Neurocognitive Disorder

Patients hospitalized in CRCU will be informed of the research. Those who do not object to participating in the research and who meet the eligibility criteria will be included. Their participation will begin with an initial functional and joint assessment of the patient's hand by an occupational therapist to determine the diameter of cutlery handles best suited to the patient's grip (25, 30, 35 or 40 mm). The patient's autonomy ("Eating" criterion on the Katz scale) will be assessed by the same ergotherapist, and the quantity of food ingested will be measured by a dietician at 3 points: * During a lunch before using the adapted cutlery handles (Day0); * At lunch when the adapted cutlery handles are used for the first time (Day1); * At lunch after 3 days' use of the adapted cutlery handles (Day3), corresponding to the learning phase in the use of the technical aid. Lunches will be similar over the 3 days. These are standard lunches predefined by the unit's dietician. On Day0 and Day3, the ergotherapist will carry out an ecological assessment of meals. Ecological assessment is used in ergotherapy to observe and analyze the patient's interactions with his environment and their repercussions on his ability to perform a task. The aim here is to assess whether the patient exhibits compensation of the upper limb (such as shoulder elevation or trunk inclination) during the meal performed without technical aids (Day0) and that performed after the learning phase of using the adapted handle (Day3). The patient's participation will end at the end of the Day3 assessments.

This is a prospective cohort study that will enroll patients who are about to or have already undergone DBS electrode placement for a variety of disorders including, but not limited to Parkinson's disease, essential tremor, dystonia, depression, epilepsy, neuropathic pain and Alzheimer's disease. This eligible patient population is broad but unified by the fact that they will all undergo DBS to treat specific circuit dysfunctions. Pre-operative DBS patients and patients with externalized leads or internalized IPG may be included. We propose to study patients with externalized leads or internalized IPG programmed at either 'switched off' (IPG at 0 volt and off state) and 'switched on' settings We have already performed phantom safety testing for these experimental conditions and found it to be safe. We propose to perform the following scans: 1. Structural 1.5Tesla or 3Tesla MRI with 8 channel coil/or transmit-receive head coil - 3D FSPGR, standard FRFSE T2 scan, standard DTI scan (white matter tracts) and standard QSM (Quantitative Susceptibility Mapping) scan (Iron quantification). 2. Resting state and task based functional MRI with 8 channel coil Further, we propose to assess whether the aforementioned scans can be used as an adjunct to improve current DBS post-operative follow up.

Cognitive impairment related to dementia is frequently under-diagnosed in primary care settings despite the increasing rates of patient cognitive complaints and the availability of numerous cognitive assessment tools. Missed detection delays treatment of reversible conditions as well as provision of support services and critical planning. This problem is more prevalent among older African-Americans and Hispanics than older whites, and more common in rural than urban populations. The investigators developed the 5-Cog brief cognitive assessment that is simple to use, standardized, takes \<5 minutes, does not require informants, and accounts for major technical, cultural, and logistical barriers of current assessments. The investigators are conducting a simple randomized clinical trial to examine the clinical efficacy of the 5-Cog paradigm (5-Cog brief cognitive assessment paired with a clinical decision-making tool) to improve dementia care in 1,200 predominantly minority sample of older adults with cognitive concerns presenting to a primary care clinic in the Bronx. Interim analysis revealed that the 5-Cog paradigm resulted in an over 8-fold increase in new cognitive impairment diagnoses and over 3-fold increase in improved dementia care actions by primary care physicians compared to an active control arm. Following up on these very promising results, the investigators propose a hybrid Type 1 effectiveness-implementation design in real-world settings to adapt and test the effectiveness of the 5-Cog paradigm to increase detection of cognitive impairment care in older adults presenting with cognitive concerns. The aim of the pragmatic cluster-randomized trial is to test the clinical effectiveness of the 5-Cog paradigm in increasing cognitive impairment detection and improving dementia care - ascertained via electronic medical record. Randomization will be at the clinic level, and select 22 primary care practices; 6 in Bronx and 18 in urban and rural Indiana. 300 participants per practice will be enrolled for a total of 6,600 older patients with cognitive concerns. Results will also be examined in NIH designated health disparity populations including underserved minority and socio-economically challenged populations. Outcomes are new cognitive impairment diagnoses (primary) and improved dementia care (secondary) in the 90-day period following presentation of cognitive concern to the primary care physician. * New cognitive impairment diagnoses (primary): New diagnosis of dementia or Mild Cognitive Impairment by primary care physicians. For patients with a previous diagnosis of Mild Cognitive Impairment in electronic medical record, only a new diagnosis of dementia will be considered as an incident outcome. * Improved dementia care (secondary): Any of the following: 1. Tests ordered for reversible causes of cognitive impairment as per published guidelines. 2. New cognitive enhancing medication prescriptions or deprescribing anti-cholinergic. 3. Referral for cognitive/dementia evaluation by specialists (Neurology, Geriatrics, Psychiatry). 4. Referral to social worker or community-based organizations. Implementation issues and cost-effectiveness of the 5-Cog paradigm will also be examined. This proposed study focuses on scalable approaches to address the unmet need of early detection of incident cognitive impairment, including in populations that experience health disparities.

