Basal forebrain integrity, cholinergic innervation and cognition in idiopathic Parkinson's disease.

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.

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. METHODS: [18 F]-Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non-demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume-of-interest based correlation analysis. RESULTS: Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto-occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1-2. Correlations were also observed in the striatum, thalamus, and brainstem. INTERPRETATION: Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto-occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991-998.

Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson's disease.

Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.

Cholinergic system correlates of postural control changes in Parkinson's disease freezers.

Postural instability and freezing of gait are the most debilitating dopamine-refractory motor impairments in advanced stages of Parkinson's disease because of increased risk of falls and poorer quality of life. Recent findings suggest an inability to efficaciously utilize vestibular information during static posturography among people with Parkinson's disease who exhibit freezing of gait, with associated changes in cholinergic system integrity as assessed by vesicular acetylcholine transporter PET. There is a lack of adequate understanding of how postural control varies as a function of available sensory information in patients with Parkinson's disease with freezing of gait. The goal of this cross-sectional study was to examine cerebral cholinergic system changes that associate with inter-sensory postural control processing features as assessed by dynamic computerized posturography and acetylcholinesterase PET. Seventy-five participants with Parkinson's disease, 16 of whom exhibited freezing of gait, underwent computerized posturography on the NeuroCom© Equitest sensory organization test platform, striatal dopamine, and acetylcholinesterase PET scanning. Findings demonstrated that patients with Parkinson's disease with freezing of gait have greater difficulty maintaining balance in the absence of reliable proprioceptive cues as compared to those without freezing of gait [ß = 0.28 (0.021, 0.54), P = 0.034], an effect that was independent of disease severity [ß = 0.16 (0.062, 0.26), P < 0.01] and age [ß = 0.092 (-0.005, 0.19), P = 0.062]. Exploratory voxel-based analysis revealed an association between postural control and right hemispheric cholinergic network related to visual-vestibular integration and self-motion perception. High anti-cholinergic burden predicted postural control impairment in a manner dependent on right hemispheric cortical cholinergic integrity [ß = 0.34 (0.065, 0.61), P < 0.01]. Our findings advance the perspective that cortical cholinergic system might play a role in supporting postural control after nigro-striatal dopaminergic losses in Parkinson's disease. Failure of cortex-dependent visual-vestibular integration may impair detection of postural instability in absence of reliable proprioceptive cues. Better understanding of how the cholinergic system plays a role in this process may augur novel treatments and therapeutic interventions to ameliorate debilitating symptoms in patients with advanced Parkinson's disease.

Imaging of sleep disorders in pre-Parkinsonian syndromes.

PURPOSE OF REVIEW: Neuroimaging has been advanced in the last years and enabled clinicians to evaluate sleep disorders, especially isolated rapid eye movement sleep disorder (iRBD), which can be seen in alpha-synucleinopathies. iRBD is the best prodromal clinical marker for phenoconversion to these neurodegenerative diseases. This review aims to provide an update on advanced neuroimaging biomarkers in iRBD. RECENT FINDINGS: Advanced structural MRI techniques, such as diffusion tensor imaging and functional MRI, neuromelanin-sensitive MRI, and scintigraphic neuroimaging such as cholinergic PET, dopamine transporter imaging - single-photon emission computerized tomography, perfusional single-photon emission computerized tomography, and cardiac metaiodobenzylguanidine can provide diagnostic and prognostic imaging biomarkers for iRBD, in isolation and more robustly when combined. SUMMARY: New advanced neuroimaging can provide imaging biomarkers and aid in the appropriate clinical assessment and future therapeutic trials.

Vestibular Sensory Conflict During Postural Control, Freezing of Gait, and Falls in Parkinson's Disease.

