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Corpus callosal atrophy and associations with cognitive impairment in Parkinson disease
Abstract
Objective:
To investigate atrophy of the corpus callosum on MRI in Parkinson disease (PD) and its relationship to cognitive impairment.
Methods:
One hundred patients with PD and 24 healthy control participants underwent clinical and neuropsychological evaluations and structural MRI brain scans. Participants with PD were classified as cognitively normal (PD-NC; n = 28), having mild cognitive impairment (PD-MCI; n = 47), or having dementia (PDD; n = 25) by Movement Disorder Society criteria. Cognitive domain (attention/working memory, executive function, memory, language, visuospatial function) z scores were calculated. With the use of FreeSurfer image processing, volumes for total corpus callosum and its subsections (anterior, midanterior, central, midposterior, posterior) were computed and normalized by total intracranial volume. Callosal volumes were compared between participants with PD and controls and among PD cognitive groups, covarying for age, sex, and PD duration and with multiple comparison corrections. Regression analyses were performed to evaluate relationships between callosal volumes and performance in cognitive domains.
Results:
Participants with PD had reduced corpus callosum volumes in midanterior and central regions compared to healthy controls. Participants with PDD demonstrated decreased callosal volumes involving multiple subsections spanning anterior to posterior compared to participants with PD-MCI and PD-NC. Regional callosal atrophy predicted cognitive domain performance such that central volumes were associated with the attention/working memory domain; midposterior volumes with executive function, language, and memory domains; and posterior volumes with memory and visuospatial domains.
Conclusions:
Notable volume loss occurs in the corpus callosum in PD, with specific neuroanatomic distributions in PDD and relationships of regional atrophy to different cognitive domains. Callosal volume loss may contribute to clinical manifestations of PD cognitive impairment.
... Disease duration was reported either in months (n = 4) or years (n = 23) with missing data in six trials [60,64,67,74,75,88]. In the group of patients with PD-MCI, disease duration ranged from 1.3 [66] to 10.7 years [77] and in the PDD group from 2.4 [91] to 13.8 years [73], showing an expectedly longer disease duration in PDD ...
... According to our definition, visuo-perceptual abilities were examined in 9 of 33 studies with 7 different neuropsychological tests [63,66,70,73,74,81,85,87,92]. The recognition trial of the ROCF was used in three studies [66,85,87] and the subtest Incomplete letters of the VOSP in two studies [70,92]. ...
... The effect size of the performance on the Benton Visual Form Discrimination Test was comparable to ROCF performance (SMD = 1.0, 95% CI: 0.18; 1.83); however, this test was only used in one study [74]. Goldman et al. [73] used the subtest Figure ...
Background
Visuo-cognitive impairment is common in patients with Parkinson’s disease with mild cognitive impairment (PD-MCI) and constitutes a prognostic factor for the conversion to Parkinson’s disease dementia (PDD). However, systematic analyses on which neuropsychological tests are most suitable to assess visuo-cognition in PD-MCI and PDD and to differentiate these cognitive stages are lacking.
Objective
To review neuropsychological tests used to assess visuo-cognition including visuo-perceptual and visuo-spatial processing, visuo-constructive copying and drawing on command abilities; and to identify the visuo-cognitive subdomain as well as tests most suitable to discriminate between PD-MCI and PDD.
Methods
MEDLINE, PsycINFO, Web of Science Core Collection, and CENTRAL were systematically searched for relevant studies assessing visuo-cognitive outcomes in patients with PD-MCI and PDD. Risk of bias was assessed using a customized form based on well-established tools. Random-effect meta-analyses were conducted.
Results
33 studies were included in the systematic review. Data of 19 studies were entered in meta-analyses. Considerable heterogeneity regarding applied tests, test versions, and scoring systems exists. Data indicate that visuo-constructive command tasks are the subdomain best suited to discriminate between PD-MCI and PDD. Furthermore, they indicate that the Rey-Osterrieth-Complex-Figure Test (ROCF), Corsi Block-Tapping Test, Judgment of Line Orientation (JLO), and Clock Drawing Test (CDT) are tests able to differentiate between the two stages.
Conclusion
We provide suggestions for suitable visuo-cognitive tests (Corsi Block-Tapping Test, or JLO, ROCF, CDT) to improve diagnostic accuracy. Methodological challenges (e.g., heterogeneity of definitions, tests) are discussed and suggestions for future research are provided.
Registration
https://www.crd.york.ac.uk/prospero/, ID: CRD42018088244
... The use of deformation-based morphometry (DBM), a technique that assesses gray and white matter tissue changes based on the shift needed to locally deform a brain to a standard template [14,15], was recently shown to reveal structural changes that are complementary to what is reported using the more traditional voxel-based morphometry (VBM), generally limited to gray matter investigation [16]. Moreover, tissue changes occurring in the cholinergic basal forebrain and the corpus callosum (CC) have been linked to cognitive decline in PD [17,18] or DLB [19,20]. ...
... The present study explored the tissue volumes of the CC and cholinergic basal forebrain cell groups, given their importance in the manifestation of cognitive functions in PD [17,18]. We found volume reduction of the mid-posterior segment of the CC and a trend toward atrophy of the left Ch4 region in patients with MCI. ...
... We found volume reduction of the mid-posterior segment of the CC and a trend toward atrophy of the left Ch4 region in patients with MCI. Structural anomalies of the CC (including in the mid-posterior segment) were reported in PD with cognitive impairment [17,49], PD with RBD [50], and in DLB [51] patients. The Ch4 cell group contains the nucleus basalis of Meynert, which provides the principal source of cholinergic innervation to the cerebral cortex and amygdala [52]. ...
Background
Rapid-eye-movement sleep behavior disorder (RBD) is a major risk factor for Parkinson’s disease and dementia with Lewy bodies. More than a third of RBD patients have mild cognitive impairment (MCI), but their specific structural brain alterations remain poorly understood.
Objective
This study aimed to investigate the local deformation and volume of gray and white matter tissue underlying MCI in RBD.
Methods
Fifty-two idiopathic RBD patients, including 17 with MCI (33%), underwent polysomnography, neuropsychological, neurological, and magnetic resonance imaging assessments. MCI diagnosis was based on a subjective complaint, cognitive impairment on the neuropsychological battery, and preserved daily functioning. Forty-one controls were also included. Deformation-based morphometry (DBM), voxel-based morphometry (VBM), and regional volume analyses of the corpus callosum and cholinergic basal forebrain were performed. Multiple regression models were also computed using anatomical, cognitive (composite z scores), and motor parameters.
Results
Globally, patients with MCI displayed a widespread pattern of local deformation and volume atrophy in the cortical (bilateral insula, cingulate cortex, precuneus, frontal, temporal and occipital regions, right angular gyrus, and mid-posterior segment of the corpus callosum) and subcortical (brainstem, corona radiata, basal ganglia, thalamus, amygdala, and right hippocampus) regions compared to patients without MCI (DBM) or controls (DBM and VBM). Moreover, brain deformation (DBM) in patients were associated with lower performance in attention and executive functions, visuospatial abilities, and higher motor symptoms severity.
Conclusion
The present study identified novel brain structural alterations in RBD patients with MCI which correlated with poorer cognitive performance. These results are consistent with those reported in patients with synucleinopathies-related cognitive impairment.
... Parkinson's disease (PD) is widely known as a slowly progressive movement disorder, which is demonstrated with complex clinical symptoms including classic motor dysfunctions (Lees et al., 2009) and various non-motor disturbances (Jankovic, 2008). Previous neuroimaging studies have identified the involvement of the corpus callosum (CC) to be an important feature of PD not only in motor but also in non-motor functions (Chan et al., 2014;Goldman et al., 2017). CC is the largest bundle between hemispheres (Hofer and Frahm, 2006) and participates in the mediation of multifunctions (Fabri et al., 2011(Fabri et al., , 2014 through structural connectivity or functional activation. ...
... Specifically, CC is not a homogeneous component, the fibers of which maturate at different ages and have the distinct vulnerability to pathological changes (Aboitiz et al., 1992;Aboitiz and Montiel, 2003), indicating the existence of different fiber compositions (Fabri et al., 2014). Indeed, the alterations of callosal subsections differed among PD patients with different cognitive levels (Goldman et al., 2017;Bledsoe et al., 2018) and patients with different subtypes (Chan et al., 2014). Given that the different activation loci were consistently detected in discrete CC regions according to peripheral stimuli (Fabri et al., 2011) and the connections of distinct callosal subsections to cortices were differential (Caille et al., 2005), the damage in a specific callosal subsection may contribute to the corresponding clinical deficit in PD. ...
... On structural magnetic resonance imaging (MRI), PD shows callosal atrophy (Goldman et al., 2017;Lenka et al., 2017). The volume includes macrostructural information, which could elucidate the morphological change in PD. ...
