Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory in rats.

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of biconditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-s trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Community Knowledge and Awareness of Stroke in New Zealand.

INTRODUCTION: Community knowledge and stroke awareness is crucial for primary prevention of stroke and timely access to stroke treatments including acute reperfusion therapies. We conducted a national telephone survey to quantify the level of community stroke awareness. METHODS: A random sample of 400 adults in New Zealand (NZ), stratified by the 4 main ethnic groups, was surveyed. Eligible participants answered stroke awareness questions using both unprompted (open-ended) and prompted questions (using a list). Proportional odds logistic regression models were used to identify factors associated with stroke awareness. RESULTS: Only 1.5% of participants named stroke as a major cause of death. The stroke signs and symptoms most frequently identified from a list were sudden speech difficulty (94%) and sudden 1-sided weakness (92%). Without prompting, 78% of participants correctly identified at least 1 risk factor, 62% identified at least 2, and 35% identified 3 or more. When prompted with the list, scores increased 10-fold compared with unprompted responses. Ethnic disparities were observed, with Pacific peoples having the lowest level of awareness among the 4 ethnic groups. Higher education level, higher income, and personal experience of stroke were predictive of greater awareness (P ≤ .05). CONCLUSIONS: Stroke was not recognized as a major cause of death. Although identification of stroke risk factors was high with prompting, awareness was low without prompting, particularly among those with lower education and income. Nationwide, culturally tailored public awareness campaigns are necessary to improve knowledge of stroke risk factors, recognition of stroke in the community and appropriate actions to take in cases of suspected stroke.

Environmental enrichment increases prefrontal EEG power and synchrony with the hippocampus in rats with anterior thalamus lesions.

The anterior thalamic nuclei (ATN) are a major interface between the hippocampus and prefrontal cortex within an extended Papez circuit. Rat models suggest that the deficits caused by ATN damage, which is associated with "diencephalic amnesia", can be ameliorated by environmental enrichment (EE) through unknown mechanisms. We examined whether changes in theta rhythmicity within and between the hippocampus and prefrontal cortex are influenced by EE in rats with ATN lesions. Here, we show that ATN lesions and EE produced essentially opposed functional effects in terms of changes in rhythmicity between two consecutive trials when rats forage for chocolate hail. On the second trial, standard-housed rats with ATN lesions showed: (a) a clear reduction in prefrontal cortex experience-dependent power change in the theta band and in two adjacent bands; (b) little change in the theta band in hippocampal area CA1; and (c) only a modest overall reduction in experience-dependent power change at lower theta frequencies in the dentate gyrus. EE exposure prevented the decrease in prefrontal theta power in rats with ATN lesions, and in fact caused a clear increase in prefrontal cortex power across all bands. While ATN lesions did not reliably affect prefrontal-CA1 or prefrontal-dentate theta coherence, EE increased the coherence between prefrontal cortex and area CA1 in both the sham and ATN groups. Thus, EE increases functional connectivity between prefrontal cortex and hippocampus via pathways that bypass the ATN, and increases behaviorally dependent prefrontal rhythmicity. These EEG effects may contribute to improved learning and memory in the ATN-lesion model of diencephalic amnesia.

Risk of Parkinson's disease dementia related to level I MDS PD-MCI.

BACKGROUND: The International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria. METHODS: We analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow-up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia. RESULTS: Level I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia. CONCLUSIONS: Level I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society.

Anterior thalamic nuclei lesions have a greater impact than mammillothalamic tract lesions on the extended hippocampal system.

The anterior thalamic nuclei (ATN), mammillary bodies and their interconnecting fiber tract, the mammillothalamic tract (MTT), are important components of an extended hippocampal circuit for episodic memory. In humans, damage to the MTT or ATN in many disorders is associated with severe anterograde amnesia and it is assumed that their influence on memory is functionally equivalent. The relative influence of these two structures on memory has not, however, been assessed explicitly. Here, a direct comparison found that only ATN lesions impaired spatial reference memory in rats. ATN lesions produced more severe deficits on spatial working memory and reduced zif268 expression to a greater degree and in more corticolimbic sites than did MTT lesions. Conversely, MTT lesions reduced NeuN cell counts in all three subregions of the MB to a greater extent than did ATN lesions, so their relative impact cannot be explained by retrograde neuropathology of the MB. Hence ATN injury causes a more critical dysfunction than would be expected by an emphasis on the indirect influence of brainstem inputs to the extended memory system. The greater ATN lesion deficits found here may represent the consequence of disruption to the direct connections of the ATN with both hippocampal and cortical sites.