Antidepressants typically decrease amygdala response to negative stimuli while enhancing response to positive stimuli, but it is unclear at a mechanistic level how increasing serotonin would have this opposing effect. One hypothesis is that although positive and negative cues activate the same area at a global level, more detailed characterisation may reveal key differences in processing in terms of localisation or response function. Until now, due to methodological restriction, the amygdala has been mostly studied as a single structure. It is however known that it consists of a number of subfields, which are likely to play distinct roles in emotional processing. In this study the investigators will make use of 7T fMRI scanning to study the effects of a single dose (20 mg) of citalopram (selective serotonin reuptake inhibitor, SSRI) on these subfields during emotional face processing, allowing greater precision to identify underlying neural mechanisms underpinning psychological effects.

In healthy humans, brain functional representation of actions, either executed or observed, relies on the human action observation network (AON). Several studies demonstrated that AON activation is crucial for action understanding and for subserving imitation by observation of new motor skills. The demonstration of the activation of this circuit in patients with motor disorders have opened the way to new rehabilitation protocols based on the observation of meaningful actions followed by their execution (Observation to Imitate), often referred as Action Observation Therapy (AOT). In the last decade, AOT was widely used in adult stroke patients as well as in children with cerebral palsy (CP). Overall, these studies demonstrate a significant motor improvement after therapy, that is maintained at follow-up. Functional Magnetic Resonance Imaging (fMRI) studies on the effects of AOT found a positive correlation between the functional improvements of manual abilities of these patients and the enlargement of movement-related brain regions, suggesting that AOT can promote the activation of mechanisms of brain plasticity and functional reorganization of the cortical areas responsible for movements. Recently, fMRI studies have demonstrated that also other brain regions, such as the cerebellum, the thalamus and the basal ganglia, belong to the AON. Despite numerous studies on AON, the fine-grained details of this complex network, especially at subcortical level, and the reciprocal interactions between different brain regions are largely unknown. Moreover, no studies are available at submillimeter level concerning the involvement of subcortical structures. Compared with lower magnetic field systems, Ultra-High Field Magnetic Resonance (UHF-MR) permits a remarkable gain in terms of signal to noise ratio (SNR). This significant increase in SNR produces a great improvement of all imaging parameters, and can be exploited increasing spatial and/or temporal resolution. Moreover, at 7T, we assist also to an empowered sensitivity of the signal to modifications of the composition of tissue that can be translated in new or improved contrasts, such as susceptibility-weighted imaging. fMRI technique is an advanced MR method that benefits from the use of UHF thanks to the positive combination of increased SNR and increased sensitivity to the effect generating the contrast (BOLD effect). It has been demonstrated that an increase in the spatial resolution of UHF fMRI allows to describe the functional architecture of the cerebral cortex at mesoscopic (sub-millimeter) scale, hence revealing cortical columns-laminar fMRI profiles, and to segment subcortical structures, to explore their functional selectivity to external stimuli and topographic organization, and to study the cortex. Moreover, the increase in the sensitivity of fMRI at 7T allows to obtain statistically significant functional maps of brain activation not only in groups of subjects but also in individual subjects and individual events, opening new perspectives in the use of fMRI for clinical purposes. The present study aims to use 7T fMRI to understand the mechanisms of the functional organization of the AON circuit, and in particular the relationship between the cerebral cortex and other structures such as the subcortical nuclei and the cerebellum, and to explore how this organization changes in the presence of lesions acquired at an early age, such as in patients with brain lesions that arose in the pre- or perinatal period, like Cerebral Palsy (CP). We intend to enroll 28 healthy human subjects and 12 adolescents or young adults with CP. All participants will perform a 7 Tesla MRI scan, with a functional and anatomical dedicated protocol and CP patients will have a comprehensive clinical assessment before the MRI exam. The MR protocol includes 3D MR sequences with very high spatial resolution. In particular, T1-weighted sequences with isotropic voxel size of 0.8mm is used in order to highlight and segment small substructures, but at the same time evaluating the compliance of subjects, especially of patients, in maintaining the position for long acquisition, without introducing motion artifacts. Analogously, 3D FLAIR sequences are acquired for a detailed study of lesions in CP patients. fMRI acquisitions in humans are carried out by using Gradient-Echo Echo-Planar Imaging (GRE-EPI) sequences with spatial resolutions depending on the target of each functional series and by using imaging acceleration techniques as SENSE and multi-band approaches. For the study of functional connectivity and the whole AON circuit, comprehensive of the cerebellum, we will privilege whole brain coverage and relatively short temporal resolution (1-1.5 seconds), with a spatial resolution of 1.5mm isotropic voxel. On the other hand, for small substructures and laminar column studies, we will optimize an fMRI acquisition with isotropic voxel size of 0.7-0.9mm. As functional task we use paradigms already described in previous studies and adapted for the 7T scanner. Visual stimuli are presented in binocular vision by means of Liquid Cristal Display (LCD) goggles (VisuaStim-SVGA-Resonance Technology, USA). Participants observe short video-clips (lasting 4 s each), showing unimanual or bimanual actions performed by an actor, from a subjective perspective. The observed actions consist in grasping and using different tools (e.g., hammering, using a screwdriver, opening a jar etc.) or, as control condition, observation of the static initial frame of each clip. The objects are of different colors in order to avoid visual adaptation. The visual characteristics of each video are balanced between the experimental conditions to control the effects of brightness, contrast, sharpness and amount of visual information. During the rest period, in the absence of experimental stimuli, the participant have to fixate a white cross on a black background. During the entire fMRI acquisition, subject's performance are visually checked by the experimenter and kinematic parameters are recorded by using MR-compatible cameras.