Background:
The corpus callosum (CC) is an important feature of Parkinson's disease (PD) not only in motor but also in non-motor functions. However, CC is not a homogeneous component, and the damage of specific subsection may contribute to corresponding clinical deficit.
Objective:
The objective of the study is to investigate the structural alterations of different callosal subsections cross-sectionally and longitudinally in PD and evaluate their relationships to clinical performance.
Methods:
Thirty-nine PD patients who had been longitudinally reexamined and 82 normal controls (NC) were employed. According to their specific callosal-cortical connectivity, 3D CC was divided into five subsections (including prefrontal, premotor, motor, somatosensory, and temporal-parietal-occipital subsection). The fractional anisotropy (FA), mean diffusivity (MD), and volume of whole CC and its subsections were computed and compared between groups. Regression model was constructed to explore the relationships between callosal structure and clinical performance.
Results:
At baseline, PD did not show any significant macro/microstructural difference compared with NC. During disease course, there was a decreased FA and increased MD of whole CC as well as its subsections (except temporal-parietal-occipital subsection), and the volume of motor subsection was decreased. Moreover, the FA of temporal-parietal-occipital subsection and volume of motor subsection were correlated with the mood domain at baseline, and the MD of somatosensory subsection was associated with the motor domain at follow-up.
Conclusion:
The structure of CC and its connectivity-specific subsections remain preserved at a relatively early stage in PD and are progressively disrupted during disease course. Besides, different callosal subsections possess specific associations with clinical performance in PD.
... This study demonstrated no significant differences in thickness of callosal streamlines in PD-CU subjects compared with Controls, supporting early two-dimensional area-based findings (Wiltshire et al., 2005) as well as more recent three-dimensional volumetric work (Lenka et al., 2017). Two studies showed volumes of callosal subdivisions are reduced in a total PD cohort comprising participants with and without cognitive impairment and also dementia, compared with controls (Goldman et al., 2017;Vasconcellos et al., 2018). Analyses between PD-disease subgroups in Goldman et al. (2017) that their finding is likely due to significant changes in the PD participants diagnosed with dementia, and the results of the current study support this finding. ...
... This finding may represent anatomical substrates of the motor programming deficits that are common in the disorder and at their most advanced in PD patients with dementia (Szeto et al., 2020). Our finding of a lack of significant differences between cognitively normal PD and MCI subjects aligns with the work of Goldman et al. (2017), who also found no differences in callosal volumes in a PD-MCI cohort compared to cognitively unimpaired PD participants, as well as a control group. In this context, our study builds on previous research findings and indicates that the morphology of the corpus callosum is impacted in advanced PD stages and that PD patients with mild or no cognitive impairment have no observable structural alterations to the callosum. ...
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 to 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.
... Our results showed a significantly decreased fractional anisotropy in cystinosis patients compared to healthy controls in clusters within the corpus callosum's body, indicating a white matter microarchitecture abnormality, which suggests abnormal anatomical connectivity in this region (Figure 3). This bundle, which plays a central role in inter-hemispheric communication, has also recently been associated with cognitive processes [47,48]. However, controls with nephropathy also present with these abnormalities compared to healthy controls, suggesting that they may not be specific to cystinosis patients. ...
... Our results showed a significantly decreased fractional aniso ropy in cystinosis patients compared to healthy controls in clusters within the corpus c losum's body, indicating a white matter microarchitecture abnormality, which sugges abnormal anatomical connectivity in this region (Figure 3). This bundle, which plays central role in inter-hemispheric communication, has also recently been associated wi cognitive processes [47,48]. However, controls with nephropathy also present with the abnormalities compared to healthy controls, suggesting that they may not be specific cystinosis patients. ...
Despite improvement in the specific treatment, clinical and anatomo-functional central nervous system (CNS) abnormalities of various severities are still observed in cystinosis patients. Patients who develop CNS complications today have a worse compliance to cysteamine treatment. Radiological studies have shown that cortical or central (ventriculomegaly) atrophy is observed in more than two thirds of cystinosis patients’ magnetic resonance imaging (MRI) and correlates with the intelligence quotient score. Half of cystinosis patients have marked aspecific white matter hyperintensities. The development of advanced neuroimaging techniques provides new tools to further investigate CNS complications. A recent neuroimaging study using a voxel-based morphometry approach showed that cystinosis patients present a decreased grey matter volume in the left middle frontal gyrus. Diffusion tensor imaging studies have shown white matter microstructure abnormalities in children and adults with cystinosis, respectively in areas of the dorsal visual pathway and within the corpus callosum’s body. Finally, leucocyte cystine levels are associated with decreased resting cerebral blood flow, measured by arterial spin labelling, in the frontal cortex, which could be associated with the neurocognitive deficits described in these patients. These results reinforce the relevance of neuroimaging studies to further understand the mechanisms that underline CNS impairments.
... In particular, a decrease in the thickness and area of CC segments with significant correlation with cognitive dysfunction is known in psychosis, Parkinson's disease, and Alzheimer's disease. [9][10][11] Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism that leads to the accumulation of copper in different tissues. [12] In neurological WD, the accumulation of copper and its resultant cytotoxicity affects the cortical and subcortical structures of the brain. ...
... A similar association of cognitive function with CC loss is reported Parkinson's disease and Alzheimer's disease. [9][10][11] The duration of disease, serum copper, serum-free copper, 24 hour urine copper, and ceruloplasmin levels did not correlate with the morphometric measures of any segment in this study, suggesting that there was no effect of these variables on CC morphometry. However, these results may be due to the smaller sample size and the heterogeneity of patients, especially with respect to treatment. ...
Abstract:
BACKGROUND AND PURPOSE: The corpus callosum (CC) consists of topographically arranged
white matter (WM) fibers. Previous studies have indicated the CC to be discretely involved in WD.
In this study, we strived to characterize the macrostructural properties of the CC using midsagittal
cross-sectional area and thickness profile measurements. MATERIALS AND METHODS: This
study was performed using archived magnetic resonance imaging (MRI) scans of 14 patients with
WD and 14 age- and gender-matched healthy controls. Using an automated software pipeline for
morphometric profiling, the midsagittal CC was segmented into five sub-regions (CC1–5) according to
the Hofer–Frahm scheme. The mean thickness and area of different CC segments and their clinical
and cognitive correlates were identified.
RESULTS: The mean area was significantly different only in CC2
segment (94.2 ± 25.5 vs. 118.6 ±
19.7 mm2
, corrected P < 0.05). The mean thickness was significantly different in CC1
(5.06 ± 1.15 vs.
6.93 ± 0.89 mm, corrected P < 0.05), CC2
(3.73 ± 0.96 vs. 4.87 ± 1.01 mm, corrected P < 0.05), and
CC3
segments (3.42 ± 0.84 vs. 3.94 ± 0.72 mm, corrected P < 0.05). The age at onset of neurological
symptoms and MMSE score was significantly correlated with the morphometric changes of CC1
and
CC2
segments.
CONCLUSION: Morphological changes of the CC are discrete in WD. Morphometric loss of CC was
associated with an earlier onset of neurological symptoms and cognitive dysfunction in WD.
... In addition, the integrity of white matter tracts in frontal and temporal regions may be particularly vulnerable to aging (Teipel et al., 2007;Wen et al., 2019;Toniolo et al., 2020), and lower structural integrity of these tracts has been linked with increased risk for cognitive decline and ADRD (Lee et al., 2015;Yang et al., 2016;Habes et al., 2018). For example, the corpus callosum, the tract that explained the most unique variance in our analyses, may be particularly relevant for age-related disorders including ADRD as it is highly involved in hemispheric integration and inhibition central to cognition (Goldman et al., 2017;Hsieh et al., 2020). Additionally, age-related decreases in FA within the genu of the corpus callosum has been linked with lower performance across a variety of cognitive domains such as working memory, executive function, and attention (Goldman et al., 2017;Loprinzi et al., 2020). ...
... For example, the corpus callosum, the tract that explained the most unique variance in our analyses, may be particularly relevant for age-related disorders including ADRD as it is highly involved in hemispheric integration and inhibition central to cognition (Goldman et al., 2017;Hsieh et al., 2020). Additionally, age-related decreases in FA within the genu of the corpus callosum has been linked with lower performance across a variety of cognitive domains such as working memory, executive function, and attention (Goldman et al., 2017;Loprinzi et al., 2020). Further, a recent meta-analysis found evidence suggesting aerobic exercise that enhances cardiovascular fitness is associated with increases in the structural integrity of the corpus callosum (Loprinzi et al., 2020). ...
Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO2Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO2Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.
... These relationships between the regional white matter microstructure deficits and functions of different cognitive domains, including visual-spatial functions, are also commonly described in neurodegenerative diseases. 19 The visual-spatial deficits have been demonstrated to precede other cognitive impairments in VaD and are capable of distinguishing VCIND patients from cognitively normal (NC) participants. 4,20 However, the relationship between visual-spatial impairments and callosum fiber loss in patients with LA and varying degrees of cognitive deterioration is still unclear. ...
