To calculate the incidence of and determine possible risk factors for dementia in PD.Dementia has important clinical consequences for patients with PD and their caregivers, but the incidence is unknown.A population-based cohort of nondemented patients with PD (n = 171) from the county of Rogaland, Norway, was assessed at baseline and 4.2 years later with a comprehensive evaluation of motor, cognitive, and neuropsychiatric symptoms. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R) criteria, based on interview of the patient and a caregiver, cognitive rating scales, and neuropsychologic tests. A representative sample of 3,062 nondemented elderly subjects without PD served as control group.Forty-three patients with PD were demented at follow-up evaluation, equivalent to an incidence rate of 95.3 per 1,000 person-years (95% CI, 68.2 to 122.0). The risk for the development of dementia in patients with PD relative to the control subjects after adjusting for age, sex, and education was 5.9 (95% CI, 3.9 to 9.1). Predictive factors at baseline for dementia in PD in addition to age were Hoehn & Yahr score >2 (OR, 3.4; 95% CI, 1.3 to 8.6) and Mini-Mental State Examination score < 29 (OR, 3.3; 95% CI, 1.3 to 8.2).Patients with PD have an almost sixfold increased risk for becoming demented compared with subjects without PD.

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.

Increasing evidence suggests that subjective cognitive decline is associated with Alzheimer's disease pathology and with an increased risk for future dementia development. However, the clinical value of subjective cognitive decline in Parkinson's disease (PD-SCD) is unclear. The aim of the present work was to characterize PD-SCD and its progression to dementia.Forty-three PD patients and twenty normal controls were evaluated with a neuropsychological protocol. Patients were classified as PD-SCD and PD with mild cognitive impairment (PD-MCI). Follow-up assessment was conducted to a mean of 7.5 years after the baseline.Thirteen patients were diagnosed with PD-SCD (30.2%) and 22 patients were classified as PD-MCI (51.2%) at the baseline. Difficulties in language (60.5%) and memory (51.5%) were the most frequent cognitive complaints. PD-MCI showed alterations in processing speed, executive functions, visuospatial skills, memory and language. No significant differences were found between normal controls and PD-SCD in any of the neuropsychological measures. Conversion to clinically diagnosed dementia during the follow-up was 50% in PD-MCI, 33.3% in PD-SCD and 14.3% in patients without subjective cognitive complaints. Discriminant function analyses and logistic regression analyses revealed that language domain and, especially memory domain are good predictors of dementia.The present investigation is the first to conduct a long-term follow-up study of PD-SCD and its relationship with the development of dementia. The results provide relevant data about the characterization of SCD in PD patients and show that PD-SCD is a risk factor for progression to dementia.

Increasing evidence suggests that subjective cognitive decline (SCD) is a potential predictor of future cognitive decline or dementia. We investigated whether SCD in patients with Parkinson's disease (PD) is a predictor of future cognitive decline. Forty-six cognitively normal patients with PD were selected using comprehensive neuropsychological tests, and classified depending on the presence (PD-SCD(+), n = 25) or absence of SCD (PD-SCD(-), n = 21). After a mean follow-up of 2.4 years, we repeated the cognitive assessments with the same subjects. The clinical characteristics and cognitive performance of the 2 groups did not differ at baseline. At the follow-up assessment, 11 patients in the PD-SCD(+) group (44.0%) and 2 in the PD-SCD(-) group (9.5%) were diagnosed with mild cognitive impairment (MCI), and the PD-SCD(+) patients showed more rapid decline in semantic fluency and visuospatial memory tasks than those in the PD-SCD(-) group. A multivariate logistic regression analysis showed that presence of SCD (odds ratio, 8.378; 95% confidential interval, 1.472-47.683, p = 0.017) and higher Unified PD Rating Scale motor score of 20 or more (odds ratio, 4.539; 95% confidential interval, 1.004-20.528; p = 0.049) were risk factors for incident MCI. Present results demonstrate that SCD in cognitively normal patients with PD is an independent risk factor for incident MCI and acts as a predictor for future cognitive decline.Copyright © 2014. Published by Elsevier Inc.

