Alzheimer's Disease (AD)

The goal of this clinical trial is to observe feasibility and initial efficacy of a remotely delivered exercise and dementia caregiving intervention in older adults with Down syndrome and their caregivers.

This study aims to evaluate whether personalized gamma-frequency auditory stimulation enhances cognitive function and brain synchronization. While 40 Hz auditory stimulation has been widely studied, recent evidence suggests optimal frequencies vary by individual. Using a cross-over design with 20 healthy adults, the research compares "optimal" versus "non-optimal" frequencies over one-month intervention periods. Effectiveness is measured through EEG recordings and executive function tasks. The goal is to determine if personalized sensory intervention provides a more effective, non-invasive strategy for enhancing cognitive performance.

Cognitive disorders have a broad differential diagnosis, and a precise, timely diagnosis is essential for personalized treatment and care. Currently, dementia diagnoses are often not further specified according to the underlying pathology and are frequently delayed by several years. However, with the upcoming disease-modifying treatments (DMTs) for AD, an accurate, pathology-driven (i.e., etiological) diagnosis will become necessary. Blood-based biomarkers (BBMs) are promising tools for detecting Alzheimer's disease (AD), with current research showing high concordance with cerebrospinal fluid (CSF) biomarkers and amyloid PET imaging. However, it remains unclear how physicians would value the availability of BBMs for AD in routine clinical practice. The investigators hypothesize that BBMs will benefit both patients and physicians in the diagnostic process within a memory clinic setting. This study aims to investigate clinical impact and diagnostic utility of blood-based biomarkers for AD in the diagnostic process of a memory clinic. The main objectives are to investigate change in diagnosis, diagnostic certainty and patient management, due to BBM results.

The goal of this study is to determine how blood biomarker tests (ptau217 and ptau217/Aβ42) performed in primary care influence the patient trajectory in individuals with cognitive concerns. Participants will provide a blood sample for biomarker testing and undergo clinical assessments as part of diagnostic evaluation.

The goal of this clinical trial is to demonstrate potential improvements in clinical trial methods relating to dementia and cognitive decline. The main questions it aims to answer are: * Can an intervention's outcome be better assessed by a latent variable ("δ") integrating cognitive performance with functional status? * Can latent biomarkers of δ guide the selection of an intervention that will modulate dementia severity? * Can a latent variable, derived from information collected remotely from caregivers, preselect subjects most likely to respond to the intervention? * Is the effect of the intervention in fact medicated by changes in the targeted biomarker? In this case, the biomarker will be a latent variable derived from several proteins measured in blood (i.e., so-called "adipokines"). The intervention will be donepezil, a medication approved for the treatment of Alzheimer's Disease, but only recently associated with adipokine changes. Participants with cognitive impairment and their caregivers will be interviewed by telephone and those newly prescribed donepezil by their provider for cognitive impairment will be recruited and enrolled. On the basis of the caregiver's report, the cognitively impaired subjects will be assigned to two groups based on a prediction of their response to donepezil. Researchers will compare those groups to see if dementia severity, as measured by δ, improves in predicted responders, and whether the change in the d-score is mediated by changes in adipokines.

This study is testing a new investigational drug called 8M2D to learn whether it is safe and well-tolerated in humans. 8M2D has not previously been given to people. Hypothesis: Researchers believe that 8M2D can be administered safely to healthy adults and to people with early Alzheimer's disease, and that it may reduce levels of amyloid beta. Amyloid beta is a protein that builds up in the brains of people with Alzheimer's disease and is thought to contribute to its progression. The study will be conducted in three parts. In the first two parts, healthy volunteers will receive either a single dose or multiple doses of 8M2D so researchers can understand how the drug moves through the body and whether it causes any side effects. In the third part, a small group of people with early Alzheimer's disease will receive multiple doses so researchers can also begin to assess whether the drug has any effect on amyloid beta levels. Doses will be increased gradually and carefully. An independent safety board will review safety information before any dose increase is allowed. The information gathered in this study will be used to identify the appropriate dose of 8M2D and to help design future studies in people with Alzheimer's disease.