BACKGROUND: The vestibular system has been implicated in the pathophysiology of episodic motor impairments in Parkinson's disease (PD), but specific evidence remains lacking. OBJECTIVE: We investigated the relationship between the presence of freezing of gait and falls and postural failure during the performance on Romberg test condition 4 in patients with PD. METHODS: Modified Romberg sensory conflict test, fall, and freezing-of-gait assessments were performed in 92 patients with PD (70 males/22 females; mean age, 67.6 ± 7.4 years; Hoehn and Yahr stage, 2.4 ± 0.6; mean Montreal Cognitive Assessment, 26.4 ± 2.8). RESULTS: Failure during Romberg condition 4 was present in 33 patients (35.9%). Patients who failed the Romberg condition 4 were older and had more severe motor and cognitive impairments than those without. About 84.6% of all patients with freezing of gait had failure during Romberg condition 4, whereas 13.4% of patients with freezing of gait had normal performance (χ2  = 15.6; P < 0.0001). Multiple logistic regression analysis showed that the regressor effect of Romberg condition 4 test failure for the presence of freezing of gait (Wald χ2  = 5.0; P = 0.026) remained significant after accounting for the degree of severity of parkinsonian motor ratings (Wald χ2  = 6.2; P = 0.013), age (Wald χ2  = 0.3; P = 0.59), and cognition (Wald χ2  = 0.3; P = 0.75; total model: Wald χ2  = 16.1; P < 0.0001). Patients with PD who failed the Romberg condition 4 (45.5%) did not have a statistically significant difference in frequency of patients with falls compared with patients with PD without abnormal performance (30.5%; χ2  = 2.1; P = 0.15). CONCLUSIONS: The presence of deficient vestibular processing may have specific pathophysiological relevance for freezing of gait, but not falls, in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Altered Cholinergic Innervation in De Novo Parkinson's Disease with and Without Cognitive Impairment.

BACKGROUND: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention. OBJECTIVE: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment. METHODS: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed. RESULTS: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala. CONCLUSION: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

No Dopamine Agonist Modulation of Brain [18F]FEOBV Binding in Parkinson's Disease.

The [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [18F]FEOBV PET rodent studies suggest that regional brain [18F]FEOBV binding may be modulated by dopamine D2-like receptor agents. We examined associations of regional brain [18F]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist drug treatment. PD subjects (n = 108; 84 males, 24 females; mean age 68.0 ± 7.6 [SD] years), mean disease duration of 6.0 ± 4.0 years, and mean Movement Disorder Society-revised Unified PD Rating Scale III 35.5 ± 14.2 completed [18F]FEOBV brain PET imaging. Thirty-eight subjects were taking dopamine D2-like agonists. Vesicular monoamine transporter type 2 [11C]dihydrotetrabenazine (DTBZ) PET was available in a subset of 54 patients. Subjects on dopamine D2-like agonists were younger, had a longer duration of disease, and were taking a higher levodopa equivalent dose (LED) compared to subjects not taking dopamine agonists. A group comparison between subjects with versus without dopamine D2-like agonist use did not yield significant differences in cortical, striatal, thalamic, or cerebellar gray matter [18F]FEOBV binding. Confounder analysis using age, duration of disease, LED, and striatal [11C]DTBZ binding also failed to show significant regional [18F]FEOBV binding differences between these two groups. Chronic D2-like dopamine agonist use in PD subjects is not associated with significant alterations of regional brain [18F]FEOBV binding.

Differential cholinergic systems' changes in progressive supranuclear palsy versus Parkinson's disease: an exploratory analysis.

Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [18F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ2 = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.

Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson's disease: correlation with postural and gait deficits.

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]-FEOBV) PET binding in Parkinson' disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.6 ± 7.4 years) completed clinical assessments for imbalance, falls, freezing of gait (FoG), modified Romberg sensory conflict testing, and underwent VAChT PET. Volumes of interest (VOI)-based analyses included detailed thalamic and cerebellar parcellations. VSCD-associated VAChT VOI selection used stepwise logistic regression analysis. Vesicular monoamine transporter type 2 (VMAT2) [11C]dihydrotetrabenazine (DTBZ) PET imaging was available in 54 patients. Analyses of covariance were performed to compare VSCD-associated cholinergic deficits between patients with and without PIGD motor features while accounting for confounders. PET sampling passed acceptance criteria in 73 patients. This data-driven analysis identified cholinergic deficits in five brain VOIs associating with the presence of VSCD: medial geniculate nucleus (MGN) (P < 0.0001), para-hippocampal gyrus (P = 0.0043), inferior nucleus of the pulvinar (P = 0.047), fusiform gyrus (P = 0.035) and the amygdala (P = 0.019). Composite VSCD-associated [18F]FEOBV-binding deficits in these 5 regions were significantly lower in patients with imbalance (- 8.3%, F = 6.5, P = 0.015; total model: F = 5.1, P = 0.0008), falls (- 6.9%, F = 4.9, P = 0.03; total model F = 4.7, P = 0.0015), and FoG (- 14.2%, F = 9.0, P = 0.0043; total model F = 5.8, P = 0.0003), independent of age, duration of disease, gender and nigrostriatal dopaminergic losses. Post hoc analysis using MGN VAChT binding as the single cholinergic VOI demonstrated similar significant associations with imbalance, falls and FoG. VSCD-associated cholinergic network changes localize to distinct structures involved in multi-sensory, in particular vestibular, and multimodal cognitive and motor integration brain regions. Relative clinical effects of VSCD-associated cholinergic network deficits were largest for FoG followed by postural imbalance and falls. The MGN was the most significant region identified.

Cholinergic Denervation Patterns Across Cognitive Domains in Parkinson's Disease.

BACKGROUND: The cholinergic system plays a key role in cognitive impairment in Parkinson's disease (PD). Previous acetylcholinesterase positron emission tomography imaging studies found memory, attention, and executive function correlates of global cortical cholinergic losses. Vesicular acetylcholine transporter positron emission tomography allows for more accurate topographic assessment of not only cortical but also subcortical cholinergic changes. OBJECTIVE: The objectiveof this study was to investigate the topographic relationship between cognitive functioning and regional cholinergic innervation in patients with PD. METHODS: A total of 86 nondemented patients with PD (mean ± SD age 67.8 ± 7.6 years, motor disease duration 5.8 ± 4.6 years), and 12 healthy control participants (age 67.8 ± 7.8 years) underwent cholinergic [18 F]Fluoroethoxybenzovesamicol positron emission tomography imaging. Patients with PD underwent neuropsychological assessment. The z scores for each cognitive domain were determined using an age-matched, gender-matched, and educational level-matched control group. Correlations between domain-specific cognitive functioning and cholinergic innervation were examined, controlling for motor impairments and levodopa equivalent dose. Additional correlational analyses were performed using a mask limited to PD versus normal aging binding differences to assess for disease-specific versus normal aging effects. RESULTS: Voxel-based whole-brain analysis demonstrated partial overlapping topography across cognitive domains, with most robust correlations in the domains of memory, attention, and executive functioning (P < 0.01, corrected for multiple comparisons). The shared pattern included the cingulate cortex, insula/operculum, and (visual) thalamus. CONCLUSION: Our results confirm and expand on previous observations of cholinergic system involvement in cognitive functioning in PD. The topographic overlap across domains may reflect a partially shared cholinergic functionality underlying cognitive functioning, representing a combination of disease-specific and aging effects. © 2020 International Parkinson and Movement Disorder Society.

Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views.

PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented. RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.

Cholinergic system changes of falls and freezing of gait in Parkinson's disease.

OBJECTIVE: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. METHODS: Ninety-four PD subjects underwent clinical assessment and VAChT ([18 F]FEOBV) PET. RESULTS: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. INTERPRETATION: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549.

Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs.

OBJECTIVES: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [18F]-fluoroethoxybenzovesamicol ([18F]-FEOBV) radioligand. METHODS: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [18F]-FEOBV PET. RESULTS: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices. CONCLUSIONS: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Multimodal gradients of human basal forebrain connectivity.

The cholinergic innervation of the cortex originates almost entirely from populations of neurons in the basal forebrain (BF). Structurally, the ascending BF cholinergic projections are highly branched, with individual cells targeting multiple different cortical regions. However, it is not known whether the structural organization of basal forebrain projections reflects their functional integration with the cortex. We therefore used high-resolution 7T diffusion and resting state functional MRI in humans to examine multimodal gradients of BF cholinergic connectivity with the cortex. Moving from anteromedial to posterolateral BF, we observed reduced tethering between structural and functional connectivity gradients, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). The cortical expression of this structure-function gradient revealed progressively weaker tethering moving from unimodal to transmodal cortex, with the lowest tethering in midcingulo-insular cortex. We used human [18F] fluoroethoxy-benzovesamicol (FEOBV) PET to demonstrate that cortical areas with higher concentrations of cholinergic innervation tend to exhibit lower tethering between BF structural and functional connectivity, suggesting a pattern of increasingly diffuse axonal arborization. Optogenetic tracing of cholinergic projections and [18F] FEOBV PET in mice confirmed a gradient of axonal arborization across individual BF cholinergic neurons. Like humans, cholinergic neurons with the highest arborization project to cingulo-insular areas of the mouse isocortex. Altogether, our findings reveal that BF cholinergic neurons vary in their branch complexity, with certain subpopulations exhibiting greater modularity and others greater diffusivity in the functional integration of their cortical targets.