Parkinson's disease across ethnicities: A nationwide study in New Zealand.

BACKGROUND: New Zealand is an ethnically diverse country with a unified national prescribing system. This provides a good framework to use drug-tracing methodology to establish the prevalence and incidence of Parkinson's disease across different ethnic groups. The objective of this study was to determine the prevalence and incidence of Parkinson's disease in the major ethnic groups in New Zealand. METHODS: Information on Parkinson's disease-related medications was extracted from the national Pharmaceutical Collection of community-dispensed medications for the period January 1, 2005, to December 31, 2014. Diagnoses for a large subset of individuals were independently determined through national mortality and hospital admissions data sets. We used a Bayesian model, accommodating uncertainty and bias, to estimate the number of people with Parkinson's disease. RESULTS: We found the highest rate of Parkinson's disease in the European ethnic group and the lowest rate in the indigenous Maori. The 2006-2013 age-standardized incidence (per 100,000 population per year) was European, 33; Asian, 28; Pasifika, 27; Maori, 20. The 2013 age-standardized prevalence (per 100,000 population) was European, 223; Asian, 174; Pasifika, 160; Maori, 114. CONCLUSIONS: There is a differential occurrence of Parkinson's disease across the major ethnic groups within the New Zealand population, with indigenous Maori showing the lowest incidence. Varying susceptibility profiles, gene-environment interactions, and inequalities in accessing health care may play a role in the variation in rates of Parkinson's disease in New Zealand. © 2018 International Parkinson and Movement Disorder Society.

Detecting Mild Cognitive Deficits in Parkinson's Disease: Comparison of Neuropsychological Tests.

BACKGROUND: Numerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies. METHODS: Data from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2-step meta-analytic approach using standardized scores compared performance in PD with normative data. RESULTS: Pooled estimates of the differences between PD and site-specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between-study variability that could not be accounted for and led to inconclusive results. CONCLUSIONS: Normed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site-specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society.

Response to "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms".

A recent paper, "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms" (McDermott et al., 2017), provides an interesting comparison of the influence of different criteria for Parkinson's disease with mild cognitive impairment (PD-MCI) on progression to dementia (PDD). Unfortunately, McDermott et al. (2017) incorrectly stated that "only 21% of PD-MCI participants (identified with a 1.5 SD cut-off) converted to PDD within four years" (p.6) in our study (Wood et al., 2016). However, the important point made by Wood et al. (2016) was that the proportion of conversions to PDD was 51% when the PD-MCI diagnosis required a minimum of two 1.5 SD impairments within any single cognitive domain, whereas additional PD-MCI patients classified with one impairment at 1.5 SD in each of the two domains (but never two impairments in the same domain) had a non-significant risk of dementia relative to non-MCI patients (11% vs. 6% converted, respectively). Our PDD conversion rate was 38% when combining both 1.5 SD criteria (21/56 PD-MCI patients vs. 4/65 non-MCI patients converted); McDermott et al. (2017) found a 42% conversion rate over three years for similarly described PD-MCI patients (10/24 PD-MCI patients vs. 0/27 non-MCI patients converted). Our study was also part of a multinational study (n = 467) showing that PD-MCI has predictive validity beyond known demographic and PD-specific factors of influence (Hoogland et al., 2017). All three studies found that multiple cognitive domain impairments are common in PD-MCI. Nonetheless, the research community needs to clarify the association between PD-MCI subtypes and, especially, the optimal cognitive markers for dementia risk in PD patients.

α-synuclein genetic variability: A biomarker for dementia in Parkinson disease.