... Longitudinal LA study showed that the decline in the visually mediated processing speed and motor control scores were significantly associated with tissue loss in the mid-body of the CC. 17,49 Although a study on Parkinson's disease indicated that volume loss in the posterior CC segments and potentially altered projections to the parietal-occipital regions may underlie visuospatial deficits found in dementia, 19 the present study directly demonstrated the association between the damage of the body of the CC and visualspatial deficits in the LA-VaD group. The stable and extensive FA reduction in the body of the CC in the LA-VaD participants compared to the HC and LA-VCIND groups suggested that as patients with LA present with more severe cognitive decline, CC damage may be responsible for specific visual-spatial cognitive impairment and may distinguish LA-VCIND from LA-VaD. ...
Objective:
To investigate regional white matter fibers loss in Leukoaraiosis (LA) and its relationship with cognitive impairments.
Methods:
Fifty-six participants with LA and 38 healthy controls underwent clinical evaluations and MR scans. Participants with LA were classified as cognitively normal (LA-NC, n = 18), vascular cognitive impairment of none dementia (LA-VCIND, n = 24), and vascular dementia (LA-VaD, n = 14) by Mini-Mental State Examination and Clinical Dementia Rating. Cognitive domains including visual-spatial, naming, attention, language, abstraction, memory, and orientation were assessed. With the use of Tract-based spatial statistics, mean fractional anisotropy (FA) of major white matter fiber tracts were compared between LA and controls and among LA groups with varying levels of cognitive impairments. Regression analyses were performed to evaluate relationships between FA values and cognitive performance.
Results:
Participants showed significant FA reduction in the corpus callosum (CC), bilateral corona radiata, anterior limb of the internal capsule, external capsule, posterior thalamic radiation, and superior longitudinal fasciculus compared to controls and across LA groups. The LA-VaD group showed consistent damage in the body and genu of CC compared to the LA-NC and LA-VCIND groups. A positive correlation between visual-spatial and FA reduction in right anterior corona radiates in LA-VCIND and body of CC in LA- VaD.
Interpretation:
We found regional fiber loss in the CC across the cognitive spectrum in patients with LA and correlations between FA and visuospatial impairment in the anterior corona radiata in patients with LA-VCIND and in the body of CC in patients with LA-VaD.
... In neurodegenerative conditions, subsequent to neuronal cell death these axons undergo Wallerian degeneration and cause morphological/volumetric changes in CC. 5,6 In support of above there were reports on CC segmental volume atrophy in mild cognitive impairment due to Alzheimer' dementia (AD), frontotemporal dementia (FTD), Parkinson's plus syndromes, and vascular dementia. [7][8][9][10][11] In this way, CC anatomical maps with volume analysis has the potential to aid in the study of neurodegenerative and cognitive disorders as CC reflects the effects of neurodegeneration to specific cortical regions. Though the volume of each segment of CC gives more accurate information reflecting the cortical degenerative process, it has few limitations. ...
... Study by Goldman et al reported involvement on the mid-anterior and central part of CC in PD with similar picture noted in our PDD sample. 8 Whereas, DLBD is a diffuse condition with bilateral involvement. The CC cannot differentiate unilateral involvement from bilateral involvement of cerebral hemisphere. ...
Background: Phenotyping dementia is always a complex task for a clinician. There is a need for more practical biomarkers to aid clinicians.
Objective: The aim of the study is to investigate the shape profile of corpus callosum (CC) in different phenotypes of dementia.
Materials and Methods: Our study included patients who underwent neuroimaging in our facility as a part of clinical evaluation for dementia referred from Geriatric Clinic (2017–2018). We have analyzed the shape of CC and interpreted the finding using a seven-segment division.
Results: The sample included MPRAGE images of Alzheimer’ dementia (AD) (n = 24), posterior cortical atrophy- Alzheimer’ dementia (PCA-AD) (n = 7), behavioral variant of frontotemporal dementia (Bv-FTD) (n = 17), semantic variant frontotemporal dementia (Sv-FTD) (n = 11), progressive nonfluent aphasia (PNFA) (n = 4), Parkinson’s disease dementia (PDD) (n = 5), diffuse Lewy body dementia (n = 7), progressive supranuclear palsy (PSP) (n = 3), and corticobasal degeneration (CBD) (n = 3). We found in posterior dementias such as AD and PCA-AD that there was predominant atrophy of splenium of CC. In Bv-FTD, the genu and anterior half of the body of CC was atrophied, whereas in PNFA, PSP, PDD, and CBD there was atrophy of the body of CC giving a dumbbell like profile.
Conclusion: Our study findings were in agreement with the anatomical cortical regions involved in different phenotypes of dementia. Our preliminary study highlighted potential usefulness of CC in the clinical setting for phenotyping dementia in addition to clinical history and robust biomarkers.
... The same researchers described a positive association between visual memory free recall and right parietal cortex thickness [73]. Volumes of subsections of corpus callosum predicted performance in distinct cognitive domains in a study by Goldman et al.: central portion volumes correlated with attention/working memory, mid-posterior with executive functions, language and memory, and posterior section with memory and visuospatial domains [74]. ...
... PD-MCI cases had increased longitudinal rates of global brain atrophy and ventricular enlargement compared to PD-IC, suggesting that brain volume measurements could be used as biomarkers for upcoming clinical trials [86]. As such, expansion of the lateral ventricle and atrophy of the corpus callosum have been proposed as imaging biomarkers that covariate with cognitive decline [74,86,87]. ...
Cognitive dysfunction in Parkinson's disease (PD) has received increasing attention, and, together with other non-motor symptoms, exert a significant functional impact in the daily lives of patients. This article aims to compile and briefly summarize selected published data about clinical features, cognitive evaluation, biomarkers, and pathophysiology of PD-related dementia (PDD). The literature search included articles indexed in the MEDLINE/PubMed database, published in English, over the last two decades. Despite significant progress on clinical criteria and cohort studies for PD-mild cognitive impairment (PD-MCI) and PDD, there are still knowledge gaps about its exact molecular and pathological basis. Here we overview the scientific literature on the role of functional circuits, neurotransmitter systems (monoaminergic and cholinergic), basal forebrain, and brainstem nuclei dysfunction in PD-MCI. Correlations between neuroimaging and cerebrospinal fluid (CSF) biomarkers, clinical outcomes, and pathological results are described to aid in uncovering the neurodegeneration pattern in PD-MCI and PDD.
... DTI measures, such as fractional anisotropy (FA) and mean diffusivity (MD), have been widely used to provide noninvasive in vivo measures of white matter integrity in PD. 18−20 Of the reportedly altered white matter structures from PD neuroimaging studies, the CC has the most consistent disease-related changes. 21−23 Furthermore, the CC plays an important role in regulating motor and nonmotor functions in PD. 15,16 To evaluate CC damage, three-dimensional analysis is required because of the inhomogeneity of this brain structure. Wu et al. reported that structures of the whole CC and its connectivity-specific subsections are progressively disrupted during the course of PD. 14 More recently, Amandola et al. revealed that FA is lower in the right CC at both baseline and follow-up at 24 months. ...
... In addition, chronic inflammation and oxidative stress can directly damage neurons and synapses, furthering the process of CC atrophy (Finkel and Holbrook, 2000). Furthermore, the process of neuronal and synaptic degeneration in the CC can be accelerated by neurodegenerative diseases, such as Alzheimer's and Parkinson's disease (Frederiksen et al., 2011b;Goldman et al., 2017;Vermersch et al., 1994;Zhu et al., 2014), as well as lifestyle and environmental factors like lack of physical activity (Pani et al., 2022), poor diet (Lau et al., 2005), and chronic stress (Villarreal et al., 2004). ...
... • Smaller volumes of the left nucleus accumbens, left caudate, and hippocampus [29,35,36]. ...
Parkinson’s disease (PD) is the second most prevalent degenerative disorder impacting the central nervous system. PD manifests through both motor and non-motor symptoms, including rest tremors, bradykinesia, muscle rigidity, neuropsychiatric distress, anosmia, and deficits in executive function and memory. Neurofeedback (NFB) is a psychophysiological technique aimed at enabling individuals to self-regulate their brain activity by utilizing instruments that provide real-time feedback on cerebral activity. The present chapter aims to state the theory that has been produced about Neurofeedback in Parkinson’s disease. To achieve that, firstly, the conceptualization of PD has been made; secondly, the neuropsychological and neuropsychiatric symptoms were described; thirdly, the neurophysiology of PD was presented; and finally, the neurofeedback applied in PD was analyzed. Most of the studies are related to the improvement of motor performance, although the non-motor symptoms might be another aim to improve the quality of life of those patients.
