BACKGROUND AND PURPOSE:The glymphatic system facilitates perivascular clearance, and its dysfunction has been implicated in neurodegenerative diseases. Diffusion tensor imaging along the perivascular space (DTI-ALPS) has been proposed as an indirect approach to assess glymphatic function, but its reliability is debated. The choice of b-value is an aspect of possible improvement. While a b-value of 1000 seconds/mm2 is commonly used, the optimal b-value for DTI-ALPS remains unknown. This study aims to determine the optimal b-value for DTI-ALPS. MATERIALS AND METHODS:Simulations were conducted to examine how the choice of maximum b-value influences bias, precision, and effect size of the ALPS index. DTI-ALPS was applied in a cohort of 194 participants divided into 4 groups: healthy controls (HCs) (n=42), patients with Parkinson disease (n=119), patients with Parkinson disease dementia (PDD) (n=16), and patients with progressive supranuclear palsy (PSP) (n=17). ALPS indices were calculated by manually placing regions of interest on projection and association fibers in each hemisphere. Group differences in ALPS indices across b-values were analyzed using mixed models. RESULTS:In vivo, ALPS indices were higher at a b-value of 500 and 250 seconds/mm2 compared with a b-value of 1000 seconds/mm2 in both hemispheres. Simulations indicated a bias-variance trade-off: very low b-values reduced sensitivity and compromised precision, while high b-values improved precision but reduced accuracy. The simulated effect size of the ALPS index peaked at intermediate b-values (≈700 seconds/mm2). In vivo, ALPS indices were lower in patients with PDD and PSP compared with HCs, though differences varied across b-values. CONCLUSIONS:Both simulations and in vivo results suggest that the commonly used b-value of 1000 seconds/mm2 is not optimal for assessing diffusion in the perivascular spaces. Intermediate b-values at approximately 700 seconds/mm2 appear more suitable. However, further optimization of acquisition parameters is needed.

Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) might provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the presymptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a longitudinal cohort of repeatedly sampled LBD patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n = 718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn-positive CSF samples available. One hundred and ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (P = 0.001) and a longer Lag (P = 0.001) than subjects displaying α-syn seeding activity from the first available sample. The Nrep increased longitudinally in the whole cohort [β = 0.09, 95% confidence interval (95% CI) 0.06-0.12, P < 0.001], in asymptomatic LBD (β = 0.15, 95% CI 0.09-0.21, P < 0.001) and in Parkinson's disease individuals without dementia (β = 0.07, 95% CI 0.02-0.12, P = 0.01). The Lag decreased longitudinally in asymptomatic LBD (β = -0.24, 95% CI -0.42 to -0.06, P = 0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort [hazard ratio (HR) 1.57, 95% CI 1.19-2.07, P = 0.001] and the Parkinson's disease subgroup (HR 1.83, 95% CI 1.17-2.85, P = 0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95% CI 0.59-0.99, P = 0.04) and in the Parkinson's disease subgroup (HR 0.69, 95% CI 0.50-0.95, P = 0.02). The α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with progression of pathology over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.

BACKGROUND:Olfactory dysfunction is a common non-motor symptom in Parkinson's disease (PD). The objective was to evaluate the association between olfaction in PD with cross-sectional and longitudinal assessments of clinical variables and novel cerebrospinal fluid (CSF) markers. METHODS:Patients with PD and baseline olfactory function assessed using the Brief Smell Identification Test (B-SIT) were included from the BioFINDER-1 cohort. Clinical variables, CSF measures and disease status were assessed longitudinally for up to 11 years. CSF was analyzed using Roche Elecsys® NeuroToolKit, including biomarkers of neurodegeneration, glial activation, neuroinflammation and the core Alzheimer disease biomarkers. RESULTS:A total of 172 patients with PD were included, 63 with normal olfactory function and 109 with hyposmia. No differences were seen in clinical variables at baseline. Glial fibrillary acidic protein was the only CSF marker differing at baseline, being elevated in hyposmic patients with PD (12.25 ± 3.87 vs 10.46 ± 3.68, p = 0.001). At follow-up, olfactory function declined predominantly in patients with normal olfaction at baseline (β = -0.25 [-0.40 to -0.12], p = 0.001). Patients with PD with both olfactory dysfunction and amyloid-positivity (defined by the CSF Aβ42/Aβ40 ratio) declined faster in several cognitive and motor measures. Olfaction and amyloid-status were independently associated with increased risk of progressing to dementia (B-SIT score, HR = 0.77 [0.67-0.88] and amyloid-positivity, HR = 4.47 [2.30-8.67]). CONCLUSIONS:Olfactory dysfunction and amyloid-positivity are independently associated with a higher rate of cognitive decline and progression to dementia in patients with PD. Novel CSF markers of neurodegeneration and glial-activity do not differ depending on olfactory status in PD.

BACKGROUND:Assessment of myocardial sympathetic innervation with iodine-123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy is conventionally performed by determining the heart-to-mediastinum ratio (HMR) on planar images. This study aimed to investigate the feasibility of determining HMR from reprojected [123I]mIBG planar images derived from tomographic data by a ring-configured cadmium-zinc-telluride (CZT) gamma camera and its agreement with HMR determined from [123I]mIBG planar images by an Anger gamma camera, in the assessment of myocardial sympathetic innervation. METHODS:A total of 105 study participants (suspected idiopathic rapid-eye-movement sleep behavior disorder n = 55, early-stage Parkinson's Disease n = 36, and healthy controls n = 14) who were referred for [123I]mIBG myocardial scintigraphy were included, in addition to eight phantom experiments simulating a range of HMR. HMR was determined from planar and reprojected planar images acquired with an Anger gamma camera and a ring-configured CZT gamma camera, respectively, for all study participants and phantom experiments. Agreement in HMR between the two imaging methods was analyzed in Bland-Altman plots. Intra- and interobserver variability was evaluated for both imaging methods in a subset of images. RESULTS:The agreement between planar and reprojected planar images was good, with a mean difference in HMR of 0.11 (95% limits of agreement -0.16 to 0.38) for the study participants. Intra- and interobserver variability was low and comparable for both imaging methods. Results from the phantom experiments were consistent with those from the study participants. CONCLUSIONS:Determining HMR from reprojected [123I]mIBG myocardial scintigraphy planar images acquired with a ring-configured CZT gamma camera is feasible and shows good agreement with HMR determined from planar images by a conventional Anger gamma camera.

INTRODUCTION:Neuromelanin containing cell loss, neuroinflammation and synaptic dysfunction are believed to contribute to Parkinson's disease (PD) pathogenesis. [18F]DOPA PET reflects dopamine storage capacity in the putamen, while midbrain off-target retention of [18F]RO948 is hypothesized to reflect neuromelanin. OBJECTIVES:To investigate associations between disease duration, cerebrospinal fluid (CSF) markers of neurodegeneration, synaptic dysfunction, neuroinflammation, and dopamine synaptic loss as measured by [18F]DOPA PET in PD patients. We further aimed to explore whether reduced midbrain retention of [18F]RO948 relates to [18F]DOPA PET and CSF markers. METHODS:Participants were part of the BioFINDER studies. CSF biomarkers were analyzed for controls (n = 623), PD participants (n = 226) and Dementia with Lewy bodies (DLB; n = 33). [18F]RO948 PET was performed in controls (n = 514), PD (n = 77) and DLB (n = 47) and [18F]DOPA PET in PD (n = 58) and DLB (n = 22). RESULTS:PD patients showed higher CSF neurofilament light (NfL) levels (pg/ml [mean ± SD] 159 ± 139) vs. controls (137 ± 90, p < 0.001), and lower neurogranin (pg/ml [mean ± SD] 620 ± 255) vs (772 ± 283, p < 0.001). Lower [18F]DOPA uptake correlated with longer disease duration (ρ = -0.46, p < 0.001), higher NfL (ρ = -0.39, p = 0.03), lower neurogranin (ρ = 0.50, p = 0.003) and NPTX2 levels (ρ = 0.36, p = 0.049). We found no associations between neuroinflammatory markers and [18F]DOPA PET. Substantia nigra [18F]RO948 signal was lower in PD ([mean ± SD] 1.67 ± 0.22) vs controls (1.76 ± 0.3, p < 0.001) but did not correlate with disease duration, CSF markers or [18F]DOPA-PET. CONCLUSIONS:In PD patients, a decrease in [18F]DOPA PET retention correlated with disease duration as well as CSF neurodegenerative and synaptic biomarkers but not with inflammatory biomarkers or [18F]RO948 PET midbrain off-target retention.

