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Alzheimer's Research & Therapy May 2024The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in...
BACKGROUND
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
METHODS
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
RESULTS
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
CONCLUSIONS
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
Topics: Humans; Frontotemporal Dementia; Male; Locus Coeruleus; Alzheimer Disease; Female; Aged; Magnetic Resonance Imaging; Basal Nucleus of Meynert; Middle Aged; Neuropsychological Tests; Amnesia; Positron-Emission Tomography
PubMed: 38702802
DOI: 10.1186/s13195-024-01466-z -
Communications Biology May 2024An organism's ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions....
An organism's ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions. Notably, the sensorimotor expectations produced when touching one's own body attenuate such sensations, making them feel weaker and less ticklish and rendering them easily distinguishable from potentially harmful touches of external origin. How the brain learns and keeps these action-related sensory expectations updated is unclear. Here we employ psychophysics and functional magnetic resonance imaging to pinpoint the behavioral and neural substrates of dynamic recalibration of expected temporal delays in self-touch. Our psychophysical results reveal that self-touches are less attenuated after systematic exposure to delayed self-generated touches, while responses in the contralateral somatosensory cortex that normally distinguish between delayed and nondelayed self-generated touches become indistinguishable. During the exposure, the ipsilateral anterior cerebellum shows increased activity, supporting its proposed role in recalibrating sensorimotor predictions. Moreover, responses in the cingulate areas gradually increase, suggesting that as delay adaptation progresses, the nondelayed self-touches trigger activity related to cognitive conflict. Together, our results show that sensorimotor predictions in the simplest act of touching one's own body are upheld by a sophisticated and flexible neural mechanism that maintains them accurate in time.
Topics: Humans; Somatosensory Cortex; Male; Magnetic Resonance Imaging; Cerebellum; Female; Adult; Young Adult; Touch Perception; Touch
PubMed: 38702520
DOI: 10.1038/s42003-024-06188-4 -
Annals of Medicine Dec 2024
Topics: Humans; Motor Cortex; Transcranial Direct Current Stimulation; Cerebellum; Stroke; Stroke Rehabilitation; Randomized Controlled Trials as Topic
PubMed: 38686845
DOI: 10.1080/07853890.2024.2348052 -
BMC Neurology Apr 2024Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has...
BACKGROUND
Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders.
METHODS
Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS.
DISCUSSION
Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06122675, first registered November 7, 2023.
Topics: Humans; Cerebral Palsy; Deep Brain Stimulation; Child; Adolescent; Young Adult; Movement Disorders; Cerebellum; Male; Female; Adult
PubMed: 38684956
DOI: 10.1186/s12883-024-03633-z -
Transgenic Research Jun 2024Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior...
Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli-myelin basic protein is necessary for myelination and neuronal maturation during central nervous system development. In this study, we established Golli-myelin basic protein-floxed mice to elucidate the cell-type-specific effects of Golli-myelin basic protein knockout through the generation of conditional knockout mice (Golli-myelin basic proteins; E3CreN), in which Golli-myelin basic proteins were specifically deleted in cerebellar granule neurons, where Golli-myelin basic proteins are expressed abundantly in wild-type mice. To investigate the role of Golli-myelin basic proteins in cerebellar granule neurons, we further performed histopathological analyses of these mice, with results indicating no morphological changes or degeneration of the major cellular components of the cerebellum. Furthermore, behavioral analysis showed that Golli-myelin basic proteins; E3CreN mice were healthy and did not display any abnormal behavior. These results suggest that the loss of Golli-myelin basic proteins in cerebellar granule neurons does not lead to cerebellar perturbations or behavioral abnormalities. This mouse model could therefore be employed to analyze the effect of Golli-myelin basic protein deletion in specific cell types of the central nervous system, such as other neuronal cells and oligodendrocytes, or in lymphocytes of the immune system.
Topics: Animals; Neurons; Mice, Knockout; Mice; Cerebellum; Myelin Basic Protein
PubMed: 38684589
DOI: 10.1007/s11248-024-00382-0 -
PLoS Biology Apr 2024Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive...
Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.
Topics: Animals; Gerbillinae; Neurons; Acoustic Stimulation; Superior Olivary Complex; Sound Localization; Male; Olivary Nucleus; Sound; Female
PubMed: 38683852
DOI: 10.1371/journal.pbio.3002586 -
Alzheimer's & Dementia : the Journal of... Jun 2024Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial...
INTRODUCTION
Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FC) on cortical atrophy across Braak stage regions and its impact on cognition.
METHODS
We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FC with longitudinal atrophy and cognition with and without Aβ moderation.
RESULTS
Cross-sectionally, lower FC was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FC at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FC and subsequent cognitive decline.
DISCUSSION
FC is implicated in Aβ-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD.
HIGHLIGHTS
Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.
Topics: Humans; Locus Coeruleus; Male; Female; Atrophy; Cognitive Dysfunction; Magnetic Resonance Imaging; Aged; Positron-Emission Tomography; Alzheimer Disease; Cross-Sectional Studies; Temporal Lobe; Amyloid beta-Peptides; Longitudinal Studies; Neural Pathways
PubMed: 38676563
DOI: 10.1002/alz.13839 -
International Journal of Molecular... Apr 2024Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity....
Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity. Its mutation causes the autism-like ADNP syndrome (also called the Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders and motor dysfunctions. Similar to the ADNP syndrome, the haploinsufficient mouse shows low synapse density, leading to motor and cognitive ability delays. Moderate physical activity (PA) has several neuroprotective and cognitive benefits, promoting neuronal survival, differentiation, neurogenesis, and plasticity. Until now, no study has investigated the effect of moderate exercise on ADNP expression and distribution in the rat brain. The aim of the current investigation was to study the effects of moderate exercise on the ADNP expression and neuronal activation measured by the microtubule protein β-Tubulin III. In pursuit of this objective, twenty-four rats were selected and evenly distributed into two categories: sedentary control rats and rats exposed to moderate physical activity on a treadmill over a span of 12 weeks. Our results showed that moderate PA increases the expression of ADNP and β-Tubulin III in the dentate gyrus (DG) hippocampal region and cerebellum. Moreover, we found a co-localization of ADNP and β-Tubulin III in both DG and cerebellum, suggesting a direct association of ADNP with adult neuronal activation induced by moderate PA.
Topics: Animals; Male; Rats; Brain; Cerebellum; Dentate Gyrus; Nerve Tissue Proteins; Neurons; Physical Conditioning, Animal; Tubulin; Rats, Wistar
PubMed: 38673966
DOI: 10.3390/ijms25084382 -
International Journal of Molecular... Apr 2024Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs)....
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood-brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
Topics: Animals; Spinocerebellar Ataxias; Peptides; Disease Models, Animal; Dependovirus; Mice; Ataxin-7; Trinucleotide Repeat Expansion; RNA, Small Interfering; Phenotype; Genetic Vectors; Purkinje Cells; Mice, Transgenic; Cerebellum; Humans; Genetic Therapy; Alleles
PubMed: 38673939
DOI: 10.3390/ijms25084354 -
International Journal of Molecular... Apr 2024According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of...
According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response.
Topics: Animals; Dopaminergic Neurons; Male; Mice; Social Behavior; Humans; Clozapine; Raphe Nuclei; Behavior, Animal; Dopamine; Mice, Inbred C57BL
PubMed: 38673899
DOI: 10.3390/ijms25084315