... White matter tract abnormalities in PD have been extensively reported, revealing significant abnormalities. Lower FA in patients with PD was observed in a broad area, including the corpus callosum (CC) and internal and external capsules, particularly in groups with severe symptoms, psychosis or cognitive impairments, and freezing of gait (Goldman et al., 2017;Guimarães et al., 2018;Pietracupa et al., 2018;Lenka et al., 2020). However, previous results have been inconsistent; a meta-analytical approach indicated that FA reduction was identified predominantly in the body of the CC and the left inferior fronto-occipital fasciculus (Wei et al., 2021). ...
Background
Limbic structures have recently garnered increased attention in Parkinson’s disease (PD) research. This study aims to explore changes at the whole-brain level in the structural network, specifically the white matter fibres connecting the thalamus and limbic system, and their correlation with the clinical characteristics of patients with PD.
Methods
Between December 2020 and November 2021, we prospectively enrolled 42 patients with PD and healthy controls at the movement disorder centre. All participants underwent diffusion tensor imaging (DTI), 3D T1-weighted imaging (3D-T1WI), and routine brain magnetic resonance imaging on a 3.0 T MR scanner. We employed the tract-based spatial statistical (TBSS) analytic approach, examined structural network properties, and conducted probabilistic fibre tractography to identify alterations in white matter pathways and the topological organisation associated with PD.
Results
In patients with PD, significant changes were observed in the fibrous tracts of the prefrontal lobe, corpus callosum, and thalamus. Notably, the fibrous tracts in the prefrontal lobe and corpus callosum showed a moderate negative correlation with the Freezing of Gait Questionnaire (FOG-Q) scores ( r = −0.423, p = 0.011). The hippocampus and orbitofrontal gyrus exhibited more fibre bundle parameter changes than other limbic structures. The mean streamline length between the thalamus and the orbitofrontal gyrus demonstrated a moderate negative correlation with Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III ( r = −0.435, p = 0.006). Topological parameters, including characteristic path length ( L p ), global efficiency ( E g ), normalised shortest path length ( λ ) and nodal local efficiency ( N le ), correlated moderately with the MDS-UPDRS, HAMA, MoCA, PDQ-39, and FOG-Q, respectively.
Conclusion
DTI is a valuable tool for detecting changes in water molecule dispersion and the topological structure of the brain in patients with PD. The thalamus may play a significant role in the gait abnormalities observed in PD.
... This hypothesis is further corroborated by two observations: i) all MRI metrics in the CC genu were comparable between PD-unsteady and PSP, two conditions sharing postural instability, and ii) PD patients without PI had no difference in the callosal metrics compared to control subjects. Our results showing differences between unsteady and steady PD patients may help interpreting previous heterogeneous results on CC involvement in PD patients (Yang et al., 2023), with some authors reporting CC damage in various segments (Amandola et al., 2022;Suo et al., 2021;Zhang and Burock, 2020;Bledsoe et al., 2018;Goldman et al., 2017) and others reporting CC sparing in PD (Worker et al., 2014;Rosskopf et al., 2014;Wen et al., 2016;Owens-Walton et al., 2022). Among the causes of inconsistency between study results there might be indeed the merging of data from both steady and unsteady PD patients, together with the use of a non-standardized region-of-interest approach (i.e., averaging DTI metrics over three, five or six distinct callosal subregions) which may have hidden subtle differences within a specific CC region or located across two adjacent CC subregions. ...
Introduction
Postural instability (PI) is a common disabling symptom in Parkinson’s disease (PD) patients, but the brain alterations underlying this sign are not fully understood yet. This study aimed to investigate the association between PI and callosal damage in PD and progressive supranuclear palsy (PSP) patients, using multimodal MR imaging.
Methods
One-hundred and two PD patients stratified according to the presence/absence of PI (PD-steady N=58; PD-unsteady N=44), 69 PSP patients, and 38 healthy controls (HC) underwent structural and diffusion 3T brain MRI. Thickness, fractional anisotropy (FA) and mean diffusivity (MD) were calculated over 50 equidistant points covering the whole midsagittal profile of the corpus callosum (CC) and compared among groups. Associations between imaging metrics and postural instability score were investigated using linear regression.
Results
Both PSP and PD-unsteady patient groups showed CC involvement in comparison with HC, while no difference was found between PD-steady patients and controls. The CC damage was more severe and widespread in PSP than in PD patients. The CC genu was the regions most damaged in PD-unsteady patients compared with PD-steady patients, showing significant microstructural alterations of MD and FA metrics. Linear regression analysis pointed at the MD in the CC genu as the main contributor to PI among the considered MRI metrics.
Conclusion
This study identified callosal microstructural alterations associated with PI in unsteady PD and PSP patients, which provide new insights on PI pathophysiology and might serve as imaging biomarkers for assessing postural instability progression and treatment response.
... With a comprehensive classification system that factored clinical, demographic, and symptomatic presentations to categorize patients into mild and moderate-severe groups, they found significant differences only between the moderate-severe group and the healthy controls. The CC volume in the mid-anterior and central regions were found to be reduced in PD patients on MRI as compared to healthy controls by Goldman et al. (101). Shape changes and volume loss in the putamen, and shape changes in the caudate were shown to distinguish between PD and healthy controls (102). ...
Introduction
Normal Pressure Hydrocephalus (NPH) is a prominent type of reversible dementia that may be treated with shunt surgery, and it is crucial to differentiate it from irreversible degeneration caused by its symptomatic mimics like Alzheimer’s Dementia (AD) and Parkinson’s Disease (PD). Similarly, it is important to distinguish between (normal pressure) hydrocephalus and irreversible atrophy/degeneration which are among the chronic effects of Traumatic Brain Injury (cTBI), as the former may be reversed through shunt placement. The purpose of this review is to elucidate the structural imaging markers which may be foundational to the development of accurate, noninvasive, and accessible solutions to this problem.
Methods
By searching the PubMed database for keywords related to NPH, AD, PD, and cTBI, we reviewed studies that examined the (1) distinct neuroanatomical markers of degeneration in NPH versus AD and PD, and atrophy versus hydrocephalus in cTBI and (2) computational methods for their (semi-) automatic assessment on Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans.
Results
Structural markers of NPH and those that can distinguish it from AD have been well studied, but only a few studies have explored its structural distinction between PD. The structural implications of cTBI over time have been studied. But neuroanatomical markers that can predict shunt response in patients with either symptomatic idiopathic NPH or post-traumatic hydrocephalus have not been reliably established. MRI-based markers dominate this field of investigation as compared to CT, which is also reflected in the disproportionate number of MRI-based computational methods for their automatic assessment.
Conclusion
Along with an up-to-date literature review on the structural neurodegeneration due to NPH versus AD/PD, and hydrocephalus versus atrophy in cTBI, this article sheds light on the potential of structural imaging markers as (differential) diagnostic aids for the timely recognition of patients with reversible (normal pressure) hydrocephalus, and opportunities to develop computational tools for their objective assessment.
... The latter point refers to evidence from studies in idiopathic Parkinson's disease. 43,44 However, in the context of Huntington's disease, significant atrophy in the basal ganglia 45-48 enables the two regions of interest (caudate and putamen) susceptible to a partial volume effect. This phenomenon can introduce a bias in the activity quantification of the PET images, 49,50 and considerably impact the validity of extracted DVRs. ...
Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington’s disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller–Gartner algorithm) were applied. Differences were sought in Unified Huntington’s Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.
... In both males and females treated with tri-combo after TBI, the lesion volume remained significantly lower (by ;40%) compared with the vehicle group even at 98 d after TBI (Fig. 5a,b). TBI is known to promote macrostructural volume loss in the CC in both rodents and humans that is linked to cognitive and motor function deficits (Jokinen et al., 2007;Wu et al., 2010;Frederiksen et al., 2011;Goldman et al., 2017;Leconte et al., 2020). The tri-combotreated male mice showed a significantly smaller reduction in EC area (;25%) and CC thickness (;11%) compared with the vehicle-treated group at 98 d after TBI (Fig. 5c). ...
The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species; ROS), tert-butylhydroquinone (promotes disposal of ROS), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes.SIGNIFICANCE STATEMENTOf the several mechanisms that contribute to TBI pathophysiology, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation play a major role. The present study shows the therapeutic potential of a combination of apocynin, tert-butylhydroquinone, and salubrinal to prevent oxidative stress and ER stress and the interrelated inflammatory response in mice subjected to TBI. The beneficial effects of the tri-combo include alleviation of TBI-induced motor and cognitive deficits and lesion volume. The neuroprotective effects of the tri-combo are also linked to its ability to prevent TBI-induced white matter damage. Importantly, neuroprotection by the tri-combo treatment was observed to be not dependent on sex or age. Our data demonstrate that a polypharmacological strategy is efficacious after TBI.