The goal of this clinical trial is to determine whether acoustic stimulation during sleep can enhance slow-wave sleep (SWS), improve cognitive function, and reduce AD-related pathology in individuals with mild cognitive impairment (MCI), compared with cognitively healthy participants. The main questions it aims to answer are: 1. Does acoustic stimulation increase SWS (e.g., slow oscillation and sleep spindle activity) in individuals with MCI? 2. Does enhancing SWS lead to improvements in memory and cognitive performance? 3. Does acoustic stimulation influence plasma p-tau217 levels as a marker of underlying Alzheimer's disease pathology? Researchers will compare participants receiving acoustic stimulation during sleep with those not receiving stimulation to evaluate its effects on sleep architecture, cognition, and plasma biomarkers. Participants will: * Undergo sleep recordings to assess sleep architecture, including SWS, slow oscillations, and sleep spindles * Receive acoustic stimulation during sleep across multiple nights * Complete cognitive assessments, particularly memory-related tasks * Provide blood samples to measure plasma p-tau217 levels * Provide clinical and demographic information for analysis

Perceiving and representing the passage of time allows us to temporally organize perceptions and memories for the coordination of actions, planning, and the mobilization of cognitive processes toward a goal. This innovative project aims to clarify the profile of time impairment associated with normal aging and the progression of age-related pathologies. This project proposes to develop a new neuropsychological tool for quantifying and preventing changes in the relationship to time associated with Alzheimer's disease. Four aspects of time are distinguished, which are measured separately and distributed along a continuum between perception and memory: (a) perception of simultaneity and order; (b) processing of durations; (c) subjective sense of the passage of time; and (d) mental time travel. Crucially, many neurological and psychiatric disorders are associated with impairment in one or more aspects of time. However, time remains largely unexplored in clinical practice. Patients with Alzheimer's disease will complete the CHRONOS battery. This battery allows for a rapid assessment (approximately ten minutes) of the four aspects of time. This new battery will enable the identification of behavioral markers aimed at improving prognosis and prevention regarding individual cognitive trajectories of aging. The relationship to time is closely linked to each person's personal experience. This project will help to put into words difficulties that are not always expressed in terms of time. Thus, considering these pathologies from the perspective of time aims to better understand and prevent their difficulties and to guide the identification of new markers and new avenues for remediation.

It is now established that disturbances in social cognition are frequent in neurology and that they contribute to the development of social conduct disorders. Their assessment is therefore essential, particularly in order to propose early and adapted care. However, this assessment remains limited today. A new serious game-type test, REALSoCog, has been developed to address the shortcomings of current tools and to highlight disturbances in social behaviors. The latter are not always observed in consultation although they are often reported by caregivers. The objective of this research is therefore to validate the REALSoCog task in a pathological population (currently being standardized in the general population: CER-U, IRB N°: 00012020-115). The clinical interest of this task will be tested with a group of patients suffering from a neurodegenerative disease (Alzheimer's disease (AD), dementia with Lewy bodies (DCL), fronto-temporal lobar degeneration (FTD)) in order to assess its sensitivity and specificity in the detection of social-cognitive disturbances, and in particular in terms of social behaviors (detection of social behavioral disorders reported in daily life). The objective is also to document the socio-cognitive profiles in the mentioned diseases thanks to a more ecological test, and to better understand the links between socio-cognitive processes on the one hand, and individual characteristics on the other hand (e.g. mood and social participation).