Study Rationale: This prospective study, to be conducted in two centers (UZ Leuven and UZ Gent), aims to validate cardiac \[18F\]-MFBG PET in distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA-P) and differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Both PD and DLB, caused by alpha-synuclein deposits (Lewy bodies), exhibit not only nigrostriatal dopaminergic deficits but also early peripheral changes in myocardial norepinephrine (NE) innervation. These defects can be visualized and quantified using NE transporter tracers. \[18F\]-MFBG was developed several years ago with high-yield production and has already been employed in multiple centers worldwide, mainly in the context of imaging neuroendocrine tumors. \[18F\]-MFBG offers logistical, technical, and pharmacological advantages, including faster scanning, high spatial resolution, and improved quantification compared to the existing method using \[123I\]-MIBG SPECT. Participant Population: The study will include 28 healthy volunteers (CON), of which 3 will participate in \[18F\]-MFBG PET dosimetry (part 1) and 25 in the main study for optimization/age-dependence of cardiac \[18F\]-MFBG parameters (part 2). In part 3, 40 PD, 15 MSA-P, 15 DLB, and 15 AD patients with biomarker-confirmed diagnoses will be included. Total: 113 subjects. Intervention: All subjects will undergo three examinations in the main work packages (parts 2 and 3) dynamic cardiac \[18F\]-MFBG PET, with dynamic \[123I\]-MIBG SPECT as a comparator, as well as cerebral \[18F\]-PE2I PET. Endpoints: Primary: Non-inferiority in discriminating populations using \[18F\]-MFBG; Secondary: effect size, relationship between myocardial uptake and cerebral dopamine active transporter (DAT) changes, autonomic dysfunction, regional myocardial variation. Secondary: 1. Determine the effect size (ES) of the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB compared to \[123I\]-MIBG SPECT and \[123I\]-MIBG planar scintigraphy. 2. Identify any significant correlation between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and the reduction in \[18F\]-PE2I binding in early to moderate disease stages. 3. Assess the relationship between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and measures of autonomic dysfunction. 4. Examine the regional pattern of reduced \[18F\]-MFBG uptake in PD/DLB compared to controls, with an endpoint considered met if different regional segment scores are evident between PD/MSA-P or DLB/AD or subtypes of PD.

This is an open-label, first in human (FiH) positron emission tomography (PET) microdose study in patients with suspected α-synuclein pathology and healthy volunteers (HVs) using \[18F\]ACI-15916 as a novel radioligand. This study will be dedicated to qualification of the ligand \[18F\]ACI-15916 to measure α-synuclein pathology using PET investigations, including estimation of effective dose and test-retest reliability. The study consists of four parts in which a total of up to 46 participants may be included: * Part 1: Up to 5 HVs and up to 5 patients with Parkinson's Disease (PD) will be included. * Part 2: Up to 30 additional subjects including: HV cases (maximum 10) and patients with α-synucleinopathies such as PD, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). * Part 3: Up to 10 participants from Part 1 and/or Part 2 will have a second PET measurement within one month after their initial PET measurement to evaluate test-retest variability and reproducibility. * Part 4. Up to 6 HVs (3 female and 3 male) will undergo a whole-body PET-CT examination to estimate the effective dose after one administration of \[18F\]ACI-15916. The four study parts can overlap. The study consists of a screening period of up to 60 days to assess participants' eligibility, a PET scan with \[18F\]ACI-15916 along with arterial blood sampling, and a safety phone call following the scanning visit. For participants in Part 3, a second PET scan with \[18F\]ACI-15916 will be performed up to one month after the first scan to evaluate test-retest variability and reproducibility, followed by a new safety phone call. For subjects in Part 4 (dosimetry), no arterial blood sampling will be performed. The total study duration will be up to 10 weeks for Part 1, 2 and 4 participants and up to 14 weeks for Part 3 participants.