Non-invasive evaluation of glymphatic function has emerged as a crucial goal in neuroimaging, and diffusion tensor imaging along the perivascular space (DTI-ALPS) has emerged as a candidate method for this purpose. Reduced ALPS index has been suggested to indicate impaired glymphatic function. However, the potential impact of crossing fibres on the ALPS index has not been assessed, which was the aim of this cross-sectional study. For this purpose, we used DTI-ALPS in a cohort with three groups: Parkinson's disease (PD) (n = 60, mean age 63.3 +/- 1.5, 33 males), progressive supranuclear palsy (PSP) (n = 17, mean age 70.9 +/- 1.5, 9 males) and healthy controls (n = 41, mean age 64.5 +/- 8.4, 15 males). The ALPS index was calculated blinded to diagnosis, by manually placing two sets of regions of interest (ROI) on the projection and association fibres of each hemisphere. Annotation was performed twice: once on conventional diffusion-encoded colour maps weighted by fractional anisotropy and once on maps with weights adjusted for high incidence of crossing fibres. PSP patients had significantly lower conventional ALPS indices compared with both healthy controls (right hemisphere: P = 0.009; left hemisphere: P < 0.001) and PD patients (right hemisphere: P = 0.024; left hemisphere: P < 0.001). There were no differences between healthy controls and PD patients. After adjusting the ROI to avoid regions of crossing fibres, the ALPS index significantly decreased in healthy controls (right hemisphere: P < 0.001; left hemisphere: P < 0.001) and PD (right hemisphere: P < 0.001; left hemisphere: P < 0.001). In PSP, the adjusted ALPS index was lower compared with the conventional one only in the right hemisphere (P = 0.047). Overall, this adjustment led to less significant differences among diagnostic groups. Specifically, with the adjusted ALPS index, PSP patients showed significantly lower ALPS index compared with healthy controls (right hemisphere: P = 0.044; left hemisphere: P = 0.029) and PD patients (P = 0.003 for the left hemisphere only). Our results suggest that crossing fibres significantly inflate the ALPS index and should be considered a critical pitfall of this method. This factor could partly explain the variability observed in previous studies. Unlike previous research, we observed no differences between PD and healthy controls, likely because most patients in our cohort were in the early phase of the disease. Thus, the ALPS index may not be a sensitive indicator of glymphatic function at least in the initial stages of neurodegeneration in PD.

Disease-specific fluid biomarkers are in demand for parkinsonian syndromes (PS). Corticotropin-releasing hormone (CRH) was proposed as a biomarker for Lewy body disease. As such, this project aimed to confirm CRH as a potential biomarker for different PS. CRH and misfolded alpha-synuclein (alpha Syn) were measured in CSF. The primary cohort included Lewy body disease patients (i.e. Parkinson's disease or dementia with Lewy bodies, n = 77), atypical PS (n = 37) and non-parkinsonian neurodegenerative diseases (n = 164), as well as controls (n = 354). A replication cohort included Lewy body disease (n = 27), atypical PS (n = 58) and controls (n = 58). CRH was downregulated in alpha Syn positive Lewy body disease, alpha Syn positive controls and in all atypical PS compared with alpha Syn negative controls (P = 3.3e-05, P = 3.1e-10, P = 2.9e-03). CRH was also decreased in alpha Syn positive Lewy body disease compared with alpha Syn negative non-PS (P = 2e-03) and correlated with cognitive impairment and inflammation in alpha Syn positive Lewy body disease. We show that CRH is a promising biomarker for Lewy body disease and atypical PS and its association with inflammation and cognitive decline. Reductions in CRH in Lewy body disease and other PS suggest this decrease may relate to dopaminergic degeneration instead of alpha Syn pathology.

Introduction: Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is a common clinical problem. We aimed to apply the T1-/T2-weighted ratio imaging technique, based on standard clinical MRI, to reveal differences in neurodegeneration in three large cohorts. Methods: Three cohorts, with a total of 405 participants (269 PD, 44 PSP, 38 MSA, 54 controls), were combined and T1/T2-weighted ratio image analyses were carried out. A combination of automatic segmentation and atlas-based ROI were used in this study. The cohorts were combined using the ComBat batch correction procedure. Results: Group differences were found in the putamen (p = 0.040), with higher T1/T2-weighted ratio in this region in PSP compared to PD and healthy controls (pvalues 0.010 and 0.007 respectively). Using putaminal T1/T2-weighted ratio for diagnostic separation, a fair performance was found in separating PSP from healthy controls, with an area under the receiver operating characteristic curve of 0.701. Conclusion: Different patterns of T1/T2-weighted ratio, reflecting differences in underlying pathophysiology, were found between the groups. Since T1/T2-weighted ratio can be applied to standard clinical MRI sequences to allow more quantitative analyses, this seems to be a promising biomarker for diagnostics and treatment evaluation of parkinsonian disorders for clinical trials.

There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer's disease (AD) pathology (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson's disease or dementia with Lewy bodies at baseline. Among these LB-positive patients, 48% had AD pathology. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). When examining independent cross-sectional effects, LB pathology but not amyloid-β or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-β, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson's disease. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials.

Introduction: The diagnosis of progressive supranuclear palsy (PSP) is often challenging since PSP may clinically resemble other neurodegenerative disorders. Recently, the tau PET tracer [F-18]RO948, a potential new biomarker for PSP, was developed. The aim of this study was to determine the ability of three different biomarkers, including [F-18]RO948 PET, to distinguish PSP patients from healthy controls and from patients with alpha-synucleinopathies. Methods: Patients with PSP (n = 23), alpha-synucleinopathies (n = 47) and healthy controls (n = 61) were included from the BioFINDER-2 study. [F-18]RO948 stan-dardized uptake value ratios (SUVR), magnetic resonance imaging midbrain/pons ratio, and cerebrospinal fluid neurofilament light (NfL) levels were compared between diagnostic groups individually and in combination. Results: [F-18]RO948 PET SUVR in the globus pallidus, NfL, and midbrain/pons area ratios were all able to differentiate PSP patients from controls and from patients with alpha-synucleinopathies ([F-18]RO948 [mean +/- SD]: controls 1.24 +/- 0.22; PSP 1.47 +/- 0.4; PD 1.18 +/- 0.2; DLB 1.25 +/- 24, p < 0.05), (NfL pg/mL [mean +/- SD]: controls 1055 +/- 569; PSP 2197 +/- 1010; PD 1038 +/- 416; DLB 1548 +/- 687, p < 0.001) and (midbrain/pons ratio [mean +/- SD]: controls 0.46 +/- 0.07; PSP 0.34 +/- 0.09; PD 0.43 +/- 0.06; DLB 0.40 +/- 0.07, p < 0.01). Receiver operating characteristic (ROC) analyses indicated that combining the three biomarkers resulted in the highest area under the ROC values (0.94 [0.88-1.00]) for separating controls from PSP and (0.92 [0.85-0.99]) for separating PSP from alpha-synucleinopathies. Conclusions: All studied biomarkers could individually separate PSP from controls and alpha-synucleinopathies patients at a group level. The optimal prediction models included NfL and midbrain/pons ratio for separating controls from PSP and all three biomarkers for separating PSP from alpha-synucleinopathies.

The diagnosis of Parkinsonian disorders is currently based on clinical criteria, which have limited sensitivity until most dopaminergic neurons are lost. Here we show that cerebrospinal fluid levels of DOPA decarboxylase (DDC) (also known as aromatic l -amino acid decarboxylase) can accurately identify patients with Lewy body disease (LBD) (area under the curve (AUC) = 0.89; P FDR = 2.6 × 10 −13 ) and are associated with worse cognitive performance ( P < 0.05). We also found that DDC can detect preclinical LBD stages in clinically unimpaired individuals with a positive seed amplification α-synuclein assay (AUC = 0.81, P = 1.0 × 10 −5 ) and that this biomarker could predict progression to clinical LBD over a 3-year period in preclinical cases (hazard ratio = 3.7 per s.d. change, confidence interval = 1.1–12.7). Moreover, DDC levels were also increased in atypical Parkinsonian disorders but not in non-Parkinsonian neurodegenerative disorders. These cerebrospinal fluid results were replicated in an independent cohort, where we also found that DDC levels in plasma could identify both LBD and atypical Parkinsonian disorders (AUC = 0.92, P = 1.3 × 10 −14 ). Our results show that DDC might have a future role in clinical practice as a biomarker of dopaminergic dysfunction to detect Parkinsonian disorders even during the preclinical disease stages and predict their progression to clinical LBD.