Cognitive and Cholinergic Systems Trajectories in Parkinson Disease.

Objective: Cognitive decline in Parkinson disease (PD) is a disabling and highly variable non-motor feature. While cholinergic systems degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [ 18 F]-fluoroethoxybenzovesamicol ([ 18 F]-FEOBV) binding predicts longitudinal cognitive changes in mild to moderate, non-demented PD subjects. Methods: Seventy-five non-demented, mild-moderate PD subjects received baseline standardized cognitive evaluations and [ 18 F]-FEOBV PET imaging with repeat cognitive evaluations 2 years later. Participants were classified into four cognitive classes based on stability or change in cognition: Persistent normal (no MCI at baseline and follow-up), Persistent MCI, MCI conversion, and MCI reversion. Whole-brain voxel comparisons with normal controls, and voxel-based and cluster volume-of-interest correlation analyses with longitudinal cognitive changes were performed. Results: Whole-brain voxel comparisons of each class with a matched control group revealed unique bi-directional differences in baseline regional [ 18 F]-FEOBV binding. Increased regional [ 18 F]-FEOBV binding in predominantly anterior cortical and sub-cortical regions was found in the persistent normal and MCI reversion groups. Whole-brain voxel correlation analysis between baseline [ 18 F]-FEOBV binding and two-year longitudinal percent changes in cognition identified a specific regional pattern of reduced posterior cortical, limbic and paralimbic [ 18 F]-FEOBV binding predictive of global cognitive declines and across five cognitive domains at two-year follow-ups. Interpretation: Cholinergic system changes correlate with varying cognitive trajectories in mild-moderate PD. Upregulation of cholinergic neurotransmission may be an important compensatory process in mild-moderate PD.

Challenges and innovations in brain PET analysis of neurodegenerative disorders: a mini-review on partial volume effects, small brain region studies, and reference region selection.

Positron Emission Tomography (PET) brain imaging is increasingly utilized in clinical and research settings due to its unique ability to study biological processes and subtle changes in living subjects. However, PET imaging is not without its limitations. Currently, bias introduced by partial volume effect (PVE) and poor signal-to-noise ratios of some radiotracers can hamper accurate quantification. Technological advancements like ultra-high-resolution scanners and improvements in radiochemistry are on the horizon to address these challenges. This will enable the study of smaller brain regions and may require more sophisticated methods (e.g., data-driven approaches like unsupervised clustering) for reference region selection and to improve quantification accuracy. This review delves into some of these critical aspects of PET molecular imaging and offers suggested strategies for improvement. This will be illustrated by showing examples for dopaminergic and cholinergic nerve terminal ligands.

Composite measures of motor performance and self-efficacy are better determinants of postural instability and gait difficulties than individual clinical measures in Parkinson's disease.

BACKGROUND: Postural instability and gait difficulties (PIGD) are a significant cause of disability and loss of quality of life (QoL) in Parkinson's Disease. Most research on clinical predictors of PIGD measures have focused on individual clinical often motor performance variables, However, PIGD motor features often result in fear of falling (FoF) lowering a patient's mobility self-efficacy. The purpose of this study was to assess composite measures of motor and self-efficacy determinants PIGD motor features in PD and compare these to analysis of individual clinical metrics. METHODS: 75 PD participants underwent detailed motor and non-motor test batteries. Principal component analysis (PCA) was used to identify clusters of covarying correlates of slow walking, imbalance, falls, freezing of gait, FoG and compare these to traditional univariate analyses. RESULTS: A single PCA-derived composite measure of motor performance and self-efficacy of mobility was the most robust determinant of all PIGD motor features except for falls. In contrast, analysis of the individual clinical variables showed more limited and diverging findings, including evidence of better cognitive performance but more severe motor parkinsonian ratings in the fall group. CONCLUSION: There are robust associations between composite measures of motor performance and self-efficacy of mobility and all PIGD motor features except for falls. Univariate analysis of individual clinical measures showed limited correlates of PIGD motor features. Patient's own perception of motor performance, FoF, and QoL deserve more attention as PIGD therapeutic targets in PD.

Regional serotonin terminal density in aging human brain: A [11C]DASB PET study.

There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions.