Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases.

Background: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD.

Structural connectivity and brain network analyses in Parkinson's disease: A cross-sectional and longitudinal study.

Introduction: Parkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common neurodegenerative disease. Magnetic resonance imaging (MRI) can reveal underlying brain changes associated with PD.

Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease.

Introduction: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear.

Methods: We studied both cholinergic projection systems using a free water-corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls.

Results: Free water in the NBM-cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition.

Atrophy of the Cholinergic Basal Forebrain can Detect Presynaptic Cholinergic Loss in Parkinson's Disease.

Objectives: Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non-motor outcome studies in Parkinson's disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample.

Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson's disease.

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain.

Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer's disease.

Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants.

Quantitative EEG and cholinergic basal forebrain atrophy in Parkinson's disease and mild cognitive impairment.

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls.

Cholinergic basal forebrain and hippocampal structure influence visuospatial memory in Parkinson's disease.

Visuospatial impairment in Parkinson's disease (PD) heralds the onset of a progressive dementia syndrome and might be associated with cholinergic dysfunction. It remains unclear however, whether degeneration of the cholinergic basal forebrain is directly related to cognitive decline, or whether relationships between this region and cognitive function are mediated by closely related brain structures such as those in the medial temporal lobe. To evaluate relationships between structure of the cholinergic basal forebrain, medial temporal lobe and cognition, 27 PD patients without dementia and 20 controls underwent neuropsychological assessment and MRI.

Preserved cholinergic forebrain integrity reduces structural connectome vulnerability in mild cognitive impairment.

Neurodegeneration leads to redistribution of processing, which is reflected in a reorganisation of the structural connectome. This might affect its vulnerability to structural damage. Cortical acetylcholine allows favourable adaptation to pathology within the memory circuit.

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders.

Purpose Of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders.

Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors.

Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease.

Background: Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment.

Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease.

Background: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease.

Objectives: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms.

Methods: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative.

Practical Priors for Bayesian Inference of Latent Biomarkers.

Latent biomarkers are quantities that strongly relate to patient's disease diagnosis and prognosis, but are difficult to measure or even not directly observable. The objective of this study was to develop, analyze and validate new priors for Bayesian inference of such biomarkers. Theoretical analysis revealed a relationship between the estimates inferred from the model and the true values of measured quantities, and the impact of the priors.

A Key Role for Subiculum-Fornix Connectivity in Recollection in Older Age.

Individual differences in memory during aging are associated with the microstructure of the fornix, a bidirectional tract connecting the hippocampus with the diencephalon, basal forebrain and cortex. To investigate the origin of alterations in fornix microstructure, measurement of hippocampal subfield volumes was combined with diffusion MRI and cognitive evaluation in a new sample of 31 healthy human participants aged 50-89 years. The fornix, uncinate and parahippocampal cingulum were reconstructed using diffusion MRI tractography.

Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia.

Purpose Of Review: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis.

Recent Findings: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD).

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression.

Cholinergic basal forebrain structure influences the reconfiguration of white matter connections to support residual memory in mild cognitive impairment.

The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC).

Dopamine-agonists and impulsivity in Parkinson's disease: impulsive choices vs. impulsive actions.

The control of impulse behavior is a multidimensional concept subdivided into separate subcomponents, which are thought to represent different underlying mechanisms due to either disinhibitory processes or poor decision-making. In patients with Parkinson's disease (PD), dopamine-agonist (DA) therapy has been associated with increased impulsive behavior. However, the relationship among these different components in the disease and the role of DA is not well understood.

Imaging impulse control disorders in Parkinson's disease and their relationship to addiction.

Established substance addictions and impulse control disorders (ICDs) such as pathological gambling share similar underlying neurobiology, and recent data extends these commonalities to the risk factors that increase an individuals' susceptibility to develop such behaviours. In Parkinson's disease (PD), impulse control disorders (ICDs) are increasingly recognised to develop after patients begin dopamine (DA) restoration therapy, in particular DA agonists. In both the PD and non-PD population, more impulsive individuals are at increased risk for impulse control disorders.

The neurobiology and neural circuitry of cognitive changes in Parkinson's disease revealed by functional neuroimaging.

Patients with Parkinson's disease (PD) often develop a spectrum of cognitive symptoms that can evolve into dementia. Dopamine (DA) replacement medications, though improving motor symptoms, can exert both positive and negative effects on cognitive ability, depending on the severity of the disease and the specific skill being tested. By considering the behavioral and clinical aspects of disease- and treatment-mediated changes in cognition alongside the pathophysiology of PD, an understanding of the factors that govern the heterogeneous expression of cognitive impairment in PD is beginning to emerge.

A role for the subthalamic nucleus in response inhibition during conflict.

The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: a [11C] FLB-457 and PET study.

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG.

The role of the subthalamic nucleus in response inhibition: evidence from local field potential recordings in the human subthalamic nucleus.

Response inhibition as measured during a stop-signal task refers to the ability to halt an action that has already been set in motion. Cortical and sub-cortical structures, such as the subthalamic nucleus (STN), that are active during attempts to inhibit action are thought to contribute to a 'stop-process' that must gain dominance over a 'go-process' if inhibition is to be successful. We recorded local field potential activity from the STN of Parkinson's disease patients with implanted deep brain stimulation electrodes during a stop-signal task.

Combining functional imaging with brain stimulation in Parkinson's disease.

Brain stimulation techniques such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) constitute promising clinical and research tools to investigate neural mechanisms underlying neurological and psychiatric diseases. They have enormous potential in modifying brain activity and subsequent function. However, it is still a matter of debate how either of these stimulation approaches operates to produce the clinical outcomes observed in patients.

Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus.

The pedunculopontine nucleus is composed of cholinergic and non-cholinergic neurones and is located in the caudal pontomesencephalic tegmentum. Evidence suggests that the nucleus plays a role in the production and control of movement. The nucleus has dense interconnections with the basal ganglia, as well as with other areas of the brain associated with motor control.