... In our study, splenium location was associated with worse results in episodic memory throughout the follow-up, in global efficiency at the end of treatment and in executive functions at the most recent follow-up (lexical fluency). Visual memory performance and verbal information retrieval have been associated with splenium integrity [32]. Memory disorders in patients with splenial PCNSL may be related to lesions into the posterior callosal fibers, which link the hippocampi, or to lesions into the fornix, the hippocampi, or the retrosplenial region [33]. ...
Introduction
The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSLs). In this cohort study, we described the neurocognition of patients with PCNSL-CC and its posttherapeutic evolution.
Methods
Immunocompetent patients with PCNSL-CC were identified retrospectively at the Pitié-Salpêtrière Hospital. We described their clinical presentation. Neuropsychological test scores (MMSE; digit spans; Free and Cued Selective Reminding Test; Image Oral Naming Test; Frontal Assessment Battery; Trail Making Test; Stroop and verbal fluency tests; Rey’s Complex Figure test) and factors impacting them were analyzed.
Results
Twenty-seven patients were included (median age: 67 years, median Karnofsky Performance Status: 70); cognitive impairment and balance disorders were present in 74% and 59%, respectively. At diagnosis, neuropsychological test results were abnormal for global cognitive efficiency (63% of patients), memory (33–80% depending on the test) and executive functions (44–100%). Results for visuospatial and language tests were normal. All patients received high-dose methotrexate-based polychemotherapy, followed in one patient by whole-brain radiotherapy; 67% of patients achieved complete response (CR). With a median follow-up of 48 months (range 6–156), patients in CR had persistent abnormal test results for global cognitive efficiency in 17%, executive function in 18–60%, depending on the test, and memory in 40–60%. Splenium location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up.
Conclusions
PCNSL-CC is associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR and warrant specific rehabilitation. Older age (≥ 60) and splenium location are associated with worse neurocognitive outcomes.
... Parkinson's disease patients were categorized into two groups, comprising the PD with normal cognition (PD-NC) and PD with cognitive impairment (PD-CI), on the basis of MDS Task Force criteria for mild cognitive impairment (PD-MCI) and Parkinson's disease dementia (PDD) and previously published studies (Goldman et al., 2017). In brief, the patients who met clinically established PD diagnosis, presented cognitive decline reported by either the patient, informant or clinician, and impairment on a scale of global cognitive abilities (i.e., the Montreal Cognitive Assessment [MoCA]) without impaired functional independence in daily life were classified as PD-MCI (Litvan et al., 2012); the patients who presented a dementia syndrome developing based on the established PD diagnosis, more than one cognitive domain impairment, functional deficits in daily life, typical cognitive features and behavioral symptoms were classified as PDD (Emre et al., 2007). ...
Objective
This study intended to investigate whether retinal nerve fiber layer (RNFL) thickness could become a potential marker in patients with Parkinson’s disease with cognitive impairment (PD-CI).
Methods
Fifty-seven PD patients and 45 age-matched healthy controls (HCs) were recruited in our cross-sectional study and completed optical coherence tomography (OCT) evaluations. PD with normal cognition (PD-NC) and cognitive impairment (PD-CI) patients were divided following the 2015 Movement Disorder Society criteria. RNFL thickness was quantified in subfields of the 3.0-mm circle surrounding the optic disk; while a battery of neuropsychiatric assessments was conducted to estimate the Parkinsonism severity. General linear models and one-way ANOVA were adopted to assess RNFL thickness between subgroups with different cognitive statuses; logistic regression analyses were applied to determine the relation between RNFL and PD-CI cases.
Results
Compared with HCs, more thinning of the RNFL was observed in the inferior and temporal sectors in PD patients, especially in the PD-CI group. Inferior RNFL thickness was reduced in PD-CI compared with PD-NC patients. Logistic regression analysis found that inferior RNFL thickness was independently associated with PD-CI cases (odds ratio = 0.923, p = 0.014). Receiver operating characteristic analysis showed that the RNFL-involved combined model provided a high accuracy in screening cognitive deficiency in PD cases (area under the curve = 0.85, p < 0.001).
Conclusion
Reduced RNFL thickness especially in the inferior sector is independently associated with PD-CI patients. Our study present new perspectives into verifying possible indicators for neuropathological processes or disease severity in Parkinsonians with cognitive dysfunction.
... FreeSurfer CC segmentation is precise, with an average coefficient of variation ranging from 1% to 4%, the Dice accuracy range has been observed between .79 and .84 for the cross-sectional and longitudinal streams, respectively. 27 The CC is a promising marker for several neurodegenerative diseases such as Alzheimer's disease, 30 Parkinson's disease, 31 amyotrophic lateral sclerosis, 32 and particularly MS. 33 Its significance in MS is intimately tied to the CC being a large white matter structure in a disease that predominantly affects myelin. Several studies have ...
Background and purpose:
Corpus callosum (CC) atrophy is predictive of future disability in multiple sclerosis (MS). However, current segmentation methods are either labor- or computationally intensive. We therefore developed an automated deep learning-based CC segmentation tool and hypothesized that its output would correlate with disability.
Methods:
A cohort of 631 MS patients (449 females, baseline age 41 ± 11 years) with both 3-dimensional T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI was used for the development. Data from 204 patients were manually segmented to train convolutional neural networks in extracting the midsagittal intracranial and CC areas. Remaining data were used to compare segmentations with FreeSurfer and benchmark the outputs with regard to clinical correlations. A 1.5 and 3 Tesla reproducibility cohort of 9 MS patients evaluated the segmentation robustness.
Results:
The deep learning-based tool was accurate in selecting the appropriate slice for segmentation (98% accuracy within 3 mm of the manual ground truth) and segmenting the CC (Dice coefficient .88-.91) and intracranial areas (.97-.98). The accuracy was lower with higher atrophy. Reproducibility was excellent (intraclass correlation coefficient > .90) for T1-weighted scans and moderate-good for FLAIR (.74-.75). Segmentations were associated with baseline and future (average follow-up time 6-7 years) Expanded Disability Status Scale (ρ = -.13 to -.24) and Symbol Digit Modalities Test (r = .18-.29) scores.
Conclusions:
We present a fully automatic deep learning-based CC segmentation tool optimized to modern imaging in MS with clinical correlations on par with computationally expensive alternatives.
... In PD, widespread white matter damage has been found to precede atrophy of gray matter regions (Hattori et al., 2012;Rae et al., 2012;Rektor et al., 2018), and this provides a potential neural basis for why the recognition of self-conscious emotions may be disrupted earlier. Bertoux et al. (2020) also identified a distinct role for the corpus callosum in the recognition of self-conscious emotion, and abnormalities in this brain region are known to contribute to other types of cognitive impairment in PD (Bledsoe, Stebbins, Merkitch, & Goldman, 2018;Goldman et al., 2017;Rektor et al., 2018). Future studies are now needed that incorporate brain imaging to directly test how behavioral changes in different types of emotion recognition map onto structural changes over time. ...
Objective:
Emotion recognition is a fundamental neurocognitive capacity that is a critical predictor of interpersonal function and, in turn, mental health. Although people with Parkinson's disease (PD) often exhibit difficulties recognizing emotions, almost all studies to date have focused on basic emotions (happiness, sadness, anger, surprise, fear, and disgust), with little consideration of how more cognitively complex self-conscious emotions such as contempt, embarrassment, and pride might also be affected. Further, the few studies that have considered self-conscious emotions have relied on high intensity, static stimuli. The aim of the present study was to therefore provide the first examination of how self-conscious emotion recognition is affected by PD using a dynamic, dual-intensity measure that more closely captures how emotion recognition judgements are made in daily life.
Method:
People with PD (n = 42) and neurotypical controls (n = 42) completed a validated measure of self-conscious facial emotion recognition. For comparative purposes, in addition to a broader clinical test battery, both groups also completed a traditional static emotion recognition measure and a measure of self-conscious emotional experience.
Results:
Relative to controls, the PD group did not differ in their capacity to recognize basic emotions but were impaired in their recognition of self-conscious emotions. These difficulties were associated with elevated negative affect and poorer subjective well-being.
Conclusions:
Difficulties recognizing self-conscious emotions may be more problematic for people with PD than difficulties recognizing basic ones, with implications for interventions focused on helping people with this disorder develop and maintain strong social networks.
Practitioner points:
This is the first direct investigation into how the recognition of self-conscious emotion is affected in Parkinson's disease using dynamic, dual-intensity stimuli, thus providing an important extension to prior literature that has focused solely on basic emotion recognition and/or relied on static, high-intensity stimuli. Results revealed preserved basic facial emotional recognition coexisting with impairment in all three self-conscious emotions assessed, therefore suggesting that the latter stimuli type may function as a more sensitive indicator of Parkinson's disease-related social cognitive impairment. Problems with self-conscious emotion recognition in people with Parkinson's disease were associated with poorer broader subjective well-being and increased negative affect. This aligns with the broader literature linking interpersonal difficulties with poorer clinical outcomes in this cohort.