OBJECTIVE: The relationship between Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) has long been debated. Although PD is primarily considered a motor disorder, cognitive impairment is often present at diagnosis, and only ∼20% of patients remain cognitively intact in the long term. Alpha-synuclein (SNCA) was first implicated in the pathogenesis of the disease when point mutations and locus multiplications were identified in familial parkinsonism with dementia. In worldwide populations, SNCA genetic variability remains the most reproducible risk factor for idiopathic PD. However, few investigators have looked at SNCA variability in terms of cognitive outcomes. METHODS: We have used targeted high-throughput sequencing to characterize the 135kb SNCA locus in a large multinational cohort of patients with PD, PDD, and DLB and healthy controls. RESULTS: An analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3' or the 5' of the SNCA gene. In addition, we define a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat. INTERPRETATION: Our data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification. Ann Neurol 2016;79:991-999.

Mild cognitive impairment as a risk factor for Parkinson's disease dementia.

BACKGROUND: The International Parkinson and Movement Disorder Society criteria for mild cognitive impairment in PD were recently formulated. OBJECTIVES: The aim of this international study was to evaluate the predictive validity of the comprehensive (level II) version of these criteria by assessment of their contribution to the hazard of PD dementia. METHODS: Individual patient data were selected from four separate studies on cognition in PD that provided information on demographics, motor examination, depression, neuropsychological examination suitable for application of level II criteria, and longitudinal follow-up for conversion to dementia. Survival analysis evaluated the predictive value of level II criteria for cognitive decline toward dementia as expressed by the relative hazard of dementia. RESULTS: A total of 467 patients were included. The analyses showed a clear contribution of impairment according to level II mild cognitive impairment criteria, age, and severity of PD motor symptoms to the hazard of dementia. There was a trend of increasing hazard of dementia with declining neuropsychological performance. CONCLUSIONS: This is the first large international study evaluating the predictive validity of level II mild cognitive impairment criteria for PD. The results showed a clear and unique contribution of classification according to level II criteria to the hazard of PD dementia. This finding supports their predictive validity and shows that they contribute important new information on the hazard of dementia, beyond known demographic and PD-specific factors of influence. © 2017 International Parkinson and Movement Disorder Society.

Attention lapses and behavioural microsleeps during tracking, psychomotor vigilance, and dual tasks.

This study examined the incidence of attention lapses and microsleeps under contrasting levels of task complexity during three tasks: PVT, 2-D tracking and a dual task combining the two. More attention lapses per participant (median 15vs. 3; range 1-74vs. 0-76, p=0.001), with the greatest increase with time spent-on-task (p=0.002), were evident on the more cognitively-demanding dual task than on the PVT. Conversely, fewer microsleeps (median 0vs. 0; range 0-1vs. 0-18, p=0.022) occurred during the more complex task compared to the tracking task. An increase in microsleep rate with time spent-on-task (p=0.035) was evident during the tracking task but not the dual task. These results indicate that the higher cognitive load, associated with an increase in task complexity, increased the likelihood of attention lapses, while a reduction in task complexity increased the likelihood of microsleeps.

Acute tryptophan depletion and Lewy body dementias.

BACKGROUND: Studies using acute tryptophan depletion (ATD) to examine the effects of a rapid reduction in serotonin function have shown a reduction in global cognitive status during ATD in Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the severe cholinergic loss evident in dementia with Lewy bodies (DLB) and Parkinson's disease and dementia (PDD), we predicted that a reduction of global cognitive status during ATD would be greater in these conditions than in AD. METHODS: Patients having DLB or PDD underwent ATD in a double-blind, placebo-controlled, randomized, counterbalanced, crossover design. RESULTS: While the study intended to test 20 patients, the protocol was poorly tolerated and terminated after six patients attempted, but only four patients - three with DLB and one with PDD - completed the protocol. The Modified Mini-Mental State Examination (3MSE) score was reduced in all three DLB patients and unchanged in the PDD and dementia patient during ATD compared with placebo. CONCLUSIONS: This reduction in global cognitive function and the poor tolerability may fit with the hypothesis that people with dementia with Lewy bodies have sensitivity to the effects of reduced serotonin function.

Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex, but enrichment rescues CA1 spines only.

