Cognition-Related Functional Topographies in Parkinson's Disease: Localized Loss of the Ventral Default Mode Network.

Cognitive dysfunction in Parkinson's disease (PD) is associated with increased expression of the PD cognition-related pattern (PDCP), which overlaps with the normal default mode network (DMN). Here, we sought to determine the degree to which the former network represents loss of the latter as a manifestation of the disease process. To address this, we first analyzed metabolic images (fluorodeoxyglucose positron emission tomography [PET]) from a large PD sample with varying cognitive performance. Cognitive impairment in these patients correlated with increased PDCP expression as well as DMN loss. We next determined the spatial relationship of the 2 topographies at the subnetwork level. To this end, we analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from an independent population. This approach uncovered a significant PD cognition-related network that resembled previously identified PET- and rs-fMRI-based PDCP topographies. Further analysis revealed selective loss of the ventral DMN subnetwork (precuneus and posterior cingulate cortex) in PD, whereas the anterior and posterior components were not affected by the disease. Importantly, the PDCP also included a number of non-DMN regions such as the dorsolateral prefrontal and medial temporal cortex. The findings show that the PDCP is a reproducible cognition-related network that is topographically distinct from the normal DMN.

Parkinson's disease-related network topographies characterized with resting state functional MRI.

Spatial covariance mapping can be used to identify and measure the activity of disease-related functional brain networks. While this approach has been widely used in the analysis of cerebral blood flow and metabolic PET scans, it is not clear whether it can be reliably applied to resting state functional MRI (rs-fMRI) data. In this study, we present a novel method based on independent component analysis (ICA) to characterize specific network topographies associated with Parkinson's disease (PD). Using rs-fMRI data from PD and healthy subjects, we used ICA with bootstrap resampling to identify a PD-related pattern that reliably discriminated the two groups. This topography, termed rs-MRI PD-related pattern (fPDRP), was similar to previously characterized disease-related patterns identified using metabolic PET imaging. Following pattern identification, we validated the fPDRP by computing its expression in rs-fMRI testing data on a prospective case basis. Indeed, significant increases in fPDRP expression were found in separate sets of PD and control subjects. In addition to providing a similar degree of group separation as PET, fPDRP values correlated with motor disability and declined toward normal with levodopa administration. Finally, we used this approach in conjunction with neuropsychological performance measures to identify a separate PD cognition-related pattern in the patients. This pattern, termed rs-fMRI PD cognition-related pattern (fPDCP), was topographically similar to its PET-derived counterpart. Subject scores for the fPDCP correlated with executive function in both training and testing data. These findings suggest that ICA can be used in conjunction with bootstrap resampling to identify and validate stable disease-related network topographies in rs-fMRI. Hum Brain Mapp 38:617-630, 2017. © 2016 Wiley Periodicals, Inc.

Parkinson's disease cognitive network correlates with caudate dopamine.

Prior evidence has suggested a link between caudate dopaminergic functioning and cognition in Parkinson's disease (PD). In this dual tracer study we analyzed the relationship between nigrostriatal dopaminergic dysfunction and the expression of the previously validated PD cognition-related metabolic pattern (PDCP). In this study, 17 non-demented PD patients underwent positron emission tomography (PET) imaging with [(18)F]-fluorodeoxyglucose to measure PDCP expression, and [(18)F]-fluoropropyl-ß-CIT (FPCIT) to measure dopamine transporter (DAT) binding. Automated voxel-by-voxel searches of the FPCIT PET volumes were performed to identify regions in which DAT binding significantly correlated with PDCP expression values. The findings were validated using prespecified anatomical regions-of-interest (ROIs). Voxel-wise interrogation of the FPCIT PET scans revealed a single significant cluster in which DAT binding correlated with PDCP expression (p<0.05, corrected). This cluster was localized to the left caudate nucleus; an analogous correlation (r=-0.63, p<0.01) was also present in the "mirror" region of the right hemisphere. These findings were confirmed by the presence of a significant correlation (r=-0.67, p<0.005) between PDCP expression and DAT binding in caudate ROIs, which survived adjustment for age, disease duration, and clinical severity ratings. Correlation between caudate DAT binding and subject expression of the PD motor-related metabolic pattern was not significant (p>0.21). In summary, this study demonstrates a significant relationship between loss of dopaminergic input to the caudate nucleus and the expression of a cognition-related disease network in unmedicated PD patients. These baseline measures likely function in concert to determine the cognitive effects of dopaminergic therapy in PD.

A multivariate metabolic imaging marker for behavioral variant frontotemporal dementia.