While knowledge about dementia and its causes is increasing rapidly, healthcare systems remain ill-equipped to detect cognitive decline in the early stages of neurodegenerative diseases such as Alzheimer's disease (AD). However, improving the early identification of AD in the population is a prerequisite for dementia prevention and providing future disease-modifying treatments for individuals most likely to benefit. Subjective cognitive deficits (SCD) and mild cognitive impairment (MCI) may indicate prodromal AD, even in the absence of functional impairment; in conjunction with an AD-typical biomarker profile (such as abnormal protein markers in the cerebrospinal fluid, CSF), the risk of further cognitive decline increases significantly. Offering cognitive screening to individuals with SCD or MCI may therefore open a window of opportunity for early interventions. Currently, there is no system in place for targeted, standardized identification of cases with minimal cognitive decline in Germany or worldwide, hindering efforts to detect neurodegenerative and other causes of cognitive impairment in large segments of the population. The lack of a robust approach for detecting early changes with acceptable accuracy outside of specialist clinics results in disappointingly low diagnostic rates. This is despite evidence showing that structured case finding programs can significantly improve the early detection of cognitive decline. This project will build on an existing network of general practitioners (GPs) and specialists in private practice (neurologists, psychiatrist and geriatricians). The investigator's efforts will aim to strengthen and expand this network, resulting in a larger pool of doctors in the community who have specialized knowledge and a strong commitment to the care of people with dementia. Over the course of the project, the investigators will introduce participating physicians to proprietary digital cognitive tests and blood-based biomarkers (provided by Roche). Building on the success of the ongoing COGSCREEN project, which deploys a community-based recruitment strategy (project number 22-0786), this initiative will equip the Munich healthcare system with the necessary tools to effectively identify individuals most likely to benefit from upcoming disease-modifying treatments for AD. This will serve as a template for the implementation of a precision medicine approach to early diagnosis of AD in Germany and beyond.

Official Title Prospective Single-Arm Safety Study of Cervical Lymphaticovenular Anastomosis (LVA) in Patients with Alzheimer's Disease Purpose of the Study Researchers are conducting this study to see if a minimally invasive microsurgery, called Cervical Lymphaticovenular Anastomosis (LVA), is safe for people with Alzheimer's Disease. How the Surgery Works Alzheimer's Disease is linked to the buildup of metabolic waste products (certain proteins) in the brain. Recent medical discoveries show that these wastes normally drain through small channels in the neck into the blood system. In this study, surgeons will use high-powered microscopes to connect these drainage channels (lymphatic vessels) in the neck directly to small nearby veins. The goal is to create a "detour" that helps the brain clear out these harmful proteins more effectively. What to Expect Safety First: The main goal is to find out if the surgery is safe and well-tolerated by patients. The Procedure: The surgery is performed under general anesthesia and typically takes 4 to 6 hours. It involves small (about 5 cm) incisions on both sides of the neck. Follow-up: Participants will be monitored for at least 12 months. Researchers will use memory tests, brain scans (MRI and PET), and blood tests to see if the surgery helps with daily activities or slows down memory loss.

Older adults and their care partners will participate in music therapy sessions for approximately 8 weeks. Before and after the 8 week study period, participants will fill out questionnaires about their mood, stress levels, and emotions. During the music therapy sessions, they may be observed or asked questions about the music therapy sessions.

This study tests the radiolabeled molecule ("tracer"), \[¹¹C\]HSP990, using positron emission tomography (PET) imaging to assess whether it can be used to measure levels of Heat Shock Protein 90 (Hsp90). The protein Hsp90 plays an important role in how proteins in the brain fold into their three-dimensional structure and how this protein helps maintain cellular homeostasis. Since neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by disrupted three-dimensional protein folding resulting in protein aggregation, we also aim to measure Hsp90 levels in patients with these conditions. \[¹¹C\]HSP990 is a promising tracer for this purpose and has already been extensively tested in animal models with safe and favorable results. The investigator now aims to evaluate this tracer in the human brain in healthy volunteers as well as in patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. The investigator expects that Hsp90 protein levels will be present at reduced concentrations in patients, possibly in different brain regions depending on the distribution of the disease-causing proteins associated with these disorders. Since the discovery of the important role of Hsp90 in neurodegenerative diseases, several candidate drugs targeting Hsp90 have been developed in recent years. The imaging method used in this study may support the development of Hsp90-targeting medications by enabling measurement of Hsp90 levels in the brain and assessment of the effects of these drugs.