To determine the frequency and pattern of cognitive dysfunction in patients with newly diagnosed Parkinson disease (PD) and to identify its demographic and clinical correlates.A cohort of 115 consecutive patients with newly diagnosed PD and 70 healthy controls underwent a comprehensive neuropsychological assessment including tests of psychomotor speed, attention, language, memory, executive and visuospatial functions, as well as measures of affective status. Patients also received quantitative ratings of motor symptom severity and functional status. Neuropsychological performance of PD patients was compared with that of healthy controls and with available normative data. Independent demographic and clinical predictors of cognitive impairment were identified with multiple logistic regression analysis.Relative to controls, PD patients performed significantly worse on most cognitive measures. However, further analysis revealed that group differences in cognitive performance could mainly be explained by measures of immediate memory and executive function. Comparison with normative data showed that impairments were most frequent on measures of executive function, memory and psychomotor speed. In all, 24% of PD patients (4% of controls) displayed defective performance on at least three neuropsychological tests and were classified as cognitively impaired. Late onset of disease was an independent predictor of cognitive dysfunction in PD.Cognitive impairments are common even in newly diagnosed Parkinson disease patients, with deficits being most prominent in the domains of memory and executive functions. Older age at disease onset is likely to be an important determinant of cognitive dysfunction in Parkinson disease.

Ample evidence has suggested that individuals with subjective memory complaints are at a higher risk for cognitive decline. Nevertheless, the significance of subjective memory complaints in Parkinson’s disease has not been studied until now. We investigated whether the patterns of cognitive profiles and gray matter density differed in cognitively normal patients with Parkinson’s disease based on the presence of subjective memory complaints. Using a single question with a yes or no answer, cognitively normal patients with Parkinson’s disease were classified as with (n = 20) or without subjective memory complaints (n = 15). Cognitive profiles and gray matter density were examined using standardized neuropsychological tests and voxel-based morphometry. No significant differences in demographic characteristics were observed between groups. The detailed neuropsychological tests demonstrated that Parkinson’s disease patients with subjective memory complaints had significantly decreased verbal fluency and slightly lower scores on the backward digit-span test compared with those without subjective memory complaints. A voxel-based morphometry analysis revealed that Parkinson’s disease patients with subjective memory complaints had significantly decreased gray matter density in the anterior cingulate gyrus and right inferior parietal lobule compared with those without subjective memory complaints. Our data demonstrated that Parkinson’s disease patients with subjective memory complaints showed a poorer performance on tasks related to verbal fluency and attention with more severe cortical atrophy compared to those without subjective memory complaints, suggesting that subjective memory complaints in patients with Parkinson’s disease may represent an early manifestation of underlying Parkinson’s disease-related pathological changes.

We analyzed T1-weighted brain magnetic resonance imaging data of 100 cognitively normal elderly controls (NC), 127 cognitively normal Parkinson's disease (PD; PDCN) and 31 PD-associated mild cognitive impairment (PDMCI) subjects from the Norwegian ParkWest study. Using automated segmentation methods, followed by the radial distance technique and multiple linear regression we studied the effect of clinical diagnosis on hippocampal and ventricular radial distance while adjusting for age, education, and scanning site. PDCN subjects had significantly smaller bilateral hippocampal radial distance relative to NC. Nonamnestic PDMCI subjects showed smaller right hippocampal radial distance relative to NC. PDMCI subjects showed significant enlargement of all portions of the lateral ventricles relative to NC and significantly larger bilateral temporal and occipital and left frontal lateral ventricular expansion relative to PDCN subjects. Nonamnestic PDMCI subjects showed significant ventricular enlargement spanning all parts of the lateral ventricle while those with amnestic PDMCI showed changes localized to the left occipital horn. Hippocampal atrophy and lateral ventricular enlargement show promise as structural biomarkers for PD.Copyright © 2012 Elsevier Inc. All rights reserved.

Mild cognitive impairment and dementia are common non-motor features of Parkinson's disease (PD). The aim of this study was to characterise grey matter changes associated with clearly defined stages of cognitive impairment in PD using structural MRI.96 PD subjects were classified using detailed cognitive testing as PD with normal cognition (PD-N, n=57), PD with mild cognitive impairment (PD-MCI, n=23) or PD with dementia (PD-D, n=16); 34 controls matched for mean age and sex ratio also participated. Grey matter volume differences were evaluated using voxel based morphometry of grey matter segments derived from T1 weighted 3 T MRI, and multiple linear regression assessed the relationship between cognitive and motor impairments and grey matter concentration.Compared with controls, no grey matter differences were found in PD-N. PD-MCI showed limited grey matter atrophy in the temporal, parietal and frontal cortex as well as the bilateral caudal hippocampus, amygdala and right putamen. PD-D subjects exhibited far more extensive atrophy in regions involved in PD-MCI but also had reduced grey matter volume in other large areas of the temporal lobe (including the parahippocampi), the intracalcarine and lingual gyri, posterior cingulate gyrus, frontal regions and bilateral caudate. Grey matter loss in PD correlated with global cognitive score but not motor impairment in most of these regions.Marked grey matter atrophy occurs in PD with dementia but far less extensive changes are evident in PD-MCI. Some grey matter atrophy precedes the development of dementia but may be accelerated once frank dementia begins.

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disease, with its severity increasing as the neurodegenerative process advances. The present meta-analysis used anisotropic effect size seed-based d mapping software to perform analyses using both functional and structural brain imaging data. The analyses were between PD patients with mild cognitive impairment (PD-MCI) and PD patients with dementia (PDD) compared to PD cognitively unimpaired patients (PD-CU) and PD patients without dementia (PD-ND) respectively. Thirty-four studies were found and split into three analyses: 405 PD-MCI patients compared to 559 PD-CU patients from 1) 15 studies with structural imaging modalities and 2) eight studies with functional imaging modalities, as well as 178 PDD patients compared to 278 PD-ND patients (which includes both PD-CU and PD-MCI) in 3) 11 studies with structural imaging modalities. Statistical threshold was set to uncorrected p < 0.001. We found several brain regions that differed between PD-MCI and PD-CU patients: the left insula, bilateral dorsolateral prefrontal cortex, left angular gyrus, midcingulate cortex, and right supramarginal gyrus. The brain regions identified in the PD-MCI analyses are associated with the somatosensory network and executive processing. In PDD patients, the bilateral insula and right hippocampus were found as regions of structural atrophy. The insula was found in both structural analyses of PD-MCI and PDD, with unilateral insula involvement in PD-MCI extending to bilateral insula involvement in PDD. The results found both a spectrum of increasing brain atrophy in PD cognitive impairment and supports the existence of sub-typing in PD-MCI.

Mild cognitive impairment (MCI) is inconclusively associated with regional gray matter (GM) abnormalities in Parkinson's disease (PD). We aimed to quantitatively evaluate whole-brain voxel-based morphometry (VBM) studies that have investigated brain GM changes in PD patients with MCI (PD-MCI). Seed-based d Mapping, a well-validated coordinate-based meta-analytic approach, was utilized. We included 20 VBM studies that reported 22 datasets containing 504 patients with PD-MCI and 554 PD patients without MCI (PD-NCI). The most reliable finding identified in this meta-analysis was that patients with PD-MCI exhibited greater GM atrophy in the left anterior insula than those with PD-NCI. Our findings further suggest that several moderators (age, gender, educational level, disease stage, severity of motor disability, and the severity of cognitive impairments) in PD-MCI individuals, as well as scanner field-strength, may drive heterogeneous GM changes across studies. GM abnormalities in the anterior insula, an important cognitive hub involved in switching between neural networks, contribute to understanding the neural substrates of MCI in PD, which may serve as a biomarker of PD-MCI.

Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD.Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up.Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains.Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.© 2016 EAN.

This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinson's disease and mild cognitive impairment (PD-MCI) compared with healthy controls and cognitively unimpaired PD patients (PD-Cu). Three-dimensional T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract-based spatial statistics was applied to compare DT MRI indices between groups on a voxel-by-voxel basis. Voxel-based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD-Cu and PD-MCI patients did not have GM atrophy. No region of WM damage was found in PD-Cu patients when compared with healthy controls. Relative to healthy controls and PD-Cu patients, PD-MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD-MCI patients prior to the development of dementia.Copyright © 2013 Wiley Periodicals, Inc.

To use (18)F-fluorodeoxyglucose (FDG) and PET to investigate changes in regional metabolism associated with mild cognitive impairment (MCI) in Parkinson disease (PD). Cognitive abnormalities are common in PD. However, little is known about the functional abnormalities that underlie the manifestations of MCI in this disorder.We used FDG PET to measure regional glucose metabolism in patients with PD with multiple-domain MCI (MD-MCI; n = 18), with single-domain MCI (SD-MCI; n = 15), and without MCI (N-MCI; n = 18). These patients were matched for age, education, disease duration, and motor disability. Maps of regional metabolism in the three groups were compared using statistical parametric mapping (SPM). We also computed the expression of a previously validated cognition-related spatial covariance pattern (PDCP) in the patient groups and in an age-matched healthy control cohort (n = 15). PDCP expression was compared across groups using analysis of variance.SPM revealed decreased prefrontal and parietal metabolism (p < 0.001) in MD-MCI relative to N-MCI, as well as an increase in brainstem/cerebellar metabolism (p < 0.001) in this group. In these regions, SD-MCI occupied an intermediate position between the two other groups. PDCP expression was abnormally elevated in the N-, SD-, and MD-MCI groups (p < 0.05), increasing stepwise with worsening cognitive impairment (p < 0.01).Early cognitive decline in Parkinson disease as defined by mild cognitive impairment is associated with discrete regional changes and abnormal metabolic network activity. The quantification of these alterations with (18)F-fluorodeoxyglucose PET may allow for the objective assessment of the progression and treatment of this disease manifestation.

Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naive PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, < 1 year), 18 patients with a longer duration (PD-MCI-LD, >= 1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.

Cognitive impairments are common in Parkinson's disease (PD) and can even occur in the early stages. The default mode network (DMN) is highly relevant for cognitive processes; however, it remains largely unknown if changes in the DMN connectivity are related to the cognitive decline in drug-naïve early stage PD patients with a mild cognitive impairment (MCI). This study used resting-state functional MRI (fMRI) to explore the brain connectivity of the DMN in early stage drug-naïve PD patients with MCI. We recruited 32 early stage drug-naïve PD patients and 22 matched healthy controls (HC). Among the PD patients, 14 were classified as having MCI (PD-MCI) and 18 were classified as having unimpaired cognition (PD-CU). The functional integration of the DMN was evaluated by a seed-based correlation approach. The brain connectivity analysis revealed reduced functional connectivity (FC) in both PD subgroups compared with HC. The PD-MCI group showed a significant reduction in FC between the DMN and a set of regions, including the precentral gyrus, middle temporal gyrus, insula, anterior inferior parietal lobule and middle frontal gyrus. Compared to the PD-CU group, the PD-MCI group demonstrated a significantly decreased FC in the middle frontal and middle temporal gyri. Additionally, compared to HC, the PD-MCI group had a significantly decreased FC within the DMN, mainly in the FC between the hippocampal formation and inferior frontal gyrus, between the posterior cingulate cortex and posterior inferior parietal lobule, and between the anterior temporal lobe and inferior frontal gyrus. Compared to the PD-CU group, the only significantly decreased FC within the DMN in the PD-MCI group was between the anterior temporal lobe and inferior frontal gyrus. In all PD patients, the decreased FC between anterior temporal lobe and middle temporal gyrus was positively correlated with attention/working performance, and the reduced FC between the hippocampal formation and inferior frontal gyrus was also positively correlated with memory function. Our findings suggest that an altered DMN connectivity characterizes PD-MCI patients. These findings may be helpful for facilitating the further understanding of the potential mechanisms underlying MCI in PD. However, our results are preliminary, and further investigation is needed.