INTRODUCTION: The heterogeneity of behavioral variant frontotemporal dementia (bvFTD) calls for multivariate imaging biomarkers. METHODS: We studied a total of 148 dementia patients from the Feinstein Institute (Center-A: 25 bvFTD and 10 Alzheimer's disease), Technical University of Munich (Center-B: 44 bvFTD and 29 FTD language variants), and Alzheimer's Disease Neuroimaging Initiative (40 Alzheimer's disease subjects). To identify the covariance pattern of bvFTD (behavioral variant frontotemporal dementia-related pattern [bFDRP]), we applied principal component analysis to combined 18F-fluorodeoxyglucose-positron emission tomography scans from bvFTD and healthy subjects. The phenotypic specificity and clinical correlates of bFDRP expression were assessed in independent testing sets. RESULTS: The bFDRP was identified in Center-A data (24.1% of subject × voxel variance; P < .001), reproduced in Center-B data (P < .001), and independently validated using combined testing data (receiver operating characteristics-area under the curve = 0.97; P < .0001). The expression of bFDRP was specifically elevated in bvFTD patients (P < .001) and was significantly higher at more advanced disease stages (P = .035:duration; P < .01:severity). DISCUSSION: The bFDRP can be used as a quantitative imaging marker to gauge the underlying disease process and aid in the differential diagnosis of bvFTD.

Distinct brain networks underlie cognitive dysfunction in Parkinson and Alzheimer diseases.

OBJECTIVE: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology. METHODS: We analyzed 18F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period. RESULTS: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. CONCLUSIONS: Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD.

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

IMPORTANCE: Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE: To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS: The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES: Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS: Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (ß = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (ß = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (ß = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (ß = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (ß = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE: GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Alternate-form reliability of the Dementia Rating Scale-2.

The Dementia Rating Scale-2 (DRS-2) is a frequently used assessment of cognitive status among older adults in both research and clinical practice. Despite its well-established psychometric properties, its use in serial assessments has posed limitations with regard to practice effects. The primary purpose of the present study is to provide preliminary evidence of alternate-form reliability for the DRS-2. A heterogeneous sample of 52 community-dwelling adults over age 60 with no reported diagnosis of dementia were administered the DRS-2 as well as a newly developed alternate form [DRS-2: AF; Schmidt, K. S. (2004). Dementia Rating Scale-2 Alternate Form: Manual supplement. Lutz, FL: Psychological Assessment Resources]. Our results reveal strong correlations between the two forms; further, no significant differences were found between total scale and subscale scores obtained from the two forms. Therefore, the DRS-2: AF may be a valuable assessment tool in both research and clinical arenas.

Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus.

OBJECTIVE: We investigated whether systemic lupus erythematosus (SLE) disease duration or serology associate with abnormal regional glucose metabolism as measured with [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and deficits on neuropsychological testing. METHODS: Subjects with SLE with stable disease activity, without brain damage or clinical symptoms of neuropsychiatric (NP) SLE, stratified by disease duration (short-term (ST)-SLE=disease ≤2 years, long-term (LT)-SLE=disease ≥10 years), underwent clinical assessments, neuropsychological testing, resting FDG-PET scan imaging and measurement of serum titres of antibody to N-methyl-d-aspartate receptor (DNRAb). FDG-PET scans were compared with age-matched and gender-matched healthy controls. RESULTS: Subjects with LT-SLE demonstrated hypometabolism in the prefrontal and premotor cortices that correlated with accrued SLE-related damage, but not with DNRAb titre or performance on NP testing. Independent of disease duration, subjects with SLE demonstrated hypermetabolism in the hippocampus and orbitofrontal cortex that correlated with impaired memory performance and mood alterations (depression, anxiety, fatigue). Serum DNRAb also correlated independently with impaired memory performance and increased anxiety. Together, serum DNRAb titre and regional hypermetabolism were more powerful predictors of performance than either alone. INTERPRETATION: The presence of serum DNRAbs can account for some aspects of brain dysfunction in patients with SLE, and the addition of regional measurements of resting brain metabolism improves the assessment and precise attribution of central nervous system manifestations related to SLE.

Abnormal metabolic pattern associated with cognitive impairment in Parkinson's disease: a validation study.

Cognitive deficits in Parkinson's disease (PD) have been associated with a specific metabolic covariance pattern. Although the expression of this PD cognition-related pattern (PDCP) correlates with neuropsychological performance, it is not known whether the PDCP topography is reproducible across PD populations. We therefore sought to identify a PDCP topography in a new sample comprised of 19 Dutch PD subjects. Network analysis of metabolic scans from these individuals revealed a significant PDCP that resembled the original network topography. Expression values for the new PDCP correlated (P=0.001) with executive dysfunction on the Frontal Assessment Battery (FAB). Subject scores for the new PDCP correlated (P<0.001) with corresponding values for the original pattern, which also correlated (P<0.005) with FAB scores in this patient group. For further validation, subject scores for the new PDCP were computed in an independent group of 86 American PD patients. In this cohort, subject scores for the new and original PDCP topographies were closely correlated (P<0.001); significant correlations between pattern expression and cognitive performance (P<0.05) were observed for both PDCP topographies. These findings suggest that the PDCP is a replicable imaging marker of PD cognitive dysfunction.