This trial aims to evaluate the effects (i.e. safety and uptake) of a new radiotracer molecule. Study participants will take part in the study by attending two to three study visits over a period of up to 3 months (from the screening visit up to the last study visit). The study consists of three parts in which a total of up to 45 participants may be included: Part 1 may include in total up to 15 participants: * up to 5 healthy controls (HCs) * up to 5 symptomatic progranulin gene (GRN) and up to 5 symptomatic chromosome 9 open reading frame 72 (C9orf72) mutation carriers with FTD (including prodromal) either with or without motor neuron disease (MND) characteristics. If the safety and dosimetry are satisfactory in the first subjects and sufficient data are obtained from this part, Part 2 may be initiated. Part 2 may include in total up to 30 participants including: * up to 25 patients with TDP-43 proteinopathies: up to 10 additional mutation carriers (including other mutations than GRN and C9orf72, and/or asymptomatic carriers) with FTD (including prodromal) either with or without MND characteristics; up to 10 sporadic or genetic (excluding mutations with known absence of TDP-43 pathology, e.g. Superoxide Dismutase 1 (SOD1) or fused in sarcoma protein gene (FUS)) ALS; up to 10 suspected TDP-43 related sporadic FTD or FTD-MND; up to 5 patients with other neurodegenerative diseases, e.g. AD or suspected Limbic-Predominant Age-related TDP-43 Encephalopathy (LATE) pathology * up to 5 additional HVs may also be imaged, if necessary, to enable a better distinction of brain binding in this population compared to the population of subjects with TDP-43 proteinopathies Part 3 aims to assess test-retest reliability. Up to 5 participants from Part 1 and/or Part 2 will have an additional scan within 1 month after their first scan to determine test-retest reliability.

To investigate the primary brain regions of precursors of Alzheimer's disease and Alzheimer's disease by novel molecular probe \[18F\]AV45(Aβ) and \[18F\]AV1451(Tau)PET/CT imaging. And the distribution of positive lesions in the brain area affecting the simple mental state examination and the Montreal Cognitive Assessment Scale in AD patients; It is expected to provide molecular imaging information for further study of the pathogenesis of AD. After clinical transformation, objective and quantitative positive diagnostic criteria for \[18F\]AV45 and \[18F\]AV1451PET/CT in the diagnosis of early Alzheimer's disease were established to avoid the defects of relying on the subjective experience of doctors and time-consuming diagnosis.

Alpha-synucleinopathies refer to age-related neurodegenerative and dementing disorders, characterized by the accumulation of alpha-synuclein in neurons and/or glia. The anatomical location of alpha-synuclein inclusions (Lewy Bodies) and the pattern of progressive neuronal death (e.g. caudal to rostral brainstem) give rise to distinct neurological phenotypes, including Parkinson's disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB). Common to these disorders are the involvement of the central and peripheral autonomic nervous system, where Pure Autonomic Failure (PAF) is thought (a) to be restricted to the peripheral autonomic system, and (b) a clinical risk factor for the development of a central synucleinopathy, and (c) an ideal model to assess biomarkers that predict phenoconversion to PD, MSA, or DLB. Such biomarkers would aid in clinical trial inclusion criteria to ensure assessments of disease- modifying strategies to, delay, or halt, the neurodegenerative process. One of these biomarkers may be related to the neurotransmitter dopamine (DA) and related changes in the substantia nigra (SN) and brainstem. \[18F\]F-DOPA is a radiolabeled substrate for aromatic amino acid decarboxylase (AAADC), an enzyme involved in the production of dopamine. Use of this radiolabeled substrate in positron emission tomography (PET) may provide insight to changes in monoamine production and how they relate to specific phenoconversions in PAF patients. Overall, this study aims to identify changes in dopamine production in key regions including the SN, locus coeruleus, and brainstem to distinguish between patients with PD, MSA, and DLB, which may provide vital information to predict conversion from peripheral to central nervous system disease.