Cognitive impairment is common in PD, even in early stages. The construct of mild cognitive impairment has been used to identify clinically evident cognitive impairment without functional decline in PD patients (PD-MCI). The aim of the present study was to investigate brain connectivity associated with PD-MCI through RS-fMRI. RS-fMRI at 3T was collected in 42 PD patients and 20 matched healthy controls. Among PD patients, 21 were classified as having MCI (PD-MCI) and 21 as cognitively unimpaired (PD-nMCI) based on criteria for possible PD-MCI (level I category). Single-subject and group-level ICA was used to investigate the integrity of brain networks related to cognition in PD patients with and without MCI. Image data processing and statistical analysis were performed in BrainVoyager QX. In addition, we used VBM to test whether functional connectivity differences were related to structural abnormalities. PD-nMCI and PD-MCI patients compared with controls showed decreased DMN connectivity. PD-MCI patients, but not PD-nMCI, compared with controls, showed decreased functional connectivity of bilateral prefrontal cortex within the frontoparietal network. The decreased prefrontal cortex connectivity correlated with cognitive parameters but not with clinical variables. VBM analysis did not reveal any difference in local gray matter between patients and controls. Our findings suggest that an altered DMN connectivity characterizes PD patients, regardless of cognitive status, whereas a functional disconnection of the frontoparietal network could be associated with MCI in PD in the absence of detectable structural changes.

Cognitive impairment is common in Parkinson's disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants.We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains.PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson's disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling.Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson's disease.

The incidence of dementia in Parkinson's disease (PD) is not fully known, and previous studies have provided a wide range of rates owing to variations in diagnostic criteria and methodologies used. We estimated the risk of dementia in newly diagnosed cases of PD in a population-based cohort of subjects aged >65 years.We performed repetitive systematic screening of PD diagnosis, cognitive performances, and clinical dementia during 15 years (at year 0, 3, 5, 8, 10, and 15) in 3726 elderly subjects living at home in southwestern France (PAQUID). Two sets of diagnostic criteria for dementia in PD were considered: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria and Movement Disorders Society criteria.Forty-four incident cases of PD occurred in the cohort; of these, 18 (41%) developed dementia during a mean follow-up of 6.8 ± 3.6 years. Incidence rate of dementia associated with PD was 74 per 1000 patient-years. The cumulative risk of dementia was approximately 25% and 50% after 5 and 10 years of follow-up, respectively. The relative risk for developing dementia in incident PD subjects compared with non-PD subjects was 2.47 (1.55-3.95). Equivalent estimations were obtained with Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria or Movement Disorders Society criteria.PD represents a high-risk stage for dementia in the general population.Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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.© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

We investigated the relationship between white-matter alteration and cognitive status in Parkinson's disease (PD) with and without dementia by using diffusion tensor imaging.Twenty PD patients, 20 PDD (Parkinson's disease with dementia) patients and 20 age-matched healthy controls underwent diffusion tensor imaging. The mean diffusivity and fractional anisotropy (FA) map of each patient group were compared with those of the control group by using tract-based spatial statistics. Tractography images of the genu of the corpus callosum fibre tracts were generated, and mean diffusivity and FA were measured.FA values in many major tracts were significantly lower in PDD patients than in control subjects; in the prefrontal white matter and the genu of the corpus callosum they were significantly lower in PDD patients than in PD patients. There was a significant correlation between the Mini-Mental State Examination (MMSE) scores and the FA values of the prefrontal white matter and the genu of the corpus callosum in patients with PD.Our study shows a relationship between cognitive impairment and alteration of the prefrontal white matter and genu of the corpus callosum. These changes may be useful in assessing the onset of dementia in PD patients.• Dementia is a common and important non-motor sign of Parkinson's disease (PD). • The neuropathological basis of dementia in PD is not clear. • DTI shows abnormalities in the prefrontal white matter in PD with dementia. • Prefrontal white matter alteration may be useful biomarker of dementia in PD.

Dementia occurs frequently in patients with Parkinson's disease (PD). However, the nature of the dementing process remains controversial. We evaluated various cognitive functions in patients with PD, compared fractional anisotropy (FA) values between PD patients with and without dementia.Thirty-seven consecutive patients with Hoehn-Yahr stage III or IV PD participated in this study. Patients were divided into two groups: (i) PD with dementia group (PDD) and (ii) PD without dementia group (PDND). There were 11 PDD and 26 PDND cases. Ten controls were also studied.The PDD group showed significant FA reduction in the bilateral posterior cingulate bundles compared with PDND. FA values in the left posterior cingulate bundle showed significant correlations with many cognitive parameters.Our results showed that the posterior cingulate areas play some important roles in the dementing process in PDD. However, as the pathological processes responsible for dementia in PD patients may be multifaceted, further studies are necessary.