Assessment of cognition in primary care: neuropsychological evaluation of the geriatric patient.

Some aspects of memory and other thinking abilities decline as part of the normal aging process. Normal age-related cognitive decline and disease-associated cognitive impairment can be difficult to differentiate in the typical patient-physician interaction, especially in the geriatric primary care setting where patients may present with multiple physical complaints that consume the physician's attention. It is essential that clinician's recognize even modest changes in thinking abilities in the geriatric patient since these changes may be an early warning sign of an impending dementing disorder. At the very least, reduced cognitive functioning can decrease one's quality of life as well as threaten their independence. When cognitive decline is suspected, a neuropsychological evaluation can provide an objective assessment of cognitive functioning that is useful for differential diagnosis, assessing presence and progression of cognitive disorders, and providing information relevant to treatment and planning. This article explores the challenges of cognitive assessment in older adults and provides an overview of the neuropsychological evaluation, its advantages and limitations, as well as common referral questions from primary care physicians.

Network modulation following sham surgery in Parkinson's disease.

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Relationship between self-reported apathy and executive dysfunction in nondemented patients with Parkinson disease.

OBJECTIVE: The prevalence of apathy was assessed across select cognitive and psychiatric variables in 32 nondemented patients with Parkinson disease (PD) and 29 demographically matched healthy control participants. BACKGROUND: Apathy is common in PD, although differentiating apathy from motor, cognitive, and/or other neuropsychiatric symptoms can be challenging. Previous studies have reported a positive relationship between apathy and cognitive impairment, particularly executive dysfunction. METHOD: Patients were categorized according to apathy symptom severity. Stringent criteria were used to exclude patients with dementia. RESULTS: Approximately 44% of patients endorsed significant levels of apathy. Those patients performed worse than patients with nonsignificant levels of apathy on select measures of verbal fluency and on a measure of verbal and nonverbal conceptualization. Further, they reported a greater number of symptoms related to depression and behavioral disturbance than did those patients with nonsignificant levels of apathy. Apathy was significantly related to self-report of depression and executive dysfunction. Performance on cognitive tasks assessing verbal fluency, working memory, and verbal abstraction and also on a self-report measure of executive dysfunction was shown to significantly predict increasing levels of apathy. CONCLUSIONS: Our findings suggest that apathy in nondemented patients with PD seems to be strongly associated with executive dysfunction.

An examination of executive dysfunction associated with frontostriatal circuitry in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder presenting with subcortical pathology and characterized by motor deficits. However, as is frequently reported in the literature, patients with PD can also exhibit cognitive and behavioral (i.e., nonmotor) impairments, cognitive executive deficits and depression being the most prominent. Considerable attention has addressed the role that disruption to frontostriatal circuitry can play in mediating nonmotor dysfunction in PD. The three nonmotor frontostriatal circuits, which connect frontal cortical regions to the basal ganglia, originate from the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). The objective of the current study was to use our understanding of frontostriatal circuit function (via literature review) to categorize neuropsychological measures of cognitive and behavioral executive functions by circuit. To our knowledge, such an approach has not been previously attempted in the study of executive dysfunction in PD. Neuropsychological measures of executive functions and self-report behavioral inventories, categorized by circuit function, were administered to 32 nondemented patients with Parkinson's disease (NDPD) and to 29 demographically matched, healthy normal control participants (NC). Our findings revealed significant group differences for each circuit, with the PD group performing worse than the NC group. Among the patients with PD, indices of impairment were greater for tasks associated with DLPFC function than with OFC function. Further, only an index of DLPFC test performance was demonstrated to significantly discriminate individuals with and without PD. In conclusion, our findings suggest that nondemented patients with PD exhibit greater impairment on neuropsychological measures associated with DLPFC than with ACC or OFC circuit function.

Test-retest reliability of the dementia rating scale-2: alternate form.

The purpose of this study was to examine the test-retest reliability of the newly developed Dementia Rating Scale-2: Alternate Form (DRS-2:AF) in a community-dwelling sample of older adults. Participants were administered the DRS-2:AF during two separate testing sessions; the interval between sessions was between 12 and 28 days. The stability coefficient for the Total Score was quite high (0.93), and reliability coefficients for the subscale scores ranged from adequate to high. This project provides evidence for the test-retest reliability of the DRS-2:AF. Given the need for cognitive status measures with equivalent forms, the DRS-2:AF is recommended as a reliable tool in the assessment of dementia.