Alzheimer's disease and dementia with Lewy bodies (DLB) are the two main age-related neurodegenerative cognitive disorders. Differential diagnosis between these conditions is challenging, both at the prodromal and dementia stages. The lack of a precise diagnosis can be particularly harmful for patients with DLB, as up to 80% of them show severe adverse reactions to antipsychotic medications, including falls, confusion, and even death. The diagnosis of Alzheimer's disease has improved with cerebrospinal fluid (CSF) biomarkers such as Tau, phosphorylated Tau (P-Tau), and the Aβ42/Aβ40 ratio (Lehmann et al., 2018). However, differentiating Alzheimer's disease from DLB remains difficult: 1 to 3 Alzheimer's biomarkers are frequently positive in the CSF of patients with DLB: in 49% of cases at the prodromal stage and up to 72% at the dementia stage. Moreover, total α-synuclein measurement in CSF has not proven to be diagnostically reliable. The DAT-scan, sometimes used as a supportive tool, is an expensive technique and lacks sensitivity, with detection rates of only 78% in dementia-stage DLB and 54% in prodromal DLB. Given these limitations, identifying specific biomarkers for DLB, particularly pathological α-synuclein, is a critical objective. α-synuclein is the main protein component of Lewy bodies, whose abnormal β-sheet conformation promotes aggregation and prion-like propagation. Conventional measurements of total α-synuclein in CSF have failed to achieve sufficient diagnostic specificity. In contrast, detecting aggregated or pathological forms of α-synuclein in CSF appears to be a promising approach for improving the diagnosis of synucleinopathies. New techniques based on α-synuclein aggregation amplification have shown encouraging results in retrospective studies including neuropathologically confirmed cases (Bargar et al., 2021; Rossi et al., 2020). However, prospective evaluation of these methods in real-world clinical settings is still lacking. We hypothesize that a specific assay targeting pathological α-synuclein in CSF could reliably distinguish patients with DLB from those with Alzheimer's disease.

The focus of this study is to examine the protein-plaque clearance (Aß) in relation to the blood-brain-barrier, the glymphatic system, brain lymphatic system and enzymatic degradation. In order to achieve this aim the investigators intend to study participants with a Subjective Cognitive Decline, Mild Cognitive Impairment and a mild Alzheimer's disease.

The overall objective is to obtain an assessment of the pharmacokinetics of \[18F\]3F4AP in healthy volunteers and subjects with demyelinating diseases such as mild cognitive impairment (MCI), Alzheimer's Disease (AD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI) and Spinal radiculopathy (SR).

The goal of this clinical trial is to test whether we can reliably and safely measure the accumulation of pathological protein TDP-43 \[involved in rare forms of dementia such as frontotemporal dementia (FTD) and in amyotrophic lateral sclerosis (ALS)\] using a new positron emission tomography (PET) tracer called \[18F\]ACI-19626. Both healthy people and people with (suspected) TDP-43 accumulation will participate to this trial. The main questions it aims to answer are: * whether \[18F\]ACI-19626 is safe and well tolerated when injected into participants * whether \[18F\]ACI-19626 reliably detects abnormal TDP-43 in the brain using PET technique. * whether there are differences in the amount of this protein between people with diseases related to TDP-43 accumulation in the brain and people without these diseases. Participants will: * Visit the clinic to consent to their participation and to ensure they are eligible (physical and neurological examinations, questionnaires, blood and urine tests, ECG and MRI in some cases). * Visit the clinic to receive the tracer \[18F\]ACI-19626 intravenously and be scanned in a PET scanner, during which blood will be collected. * Receive a phone call from the clinic 2 to 4 days after the PET scan to report any symptoms and side-effects that they may be having. Some of the participants may be asked to come again to the clinic for a second PET scan, allowing the researchers to determine if the measurements with the first PET scan are stable and reproducible.