The purpose of the present study was to investigate the pattern of white matter (WM) changes associated with Parkinson's disease (PD)-related cognitive impairment by using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) measures. Diffusion Tensor Imaging (DTI) was performed in 21 PD-patients with dementia (PDD) and in an age-matched control group including 40 PD-patients without dementia (PD-CTRL). The Parkinson's disease-Cognitive Rating Scale (PD-CRS) was used for patients' neuropsychological assessment. Local microstructural WM differences associated with the presence of cognitive impairment were tested using tract-based spatial statistics analysis. Multiple regression models investigated the association of DTI indices with total PD-CRS score, PD-CRS raw items and other clinical measures across the whole study sample. Significant FA decreases were found in PDD compared to PD-CTRL patients mainly in the body of corpus callosum, corona radiata and cingulum. Lower PD-CRS score was significantly associated with decreased FA, MD and AD values in multiple WM tracts primarily located in prefrontal and limbic areas as well as across the corpus callosum. Lower performance in specific PD-CRS raw items was also associated with FA decreases in major WM tracts. The results suggest that multifocal microstructural changes of WM accompany the transition from normal to demented cognitive state in PD-patients. The corpus callosum, the corona radiata and the cingulum are among the regions mostly affected during this course. A progressive axonal degeneration is proposed as a key underlying mechanism.

This study assesses the patterns of structural and functional connectivity damage in patients with Parkinson's disease dementia (PDD) compared with cognitively unimpaired Parkinson's disease patients (PD-Cu) and healthy controls (HC).Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor magnetic resonance imaging (DTI) scans were obtained from 30 PD and 21 sex- and age-matched HC. The between-group difference in posterior cingulate (PCC) functional connectivity (FC) was performed to assess FC dysfunction. Atlas-based spatial statistics of DTI was applied to compare White matter (WM) fibers impairment between groups.(1) Functional connectivity: (1) PD-Cu compared with HC showed a decreased PCC functional connectivity of the right medial temporal lobe (MTL). In addition, PCC-right MTL connectivity strength of PD was significantly correlated with Montreal Cognitive Assessment (MoCA) score. (2) PDD group shows a decreased FC of PCC-right parahippocampa compared with PD-Cu group; while show a widespread decreased PCC FC compared with HC group. (2) Anatomical connectivity: (1) Relative to PD-Cu, significant lower FA values were found in the left hippocampus in PDD. (2) PDD showed higher MD values in a widespread WM regions compared with PD-Cu and HC. (3) Positive correlation was observed between MoCA score and FA value of left inferior longitudinal and hippocampus, and bilateral superior longitudinal fasciculus in PD.Cognitive decline in PD is associated with FC damage of PCC-right MTL and microstructural damage of left hippocampus. Nevertheless, combining fMRI and DTI method may provide markers able to contribute to the prediction of PDD.Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cognitive impairment is one of the most salient non-motor symptoms of Parkinson's disease (PD). Cognitive decline poses a significant burden on the patient as well as the caregiver and a better understanding of the underlying pathological processes will aid in directing disease-specific treatment. In recent years, significant progress in the understanding of the underlying mechanisms of cognition in PD has been made using neuroimaging modalities. In this review, we will discuss the evidence for gray matter atrophy and cortical thinning, diffusivity changes and white matter hyperintensities in dementia, mild cognitive impairment and in several cognitive domains. Structural MRI studies have revealed considerable changes in gray and white matter in PD patients with cognitive dysfunction, showing marked atrophy and diffusivity changes in patients with dementia. The neural substrates of mild cognitive impairment in PD are more variable, perhaps reflecting a heterogeneous cohort with patients showing deficits in various cognitive domains. This review further highlights the potential areas of future research avenues in cognitive impairment in PD.© 2019 Elsevier Inc. All rights reserved.

Voxel-based morphometry is gaining considerable interest for studies examining Parkinson's disease dementia patients. In this study, 12 patients with clinically defined Parkinson's disease and dementia and 12 non-demented patients with Parkinson's disease were examined using a T1WI three-dimensional fast spoiled gradient echo sequence. Gray matter data were analyzed using a voxel-based morphometry method and independent sample t-test based on Statistical Parametric Mapping 5 software. Differences in gray matter volume were represented with statistical parametric mapping. Compared with Parkinson's disease patients without dementia, decreased gray matter volume in Parkinson's disease dementia patients was observed in the bilateral superior temporal gyrus, bilateral posterior cingulate and left cingulate gyrus, right parahippocampal gyrus and hippocampus, right precuneus and right cuneus, left inferior frontal gyrus and left insular lobe. No increased gray matter volume was apparent. These data indicate that gray matter atrophy in the limbic system and cerebral neocortex is related to the presence of dementia.

Brain gray matter volume (GMV) reduction has been reported in Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) and in PD patients with dementia (PDD) with cumulative evidence using voxel-based morphometry (VBM). However, the findings of these studies have not been entirely concordant. Whole-brain VBM studies comparing PD-MCI with PD patients without cognitive impairment (PD-NCI) and comparing PDD with PD patients without dementia (PDND) were systematically searched in PubMed and EMBASE databases from January 1995 to December 2015. Coordinates with significant differences were extracted from each cluster. Meta-analysis was performed using AES-SDM to quantitatively evaluate the GMV changes. Five studies comparing 92 PD-MCI with 192 PD-NCI patients were included in the PD-MCI vs. PD-NCI meta-analysis. Ten studies with 168 PDD and 233 PDND patients were included in the PDD vs. PDND meta-analysis. Compared with PD-NCI, GMV reductions were observed in left superior temporal lobe, left insula and left superior frontal lobe in PD-MCI patients. Significant GMV reduction were found in bilateral superior temporal lobe extending to hippocampus, and left superior frontal lobe in PDD patients comparing with PDND. Meta-regression of PDD studies showed that disease duration was negatively correlated with GMV in the left superior frontal lobe. GMV reductions in the frontal-limbic-temporal regions were main features of cognitive decline in PD. Unilateral-to-bilateral development of GMV reduction in the frontal-limbic-temporal regions is a possible indicator for PD-MCI to PDD progression, whereas significant hippocampal GMV reduction may not be a marker for early cognitive decline in PD.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

To investigate the pattern of cortical thinning in Parkinson's disease (PD) across different disease stages and to elucidate to what extent cortical thinning is related to cognitive impairment.Ninety-six subjects including 39 controls and 57 PD patients participated in this study. PD subjects were divided into three groups (early, n=24; moderate, n=18; with dementia, n=15). High field structural brain MRI images were acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Vertex-wise group comparisons were performed and cortical thickness was correlated with motor and cognitive measures.We found a positive correlation between Mini-Mental State Examination scores and cortical thickness in the anterior temporal, dorsolateral prefrontal, posterior cingulate, temporal fusiform and occipitotemporal cortex. Unified Parkinson's Disease Rating Scale-III (motor subsection) scores showed a robust negative correlation with caudate volumes. We found that disease stage in PD was associated with thinning of the medial frontal (premotor and supplementary motor cortex), posterior cingulate, precuneus, lateral occipital, temporal and dorsolateral prefrontal cortex. Discriminant analysis and a receiver operating characteristics approach showed that mean cortical thickness and hippocampus volume have 80% accuracy in identifying PD patients with dementia. PD stage and PD dementia can be characterised by a specific pattern of cortical thinning.We conclude that measuring cortical thickness can be useful in assessing disease stage and cognitive impairment in patients with PD. In addition, cortical thickness may be useful in identifying dementia in PD.

Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB).Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686.Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference -0·6 [95% CI -1·2 to -0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, -0·1 [-0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, -0·3 [-0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (-4·3 vs 1·7, respectively, -5·9 [-11·6 to -0·2]; p=0·041) in patients with DLB, but not in those with PDD (-1·6 vs -0·1, respectively, -1·4 [-5·9 to 3·0]; p=0·522) or in the total patient population (-2·6 vs 0·4, respectively, -2·9 [-6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group).Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients.Lundbeck.Copyright © 2010 Elsevier Ltd. All rights reserved.