Injury to the anterior thalamic nuclei (ATN) may affect both hippocampus and retrosplenial cortex thus explaining some parallels between diencephalic and medial temporal lobe amnesias. We found that standard-housed rats with ATN lesions, compared with standard-housed controls, showed reduced spine density in hippocampal CA1 neurons (basal dendrites, -11.2%; apical dendrites, -9.6%) and in retrospenial granular b cortex (Rgb) neurons (apical dendrites, -20.1%) together with spatial memory deficits on cross maze and radial-arm maze tasks. Additional rats with ATN lesions were also shown to display a severe deficit on spatial working memory in the cross-maze, but subsequent enriched housing ameliorated their performance on both this task and the radial-arm maze. These enriched rats with ATN lesions also showed recovery of both basal and apical CA1 spine density to levels comparable to that of the standard-housed controls, but no recovery of Rgb spine density. Inspection of spine types in the CA1 neurons showed that ATN lesions reduced the density of thin spines and mushroom spines, but not stubby spines; while enrichment promoted recovery of thin spines. Comparison with enriched rats that received pseudo-training, which provided comparable task-related experience, but no explicit spatial memory training, suggested that basal CA1 spine density in particular was associated with spatial learning and memory performance. Distal pathology in terms of reduced integrity of hippocampal and retrosplenial microstructure provides clear support for the influence of the ATN lesions on the extended hippocampal system. The reversal by postoperative enrichment of this deficit in the hippocampus but not the retrosplenial cortex may indicate region-specific mechanisms of recovery after ATN injury.

Reduced grey matter perfusion without volume loss in early relapsing-remitting multiple sclerosis.

BACKGROUND: Grey matter (GM) pathology in multiple sclerosis (MS) is associated with progressive long-term disability. Detection of GM abnormalities in early MS may therefore be valuable in understanding and predicting the long-term course. However, structural MRI measures such as volume loss have shown only modest abnormalities in early relapsing-remitting MS (RRMS). We therefore investigated for evidence of abnormality in GM perfusion, consistent with metabolic dysfunction, in early RRMS. METHODS: 25 RRMS patients with ≤5 years disease duration and 25 age-matched healthy controls underwent 3 Tesla MRI with a pseudo-continuous arterial spin labelling sequence to quantify GM perfusion and a volumetric T1-weighted sequence to measure GM volume. Neurological status was assessed in patients and neuropsychological evaluation undertaken in all subjects. Voxel-based analysis was used to compare regional GM perfusion and volume measures in patients and controls. RESULTS: There was reduced global GM perfusion in patients versus controls (50.6±5.8 mL/100 g/min vs 54.4±7.6 mL/100 g/min, p=0.04). Voxel-based analysis revealed extensive regions of decreased cortical and deep GM perfusion in MS subjects. Reduced perfusion was associated with impaired memory scores. There was no reduction in global or regional analysis of GM volume in patients versus controls. CONCLUSIONS: The decrease in GM perfusion in the absence of volume loss is consistent with neuronal metabolic dysfunction in early RRMS. Future studies in larger cohorts and longitudinal follow-up are needed to investigate the functional and prognostic significance of the early GM perfusion deficits observed.

Early-phase amyloid PET reproduces metabolic signatures of cognitive decline in Parkinson's disease.

INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.

Generalization of Youden index for multiple-class classification problems applied to the assessment of externally validated cognition in Parkinson disease screening.

Routine cognitive screening in Parkinson disease (PD) has become essential for management, to track progression and to assess clinical status in therapeutic trials. Patients with mild cognitive impairment (PD-MCI) are more likely to progress to dementia and therefore need to be distinguished from patients with normal cognition and those with dementia. A three-class Youden index has been recently proposed to select cut-off points in three-class classification problems. In this article, we examine properties of a modification of the three-class Youden index and propose a generalization to k-class classification problems. Geometric and theoretical properties of the modified index J(k) are examined. It is shown that J(k) is equivalent to the sum of the k - 1 two-class Youden indices for the adjacent classes of the ordered alternative problem given that the ordering holds. Methods are applied in the assessment of the Montreal Cognitive Assessment test when screening cognition in PD.