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [ 18 F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [ 18 F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [ 18 F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.

To study the ability of the newly developed α-synuclein Positron Emission Tomography (PET) tracer, [ 18 F]ACI-12589, created and developed by AC Immune SA, to detect α-synuclein neuropathology in vivo , in clinically diagnosed patients with α-synucleinopathies. We intend to scan a total of up to 50 participants with different diseases associated with α-synuclein and age- and gender-matched controls. These will include participants with Parkinson’s disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy bodies (DLB), or Parkinson’s disease caused by a duplication in the α-synuclein gene, in addition to neurologically healthy volunteers. At the time of abstract submission, 23 participants have undergone [ 18 F]ACI-12589 PET scans. 20 scans consist of 0-90 min dynamic scans with arterial blood sampling for blood input activity and metabolite analysis, two are full dynamic scans and one a 60-90 min static scan without blood sampling. In addition, participants have undergone structural MRI, DaTscan or [ 18 F]DOPA PET, and cognitive and motor testing (UPDRS-III). The data are currently being processed and analyzed. Initial image analyses suggest that there is ACI-12589 retention in brain areas affected by the disease process (such as the basal ganglia and cerebellar white matter) in participants with MSA, but also a potential age-dependent retention in the basal ganglia and brain stem of controls. We will be presenting initial promising clinical data on the novel α-synuclein PET tracer [ 18 F]ACI-12589, the initial analysis of which suggests tracer binding consistent with expected patterns of α-synuclein pathology based on clinical manifestations. Further analyses are ongoing and our updated findings will be presented at the conference.

Cognitive decline is common in Parkinson’s disease (PD) and has been associated with cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers such as Aβ1‐42, total tau and phosphorylated tau in addition to inflammatory proteins. VGF, a nerve growth factor, is a promising marker that has recently been implicated in cognitive decline in dementia with Lewy bodies and could potentially play a role in PD. The aim of this study is to assess a wide panel of CSF biomarkers reflecting different neuropathological processes to determine which best predict cognitive decline and conversion to dementia in PD.

Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings.

Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). α-synuclein (αSyn) RT-QuIC has emerged as a promising assay to detect misfolded αSyn in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort αSyn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were αSyn RT-QuIC positive. Within the AZSAND/BBDP cohort, αSyn RT-QuIC identified neuropathologically verified "standard LBD" (i.e. PD, PD with AD and DLB; n = 25) vs. no LB pathology (n = 53) with high sensitivity (100%) and specificity (94%). Only 57% were αSyn RT-QuIC positive in the subgroup with "non-standard" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n = 23). Furthermore, αSyn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, αSyn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex.

People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD-related dementia compared with PD-related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD-related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD-related dementia, which occur in line with changes to the cortex in this advanced disease stage.

Introduction: Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. Objectives: The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Methods: Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Results: Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs >= 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted beta = 0.010, 95% CI 0.001-0.019). Conclusions: In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

This study seeks a better understanding of possible pathophysiological mechanisms associated with cognitive impairment and dementia in Parkinson's disease using structural and functional MRI. We investigated resting-state functional connectivity of important subdivisions of the caudate nucleus, putamen and thalamus, and also how the morphology of these structures are impacted in the disorder. We found cognitively unimpaired Parkinson's disease subjects (n = 33), compared to controls (n = 26), display increased functional connectivity of the dorsal caudate, anterior putamen and mediodorsal thalamic subdivisions with areas across the frontal lobe, as well as reduced functional connectivity of the dorsal caudate with posterior cortical and cerebellar regions. Compared to cognitively unimpaired subjects, those with mild cognitive impairment (n = 22) demonstrated reduced functional connectivity of the mediodorsal thalamus with the paracingulate cortex, while also demonstrating increased functional connectivity of the mediodorsal thalamus with the posterior cingulate cortex, compared to subjects with dementia (n = 17). Extensive volumetric and surface-based deflation was found in subjects with dementia compared to cognitively unimpaired Parkinson's disease participants and controls. Our research suggests that structures within basal ganglia-thalamocortical circuits are implicated in cognitive impairment and dementia in Parkinson's disease, with cognitive impairment and dementia associated with a breakdown in functional connectivity of the mediodorsal thalamus with para- and posterior cingulate regions of the brain respectively.

Alzheimer's disease co‐pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives.