify Alzheimer's disease also in the pre-dementia mild cognitive impairment (MCI) stage, but data from the routine clinical care memory clinic setting are needed. METHODS: We examined plasma samples of 144 memory clinic patients, including dementia of Alzheimer type (DAT, n = 54), MCI (n = 57), and subjective cognitive decline (SCD, n = 33), who either presented as self-referrals or were referred by general practitioners or neurologists or psychiatrists. The plasma biomarkers, amyloid-beta42 (Aß42), amyloid-beta40 (Aß40), phospho-Tau181 (pTau181), total-tau (tTau), and neurofilament light (NFL), as well as different ratios, were measured using the ultrasensitive single molecule array (Simoa) immunoassay technology. Statistical analysis including Kruskal-Wallis test, linear regression, and receiver operating characteristics analyses was performed. RESULTS: Of the single markers, we observed statistically significant group effects of pTau181 (H(2) = 34.43, p < 0.001) and NFL (H(2) = 27.66, p < 0.001). All individual group comparisons of pTau181 were significant, while the contrast of SCD versus MCI for NFL was not significant. In addition, the ratios of Aß42/Aß40 (H(2) = 7.50, p = 0.02) and pTau181/Aß42 (H(2) = 25.26, p < 0.001) showed significant group effects with significant difference between all groups for pTau181/Aß42 and an SCD versus MCI difference for Aß42/Aß40. PTau181 showed the highest area under the curve of 0.85 for the discrimination of SCD and DAT with a sensitivity of 80% and a specificity of 79% at a cut-off of 12.2 pg/mL. Age influenced Aß42, Aß40, and NFL concentrations. CONCLUSION: Plasma pTau181 and NFL, as well as the ratios Aß42/Aß40 and pTau181/Aß42, are biomarkers, which can differentiate diagnostic groups in a memory clinic setting outside of research studies.

[Acute Aortic Dissection: A Life-Threatening Disease Also in Neurological Emergency Medicine]. / Akute Aortendissektion: Ein lebensbedrohlicher Notfall auch in der neurologischen Notfallmedizin.

Acute aortic dissection is rare but life-threatening. The symptoms depend on the localization and reduced perfusion of the downstream organs or limbs and are therefore variable. Neurological symptoms may occur that do not immediately lead to a diagnosis and thus delay the necessary therapy. Knowing the early symptoms and warning signs of aortic dissection is therefore also crucial in neurological emergency care for quickly identifying the affected patients and for providing acute therapy. A misdiagnosis with delayed initiation of therapy can significantly worsen the patient's outcome. This study aims to establish a standardized diagnostic and therapeutic algorithm for suspected acute aortic dissection in neurological emergency care. Close interdisciplinary cooperation is mandatory.

[Brain Stimulation for the Treatment of Dementia]. / Stimulationsverfahren zur Behandlung von Demenzen.

Due to the increasing number of cases of Alzheimer's disease and the relatively moderate success with the available symptomatic and causal pharmacological therapies, there is a considerable need to explore non-pharmacological treatment options. In the field of non-invasive brain stimulation (NIBS), various methods have been investigated, particularly transcranial magnetic stimulation and transcranial electrical stimulation. In addition, deep brain stimulation (DBS) is currently being researched as an innovative method for targeted neuromodulation. Both non-invasive and invasive approaches aim to modulate neuronal activity and improve cognitive-mnestic functions. Secondary mechanisms such as long-term potentiation in NIBS or neurogenesis in DBS could also achieve long-term positive effects. Preclinical and clinical studies have already shown promising results in patients in early stages of Alzheimer's disease. However, inconsistent study and stimulation protocols and small sample sizes make it difficult to assess efficacy. Further research is warranted to enable the use of non-invasive or invasive neuromodulatory approaches in clinical practice in the near future.

[The Cost of Early Diagnosis of Cognitive Decline in German Memory Clinics]. / Kosten der Diagnostik kognitiver Störungen in deutschen Gedächtnisambulanzen.

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.

Neuro-COVID-19 is more than anosmia: clinical presentation, neurodiagnostics, therapies, and prognosis.

PURPOSE OF REVIEW: To provide an overview on current knowledge of neurological symptoms and complications of COVID-19, and to suggest management concepts. RECENT FINDINGS: Headache, dizziness, excessive tiredness, myalgia, anosmia/hyposmia, and ageusia/dysgeusia are common nonspecific neurological manifestations during early COVID-19 disease found in the majority of patients. Less frequent but more severe and specific neurological manifestations include Guillain--Barré syndrome, encephalopathy, encephalitis/meningitis, epileptic seizures, and cerebrovascular events. Beyond standard neurological examination, these require a more extensive work-up, including cerebrospinal fluid assessment, neurophysiological evaluation, neuroimaging, and cognitive testing. Symptomatic treatment is advisable unless the neurological complication's immune pathogenesis is proven. SUMMARY: Neurological manifestations of COVID-19 occur during the acute, para-infectious, and 'recovery' phase. Therapeutic management depends on the clinical presentation and neurological work-up.

[Toxicity after chimeric antigen receptor T-cell therapy : Overview and management of early and late onset side effects]. / Toxizitäten nach Chimärer-Antigenrezeptor-T-Zell-Therapie : Übersicht und Management früher und verzögerter Nebenwirkungen.

BACKGROUND: The transfusion of chimeric antigen receptor (CAR) T­cells has become established as a new treatment option in oncology; however, this is regularly associated with immune-mediated side effects, which can also run a severe course and necessitate a specific treatment and intensive medical treatment. MATERIAL AND METHODS: A literature review was carried out on CAR T-cell therapy, toxicities and the management of side effects. RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) regularly occur shortly after CAR T-cell treatment. The symptoms of CRS can range from mild flu-like symptoms to multiorgan failure. In addition to mild symptoms, such as disorientation and aphasia, ICANS can also lead to convulsive seizures and brain edema. The management of CRS and ICANS is based on the severity according to the grading of the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab and corticosteroids are recommended for CRS and corticosteroids are used for ICANS. In the further course persisting hypogammaglobulinemia and cytopenia are frequent even months after the initial treatment and promote infections even months after CAR T­cell therapy. DISCUSSION: Potentially severe complications regularly occur after CAR T-cell therapy. An interdisciplinary cooperation between intensive care physicians, hematologists, neurologists and specialists in other disciplines is of decisive importance for the optimal care of patients after CAR T­cell therapy.

Adjustment of Stent Retriever Length to Clot Extent Affects First-Pass Reperfusion in Endovascular Treatment of Acute Ischemic Stroke.

BACKGROUND: Stent retriever technology has evolved, and significantly longer devices have become available for mechanical thrombectomy (MT) of large cerebral vessel occlusions in ischemic stroke. We hypothesized that increased stent retriever length may improve the rate of complete angiographic reperfusion and decrease the respective number of attempts, resulting in a better clinical outcome. METHODS: Retrospective analysis of patients with large vessel occlusion in the anterior and posterior circulation treated with stent retriever MT. The study group was dichotomized into short (20 mm) and long (>20 mm) retrievers using propensity matching. In the anterior circulation, the clot burden score was evaluated. Primary end points were first-pass modified thrombolysis in cerebral infarction (mTICI) 3 reperfusion and first-pass mTICI ≥ 2b reperfusion, and the secondary end point was functional independence (defined as modified Rankin Scale score 0-2) at discharge and 90 days. RESULTS: Overall, 394 patients were included in the analysis. In the anterior circulation, short stent retrievers had a significantly higher rate of first-pass reperfusion in cases with low clot burden (mTICI 3: 27% vs. 17%; p = 0.009; mTICI ≥ 2b: 42 vs. 30%; p = 0.005) and in middle cerebral artery occlusions (mTICI ≥ 2b: 51 vs. 41%; p = 0.024). Higher rates of favorable outcome at discharge and 90 days were observed for the short stent retriever group (p < 0.001). CONCLUSION: Stent retriever length should be adjusted to clot burden score and vessel occlusion site.

Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease.

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

[Acute unconsciousness]. / Akute Bewusstseinsstörung.

Emergency treatment of unconscious patients is a complex task and should follow a standardised algorithm. Stabilisation of vital parameters, diagnostic procedures, and therapeutic interventions should be carried out in part simultaneously and require interdisciplinary teamwork. Diagnosis has to be made under high time pressure in order to recognize life threatening causes and initiate specific treatments. Often, the earlier the treatment starts, the better the outcome is.

The integrity of the cholinergic system determines memory performance in healthy elderly.

The cholinergic system plays a central role in episodic memory-related processes in health and disease. Cerebral acetylcholinesterase (AChE) activity, a measure of the integrity of the cholinergic system, can be assessed in vivo using positron emission tomography (PET) and [(11)C]N-methyl-4-piperidyl acetate (MP4A). A close relationship between the kinetic constant k3 of MP4A and mnestic functions has been demonstrated for patients suffering from amnestic mild cognitive impairment and Alzheimer's disease. Under the hypothesis that AChE activity and memory are intimately linked in older age, we obtained MP4A-PET and structural magnetic resonance images as well as neuropsychological data from fourteen healthy older adults. Multiple regression analysis revealed that AChE activity in areas previously implicated in mnestic functions predicted episodic memory performance irrespective of cortical atrophy. Data suggest that in older adults the integrity of the cholinergic system underlies inter-individual variability in memory function.

Imaging frontotemporal lobar degeneration.

The term frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative disorders that target the frontal and temporal lobes. It accounts for approximately 10 % of pathologically confirmed dementias but has been demonstrated to be as prevalent as Alzheimer's disease in patients below the age of 65. The 3 major clinical syndromes associated with FTLD include behavioral variant frontotemporal dementia, semantic and nonfluent variants of primary progressive aphasia. The more recently introduced term logopenic variant appears to represent an atypical form of Alzheimer's disease in the majority of cases. The neuropathology underlying these clinical syndromes is very heterogeneous and does not correlate well with the clinical phenotype. This causes great difficulties in early and reliable diagnosis and treatment of FTLD. However, significant advances have been made in recent years via the application of magnetic resonance imaging and positron emission tomography imaging methods as biomarkers. The current review aims to provide a synopsis on the value of magnetic resonance imaging-based and molecular imaging procedures in FTLD.

Cortical Tau Aggregation Patterns associated with Apraxia in Alzheimer's Disease.

Objectives: Apraxia is a core feature of Alzheimer's disease, but the pathomechanism of this characteristic symptom is not well understood. Here, we systematically investigated apraxia profiles in a well-defined group of patients with Alzheimer's disease (AD; N=32) who additionally underwent PET imaging with the second-generation tau PET tracer [18F]PI-2620. We hypothesized that specific patterns of tau pathology might be related to apraxic deficits. Methods: Patients (N=32) with a biomarker-confirmed diagnosis of Alzheimer's disease were recruited in addition to a sample cognitively unimpaired controls (CU 1 ; N=41). Both groups underwent in-depth neuropsychological assessment of apraxia (Dementia Apraxia Screening Test; DATE and the Cologne Apraxia Screening; KAS). In addition, static PET imaging with [18F]PI-2620 was performed to assess tau pathology in the AD patients. To specifically investigate the association of apraxia with regional tau-pathology, we compared the PET-data from this group with an independent sample of amyloid-negative cognitively intact participants (CU 2; N=54) by generation of z-score-deviation maps as well as voxel- based multiple regression analyses. Results: We identified significant clusters of tau-aggregation in praxis-related regions (e.g., supramarginal gyrus, angular gyrus, temporal, parietal and occipital regions) that were associated with apraxia. These regions were similar between the two apraxia assessments. No correlations between tau-tracer uptake in primary motor cortical or subcortical brain regions and apraxia were observed. Conclusions: These results suggest that tau deposition in specific cortical brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance.

Analysis of Cerebral CT Based on Supervised Machine Learning as a Predictor of Outcome After Out-of-Hospital Cardiac Arrest.

BACKGROUND AND OBJECTIVES: In light of limited intensive care capacities and a lack of accurate prognostic tools to advise caregivers and family members responsibly, this study aims to determine whether automated cerebral CT (CCT) analysis allows prognostication after out-of-hospital cardiac arrest. METHODS: In this monocentric, retrospective cohort study, a supervised machine learning classifier based on an elastic net regularized logistic regression model for gray matter alterations on nonenhanced CCT obtained after cardiac arrest was trained using 10-fold cross-validation and tested on a hold-out sample (random split 75%/25%) for outcome prediction. Following the literature, a favorable outcome was defined as a cerebral performance category of 1-2 and a poor outcome of 3-5. The diagnostic accuracy was compared with established and guideline-recommended prognostic measures within the sample, that is, gray matter-white matter ratio (GWR), neuron-specific enolase (NSE), and neurofilament light chain (NfL) in serum. RESULTS: Of 279 adult patients, 132 who underwent CCT within 14 days of cardiac arrest with good imaging quality were identified. Our approach discriminated between favorable and poor outcomes with an area under the curve (AUC) of 0.73 (95% CI 0.59-0.82). Thus, the prognostic power outperformed the GWR (AUC 0.66, 95% CI 0.56-0.76). The biomarkers NfL, measured at days 1 and 2, and NSE, measured at day 2, exceeded the reliability of the imaging markers derived from CT (AUC NfL day 1: 0.87, 95% CI 0.75-0.99; AUC NfL day 2: 0.90, 95% CI 0.79-1.00; AUC NSE day: 2 0.78, 95% CI 0.62-0.94). DISCUSSION: Our data show that machine learning-assisted gray matter analysis of CCT images offers prognostic information after out-of-hospital cardiac arrest. Thus, CCT gray matter analysis could become a reliable and time-independent addition to the standard workup with serum biomarkers sampled at predefined time points. Prospective studies are warranted to replicate these findings.

Fine-grained age-matching improves atrophy-based detection of mild cognitive impairment more than amyloid-negative reference subjects.

INTRODUCTION: In clinical practice, differentiating between age-related gray matter (GM) atrophy and neurodegeneration-related atrophy at early disease stages, such as mild cognitive impairment (MCI), remains challenging. We hypothesized that fined-grained adjustment for age effects and using amyloid-negative reference subjects could increase classification accuracy. METHODS: T1-weighted magnetic resonance imaging (MRI) data of 131 cognitively normal (CN) individuals and 91 patients with MCI from the Alzheimer's disease neuroimaging initiative (ADNI) characterized concerning amyloid status, as well as 19 CN individuals and 19 MCI patients from an independent validation sample were segmented, spatially normalized and analyzed in the framework of voxel-based morphometry (VBM). For each participant, statistical maps of GM atrophy were computed as the deviation from the GM of CN reference groups at the voxel level. CN reference groups composed with different degrees of age-matching, and mixed and strictly amyloid-negative CN reference groups were examined regarding their effect on the accuracy in distinguishing between CN and MCI. Furthermore, the effects of spatial smoothing and atrophy threshold were assessed. RESULTS: Approaches with a specific reference group for each age significantly outperformed all other age-adjustment strategies with a maximum area under the curve of 1.0 in the ADNI sample and 0.985 in the validation sample. Accounting for age in a regression-based approach improved classification accuracy over that of a single CN reference group in the age range of the patient sample. Using strictly amyloid-negative reference groups improved classification accuracy only when age was not considered. CONCLUSION: Our results demonstrate that VBM can differentiate between age-related and MCI-associated atrophy with high accuracy. Crucially, age-specific reference groups significantly increased accuracy, more so than regression-based approaches and using amyloid-negative reference groups.

Improved connectivity and cognition due to cognitive stimulation in Alzheimer's disease.

Background: Due to the increasing prevalence of Alzheimer's disease (AD) and the limited efficacy of pharmacological treatment, the interest in non-pharmacological interventions, e.g., cognitive stimulation therapy (CST), to improve cognitive dysfunction and the quality of life of AD patients are on a steady rise. Objectives: Here, we examined the efficacy of a CST program specifically conceptualized for AD dementia patients and the neural mechanisms underlying cognitive or behavioral benefits of CST. Methods: Using neuropsychological tests and MRI-based measurements of functional connectivity, we examined the (neuro-) psychological status and network changes at two time points: pre vs. post-stimulation (8 to 12 weeks) in the intervention group (n = 15) who received the CST versus a no-intervention control group (n = 15). Results: After CST, we observed significant improvement in the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-cog), and the behavioral and psychological symptoms of dementia (BPSD) scores. These cognitive improvements were associated with an up-regulated functional connectivity between the left posterior hippocampus and the trunk of the left postcentral gyrus. Conclusion: Our data indicate that CST seems to induce short-term global cognition and behavior improvements in mild to moderate AD dementia and enhances resting-state functional connectivity in learning- and memory-associated brain regions. These convergent results prove that even in mild to moderate dementia AD, neuroplasticity can be harnessed to alleviate cognitive impairment with CST.