... Moreover, it has been suggested that an intact corpus callosum is required for the presence of antiphase synchrony between homotopic regions (30). PD patients, however, often suffer from various degrees of corpus callosum atrophy (34), which might be a potential cause for the observed lack of antiphase synchrony in bilateral GPi of these patients. From a cellular perspective, high frequency bursts have been reported to be associated with gap junction structures, especially axonal complexes. ...
Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes on local and global scales. However, the characteristics of high frequency oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to investigate amplitude and interhemispheric coupling of bilateral GPi high gamma bursts in dystonia and Parkinson's Disease (PD) patients, in on and off medication states, after feedback during the Intra-Extra-Dimension shift (IED) task. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS electrodes during the IED task. Inter hemisphere phase synchrony was assessed using Inter-Site Phase Clustering (ISPC). Transient high gamma activity (~100-150Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPis with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient displayed enhanced low frequency clusters ameliorated by medication in the on-med state. Furthermore, an increased low frequency activity was observed after feedback of incorrect trials in both disease states. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD indicates the potential presence of impaired medication independent circuits related to feedback processing. Together, these findings are helpful in pointing to the potential role of GPi's synchronized high frequency activity in cognitive tasks and feedback information processing.
... Brain tissue was stored in Hibernate medium (Gibco) at 4 °C following processing, which happened within 24 h of autopsy (Extended Data Fig. 6). Microglia were isolated from the following regions, all of which have been linked to PD: [89][90][91][92] corpus callosum (13 samples), medial frontal gyrus (40 samples), superior temporal gyrus (30 samples), thalamus (23 samples), subventricular zone (18 samples) and SN (one sample). Microglia were isolated as previously described 93 , with minor modifications. ...
An increasing number of identified Parkinson’s disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesized that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we generated transcriptomic profiles of monocytes from healthy subjects and 230 individuals with sporadic PD. We observed dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, was altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
... Another study suggested that a significant reduction in the volume of the caudate, putamen, and thalamus contributes to cognitive dysfunction (141). Particularly, for the corpus callosum, patients with PD had greater volume reduction in the corpus callosum than healthy control subjects, while patients with PDD demonstrated further reduction in the callosal volume involving multiple subsections compared with patients with PD with normal cognition or MCI (149). ...
Parkinson disease is characterized by dopaminergic cell loss in the substantia nigra of the midbrain. There are various imaging markers for Parkinson disease. Recent advances in MRI have enabled elucidation of the underlying pathophysiologic changes in the nigral structure. This has contributed to accurate and early diagnosis and has improved disease progression monitoring. This article aims to review recent developments in nigral imaging for Parkinson disease and other parkinsonian syndromes, including nigrosome imaging, neuromelanin imaging, quantitative iron mapping, and diffusion-tensor imaging. In particular, this article examines nigrosome imaging using 7-T MRI and 3-T susceptibility-weighted imaging. Finally, this article discusses volumetry and its clinical importance related to symptom manifestation. This review will improve understanding of recent advancements in nigral imaging of Parkinson disease. Published under a CC BY 4.0 license.
... Additionally, such disconnectivity is a well-documented feature of SCZ [226,[230][231][232][233]307] and is also reported as a mediator of behavioral deficits in ADHD [229,232,237,238]. Demyelination, including loss of white matter in the corpus callosum (the largest white matter tract in brain) and interhemispheric disconnectivity, is also a shared feature of AD [308][309][310], PD [311][312][313][314], MS [315][316][317][318], and ALS [319][320][321]. ...
Increasing evidence links air pollution (AP) exposure to effects on the central nervous system structure and function. Particulate matter AP, especially the ultrafine (nanoparticle) components, can carry numerous metal and trace element contaminants that can reach the brain in utero and after birth. Excess brain exposure to either essential or non-essential elements can result in brain dyshomeostasis, which has been implicated in both neurodevelopmental disorders (NDDs; autism spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder) and neurodegenerative diseases (NDGDs; Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis). This review summarizes the current understanding of the extent to which the inhalational or intranasal instillation of metals reproduces in vivo the shared features of NDDs and NDGDs, including enlarged lateral ventricles, alterations in myelination, glutamatergic dysfunction, neuronal cell death, inflammation, microglial activation, oxidative stress, mitochondrial dysfunction, altered social behaviors, cognitive dysfunction, and impulsivity. Although evidence is limited to date, neuronal cell death, oxidative stress, and mitochondrial dysfunction are reproduced by numerous metals. Understanding the specific contribution of metals/trace elements to this neurotoxicity can guide the development of more realistic animal exposure models of human AP exposure and consequently lead to a more meaningful approach to mechanistic studies, potential intervention strategies, and regulatory requirements.
... Segmentation of the CC into 5 subsections with FreeSurfer in a healthy study participant. Figure design inspired byGoldman et al. (2017). ...
The specific role of the corpus callosum in language network organization is unclear, two contrasting models have been proposed: inhibition of homotopic areas allowing for independent functioning of the hemispheres versus integration of information from both hemispheres. The present study aimed to add to this discussion with the first investigation of language network connectivity in combination with corpus callosum volume measures. In 38 healthy children aged 6‐12, we performed task‐based functional magnetic resonance imaging to measure language network connectivity, used structural magnetic resonance imaging to quantify corpus callosum subsection volumes, and administered various language tests to examine language abilities. We found an increase of left intrahemispheric and bilateral language network connectivity and a decrease of right intrahemispheric connectivity associated with larger volumes of the posterior, mid‐posterior, and central subsections of the corpus callosum. Consistent with that, larger volumes of the posterior parts of the corpus callosum were significantly associated with better verbal fluency and vocabulary, the anterior corpus callosum volume was positively correlated with verbal span. Thus, children with larger volumes of CC subsections showed increased interhemispheric language network connectivity and were better in different language domains. The present study presents the first evidence that the corpus callosum is directly linked to language network connectivity and underlines the excitatory role of the corpus callosum in the integration of information from both hemispheres.
... We found statistically significant difference with higher FA in the PD group compared to the control group in and not yet reported in literature. As the disease progresses in PD, dementia, lewy body appearance and Alzheimer's disease come into play which in turn may cause FA value to reduce as the total volume of the corpus callosum will decrease [30,31]. This trend in corpus callosum has to be sensitively monitored while differentiating early and late PD cases. ...
Diffusion tensor imaging (DTI) appears as a sensitive method to study Parkinson’s disease (PD) pathophysiology and severity. Fractional anisotropy (FA) value is one of the scalar derivatives of DTI used to find out anisotropy within a voxel in a tissue and used for determining white matter integrity in aging and neurodegenerative diseases. We studied DTI derived FA in early PD subjects as their routine MRI scans were normal. 40 patients with early PD and 40 healthy controls were employed to evaluate changes in microstructural white and grey matter in the brain’s using DTI derived FA values. Comparison of FA values in the brain’s white and grey matter of patients with PD and age matched controls at the corpus callosum, centrum semiovale, pons, putamen, caudate nucleus, substantia nigra, cerebral peduncles and cerebellar peduncles, was done using a region of interest (ROI) technique, with b-value 1000s/mm2 and TE = 100 milliseconds using 1.5 T MRI system. PD patients showed differences in FA values in both the grey and white matter areas of the brain’s compared to healthy controls. Our study revealed the presence of damage in the substantia nigra, corpus callosum, putamen and cerebral peduncles mainly in the PD group. Our findings indicate that DTI and region of interest (ROI) methods can be used in patients with early PD to study microstructural alterations mainly in the substantia nigra, putamen and corpus callosum.
... Post-mortem studies have linked altered properties of the corpus callosum to normal ageing (Hou and Pakkenberg, 2012) as well as neurological disorders including schizophrenia (Woodruff et al., 1995), multiple sclerosis (Evangelou et al., 2000), Huntington's disease and progressive supranuclear palsy (Mann et al., 1993). Recent magnetic resonance imaging (MRI) studies have strengthened these conclusions with evidence of atrophy (Goldman et al., 2017;Granberg et al., 2015;Lee et al., 2016;Wang et al., 2015a), morphological changes (Ardekani et al., 2014;Pardoe et al., 2015;Wolff et al., 2015), and demyelination in the human corpus callosum (Decker et al., 2018;Køster et al., 2018) and mouse models (Xiu et al., 2015). Diffusion tensor magnetic resonance imaging (DT-MRI or DTI) has also been applied to study the corpus callosum. ...
Background
The corpus callosum is the largest white matter tract in the human brain, involved in inter-hemispheric transfer and integration of lateralised visual, sensory-motor, language, and cognitive information. Microstructural alterations are implicated in ageing as well as various neurological conditions.
New Method
Cross-sectional diffusion-weighted images of 107 healthy adults were used to create a linear regression model of the ageing corpus callosum and its sub-regions to evaluate the impact of analysis by sub-region, and to test for deviations from healthy ageing parameters in 28 subjects with mild cognitive impairment (MCI). Alterations in diffusion properties including fractional anisotropy, mean, radial and axial diffusivities were investigated as a function of age.
Results
Changes in DTI parameters showed age-dependent regional differences, likely arising from axonal diameter variation across cross-sectional regions of interest in the corpus callosum. Patterns suggestive of degeneration with healthy ageing were observed in all regions. Diffusion parameters in sub-regions projecting to pre-motor, primary, and supplementary motor areas of the brain differed for MCI versus healthy controls, and MCI subjects were more likely than healthy controls to experience a reduction in motor skills.
Comparison with Existing Methods
: Statistical analyses of the corpus callosum by five manually-defined sub-regions, instead of a single manually-defined region of interest, revealed region-specific changes in microstructure in healthy ageing and MCI, and accounted for clinically-evaluated differences in motor skills between cohorts.
Conclusion
: This method will support future studies of corpus callosum, enabling identification and measurement of white matter changes that are undetectable with the single ROI approach.
Background
Abnormal interhemispheric functional connectivity is frequently reported in Parkinson’s disease (PD), but its structural basis remains unclear. This study aimed to investigate changes in interhemispheric functional, structural, and callosal connectivity, as well as their interrelationships, in PD patients.
Methods
The study included 57 PD patients and 50 healthy controls (HCs). Interhemispheric functional connectivity was evaluated using voxel mirrored homotopic connectivity (VMHC) derived from resting-state functional MRI, while structural connectivity was measured through homotopic cortical thickness covariance from T1-weighted MRI. The corpus callosum (CC), connecting bilateral regions with VMHC differences, was assessed using fractional anisotropy (FA) from diffusion MRI. Pearson’s correlation was used to evaluate the interrelationships among imaging data and their clinical relevance.
Results
Compared to HCs, PD patients showed reduced VMHC and interhemispheric structural connectivity in similar brain regions, displaying a positive correlation trend between these measures. The affected regions encompassed the bilateral sensorimotor cortices (precentral gyrus, postcentral gyrus, and paracentral lobule) and posterior cortical areas, including the superior parietal lobule, supramarginal gyrus, precuneus, middle occipital gyrus, fusiform gyrus, as well as the superior and middle temporal gyri. FA in the CC, connecting regions with reduced VMHC, was also lower in PD patients. Additionally, interhemispheric structural, functional, and callosal connectivity reductions were, respectively, related to cognitive impairment, motor dysfunctions, and disease duration in PD.
Conclusion
The study identified convergent reductions in interhemispheric functional, structural and callosal connectivity in PD patients, emphasizing the strong link between structural and functional brain abnormalities. Our findings may provide new insights into the pathophysiology of PD.
Corpus callosum (CC) damage is the most consistent and typical change in early Parkinson’s disease (PD), and is associated with various PD symptoms. However, the precise relationship between CC subregions and specific PD symptoms have not been identified comprehensively. In this study, we investigated the association between specific CC subregion alterations and PD symptoms using diffusion-weighted imaging.
70 PD patients in early-stage from the Parkinson’s Progression Markers Initiative cohort were included. Fixel-based analysis (FBA) was used to calculate mean values of fiber density (FD), fiber cross-section (FC), and combined measure of FD and FC (FDC) for 7 CC subregions. Regression analyses between FBA metrics and PD symptom scores were performed to evaluate associations between CC subregion metrics and clinical symptom scores. Diffusion tensor imaging (DTI) metrics were also analyzed.
The score of akinetic rigid symptoms was negatively associated with FDC value of CC rostral body. The score of Activities of Daily Living was positively associated with FD value of CC anterior midbody. The score of gastrointestinal dysfunction was negatively associated with FDC value of CC rostrum. The severity of thermoregulatory dysfunction and cognitive decline was accompanied by an improvement in FBA metrics for several CC subregions. No significant associations were found using DTI metrics.
In early-stage of PD, motor, autonomic, and cognitive functions are associated with specific subregions of CC, and compensatory changes in CC may exist to maintain normal autonomic and cognitive functions.
Background: Dementia can be caused by numerous different diseases that present variable clinical courses and reveal multiple patterns of brain atrophy, making its accurate early diagnosis by conventional examinative means challenging. Although highly accurate and powerful, magnetic resonance imaging (MRI) currently plays only a supportive role in dementia diagnosis, largely due to the enormous volume and diversity of data it generates. AI-based software solutions/algorithms that can perform automated segmentation and volumetry analyses of MRI data are being increasingly used to address this issue. Numerous commercial and non-commercial software solutions for automated brain segmentation and volumetry exist, with FreeSurfer being the most frequently used. Objectives: This Review is an account of the current situation regarding the application of automated brain segmentation and volumetry to dementia diagnosis. Methods: We performed a PubMed search for "FreeSurfer AND Dementia" and obtained 493 results. Based on these search results, we conducted an in-depth source analysis to identify additional publications, software tools, and methods. Studies were analyzed for design, patient collective, and for statistical evaluation (mathematical methods, correlations). Results: In the studies identified, the main diseases and cohorts represented were Alzheimer's disease (n = 276), mild cognitive impairment (n = 157), frontotemporal dementia (n = 34), Parkinson's disease (n = 29), dementia with Lewy bodies (n = 20), and healthy controls (n = 356). The findings and methods of a selection of the studies identified were summarized and discussed. Conclusion: Our evaluation showed that, while a large number of studies and software solutions are available, many diseases are underrepresented in terms of their incidence. There is therefore plenty of scope for targeted research.
Background and purpose:
Parkinson disease is a prevalent disease, with olfactory dysfunction recognized as an early nonmotor manifestation. It is sometimes difficult to differentiate Parkinson disease from atypical parkinsonism using conventional MR imaging and motor symptoms. It is also known that olfactory loss occurs to a lesser extent or is absent in atypical parkinsonism. To the best of our knowledge, no study has examined olfactory bulb changes to differentiate Parkinson disease from atypical parkinsonism, even in an early diagnosis, and its association with conventional MR imaging findings. Hence, we aimed to assess the utility of olfactory bulb measurements in differentiating Parkinson disease from atypical parkinsonism even in the early stage.
Materials and methods:
In this retrospective study, we enrolled 108 patients with Parkinson disease, 13 with corticobasal syndrome, 15 with multiple system atrophy, and 17 with progressive supranuclear palsy who developed parkinsonism. Thirty-nine age-matched healthy subjects served as controls. All subjects underwent conventional MR imaging and 3D FIESTA for olfactory bulb measurements using manual ROI quantification of the cross-sectional olfactory bulb area using the coronal plane. Bilateral olfactory bulb measurements were averaged. For group comparisons, we used the Welch t test, and we assessed diagnostic accuracy using receiver operating characteristic analysis.
Results:
Patients with Parkinson disease had a mean olfactory bulb area of 4.2 (SD, 1.0 mm2), significantly smaller than in age-matched healthy subjects (6.6 [SD, 1.7 mm2], P < .001), and those with corticobasal syndrome (5.4 [SD, 1.2 mm2], P < .001), multiple system atrophy (6.5 [SD, 1.2 mm2], P < .001), and progressive supranuclear palsy (5.4 [SD, 1.2 mm2], P < .001). The receiver operating characteristic analysis for the olfactory bulb area measurements showed good diagnostic performance in differentiating Parkinson disease from atypical parkinsonism, with an area under the curve of 0.87, an optimal cutoff value of 5.1 mm2, and a false-positive rate of 18%. When we compared within 2 years of symptom onset, the olfactory bulb in Parkinson disease (4.2 [SD, 1.1 mm2]) remained significantly smaller than in atypical parkinsonism (versus corticobasal syndrome (6.1 [SD, 0.7 mm2]), P < .001; multiple system atrophy (6.3 [SD, 1.4 mm2]), P < .001; and progressive supranuclear palsy (5.2 [1.3 mm2], P = .003, respectively).
Conclusions:
3D FIESTA-based olfactory bulb measurement holds promise for distinguishing Parkinson disease from atypical parkinsonism, especially in the early stage.
Language dysfunction is common in Parkinson’s disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson’s Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.
Background
The laterality of motor symptoms is an important clinical feature of PD, which is not only manifested as the lateral dysfunctions of limbs but also affects the non-motor symptoms and the prognosis in PD patients. Former studies suggested that the compensatory mechanisms in the dominant hemisphere of brain may be an underlying explanation. The corpus callosum (CC) is the largest fiber connecting the two hemispheres of brain. Considering CC as the pointcut may help to explore the mechanism of the laterality of motor symptoms affecting the non-motor symptoms and prognosis in PD patients.
Purpose
To explore microstructural degeneration of CC in PD patients with unilateral motor symptoms onset based on the bi-tensor model of diffusion imaging technology, and further explore the relationship with motor and non-motor performance.
Methods
A total of 201 right-handed PD patients with unilateral motor symptoms onset were included in this study, including 91 patients with left-onset (LPD) and 110 with right-onset (RPD), as well as 100 right-handed healthy controls (HC). A bi-tensor model of diffusion tensor imaging (DTI) was applied to obtain free-water (FW), as well as fractional anisotropy (FAT) and mean diffusivity (MDT) after correcting free-water. CC was divided into halves by the median sagittal line, and each was further divided into five functional segments manually according to the specific template. A total of 10 subregions were obtained and numbered in sequence. The laterality index (LI) was calculated to quantify the asymmetry of CC and its segments. The general linear model was used for the comparisons among groups, and then partial correlation analysis was performed to explore the relationship between the diffusion parameters of CC subregions and clinical manifestations.
Results
Compared with HC, FW and FAT of CC in bilateral hemispheres were decreased in LPD group, while MDT in right hemisphere was increased. In LPD group, FAT of all CC subregions except for subregions 1, 3 and 6 were significantly lower than HC, and MDT in anterior and posterior segments of CC (CC subregions 1, 5, 6, 7 and 10) were significantly higher than HC. In RPD group, FAT of subregion 7 was significantly decreased and MDT was increased than HC. The LI analysis of CC reflected significant interhemispheric FAT asymmetry of the anterior and middle segments of CC in RPD group, with a more significant reduction in the right hemisphere of CC. Moreover, the degeneration in CC and its subregions was related to motor or non-motor symptoms in PD.
Conclusions
Extensive damage of CC was observed in LPD group than in RPD group, while asymmetrical damage was found in the anterior and middle segments of CC in RPD group, suggesting that differences in the patterns of callosal degeneration may be one of the potential mechanisms of asymmetrical motor symptoms affect the non-motor symptoms and prognosis in PD.
While previous research has demonstrated a link between the corpus callosum (CC) and theory of mind (ToM) abilities in individuals with corpus callosum agenesis (ACC), the relationship between CC volume and ToM remains unclear in healthy children. The present study examined whether CC volume influences children’s performance on ToM tasks that assess their understanding of pretense, emotion recognition, and false beliefs. Forty children aged 6–12 years underwent structural magnetic resonance imaging (MRI) and a cognitive test battery. We found that larger mid-anterior and central subsections of the CC significantly correlated with better ToM abilities. We could also demonstrate age- and sex-related effects, as the CC–ToM relationship differed between younger (6–8 years) and older (9–12 years) children, and between female and male participants. Importantly, the older children drove the association between the CC mid-anterior and central subsection volumes and ToM abilities. This study is the first to demonstrate that CC size is associated with ToM abilities in healthy children, underlining the idea that the CC plays a vital role in their socio-cognitive development. CC subsection volumes may thus not only serve as a measure of heterogeneity in neurodevelopmental populations known to exhibit socio-cognitive deficits, but also in typically developing children.
Background
Susac syndrome (SuS) is a rare autoimmune disorder mediated by the occlusion of micro-blood vessels in the brain, retina, and inner ear. Approximately 15% of cases present with the classic triad of CNS dysfunction, visual disturbances, and sensorineural hearing loss. While the literature is abundant about the severe, acute encephalopathy of SuS, not much is known about the extent of cognitive sequela in the post-era of efficient immunomodulatory treatment.
Methods
We report global cognitive function using a battery of cognitive tests in ten recovering SuS patients with an average of 2.9 (SD = 1.41) years post-disease onset.
Results
Patients showed intact delayed memory (both verbal and non-verbal) but below-average scores on tests of executive functions, and deficits in attention and copying. Results are discussed in light of the initial severity and extent of corpus callosum involvement on brain MRI.
Conclusions
study results suggest that the main cognitive sequela of SuS involves deficits in visual attention and executive functions possibly due to Corpus Callosum involvement. Additionally, this report supports a favorable prognosis for patients with SuS who receive a fast and efficacious immunomodulatory treatment protocol suggested in 2018.
Background:
The corpus callosum (CC) is the main structure transferring information between the cerebral hemispheres. Although previous large-scale genome-wide association study (GWAS) has illustrated the genetic architecture of white matter integrity of CC, CC volume is less stressed.
Methods:
Using MRI data from 33,861 individuals in UK Biobank, we conducted univariate and multivariate GWAS for CC fractional anisotropy (FA) and volume with PLINK 2.0 and MOSTest. All discovered SNPs in the multivariate framework were functionally annotated in FUMA v1.3.8. In the meanwhile, a series of gene property analyses was conducted simultaneously. In addition, we estimated genetic relationship between CC metrics and other neuropsychiatric traits and diseases.
Results:
We identified a total of 36 and 82 significant genomic loci for CC FA and volume (P < 5 × 10-8). And 53 and 27 genes were respectively mapped by four mapping strategies. For CC volume, gene-set analysis revealed pathways mainly relating to cell migration; cell-type analysis found the top enrichment in neuroglia while for CC FA in GABAergic neurons. Furthermore, we found a lot of genetic overlap and shared loci between CC FA and volume and common neuropsychiatric diseases.
Discussion:
Collectively, this study helps to better understand the genetic architecture of whole CC and CC subregions. However, the way to divide CC FA and volume in our study restricts the interpretations of our results. Future work will be needed to pay attention to the genetic structure of white matter volume, and an appropriate division of CC may help to better understand CC structure.
Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes. However, the characteristics of oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to compare oscillatory characteristics of GPi between dystonia and Parkinson's Disease (PD). A dystonia and a PD patient performed the Intra-Extra-Dimension shift (IED) task during both on and off-medication states. During the IED task, patients had to correctly choose between two visual stimuli containing shapes or lines based on a hidden rule via trial and error. Immediate auditory and visual feedback was provided upon the choice to inform participants if they chose correctly. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS leads. Transient high gamma activity (~ 100–150 Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPi with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient also displayed enhanced low frequency clusters, which were ameliorated by medication. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD patient indicates the potential presence of impaired medication independent feedback processing circuits. Together, these findings suggest a potential role for GPi’s synchronized activity in shaping feedback processing mechanisms required in cognitive tasks.
Parkinson hastalığı başta substantia nigra pars compacta, devamında globus pallidus, putamen ve nucleus caudatus'taki nöronların dejenerasyonuna bağlı dopamin salınımının azalması ya da tamamen ortadan kalkması ile karakterize hem motor hem de duysal bulguları olan nörodejeneratif bir hastalıktır. Parkinson hastalığı ile ilgili araştırmalar genellikle gri cevhere ait yapılar üzerinde yoğunlaşsa da motor bulgulardan çok daha önce ortaya çıkmaya başladığı bilinen duyusal bulguların sebebi olarak görülen beyaz cevher ile ilgili çalışmalar son yıllarda artmaktadır. Bu çalışmanın amacı Parkinson hastalığı'nda iki hemisferi birbirine bağlayan ve en büyük beyaz cevher yapısı olan corpus callosum'un etkilenimini yaş ve cinsiyet farklılıklarını da göz önüne alarak araştırmaktır. Çalışmamız, corpus callosum'u etkileyen herhangi bir tanı almamış 120 kontrol grubu midsagittal MR görüntüsü ile 120 Parkinson hastalığı tanısı almış midsagittal MR görüntüsü üzerinde retrospektif olarak corpus callosum'un uzunluk, genişlik ve açı değerleri ölçümleri karşılaştırılarak gerçekleştirilmiştir. Ölçüm sonuçlarına bakıldığında Parkinson hastalığı tanılı grupta corpus callosum yüksekliğinin, ön uç verteks arası mesafe ile ön-iç uç verteks arası mesafenin arttığı; genu ile rostrum genişliğinin ise azaldığı ve bu değişimlerin istatistiki olarak anlam ifade ettiği görülmüştür (p<0,05). Corpus callosum uzunluk ölçümlerinin cinsiyetler arasındaki karşılaştırmasına bakıldığında kadınlar ve erkekler arasında corpus callosum uzunluğu (p=0,001), yüksekliği (p=0,000), cerebrum uzunluğu (p=0,000), corpus callosum ön ucu ile verteks arası mesafe (p=0,001) ve corpus callosum ön-iç ucu ile verteks arası mesafe (p=0,002) ortalamaları arasında anlamlı bir fark bulunduğu, bu parametrelerin ortalamalarının erkeklerde kadınlardan daha yüksek olduğu gözlemlenmiştir. Corpus callosum uzunluk ve genişlik ölçümleri hem kontrol grubunda hem de Parkinson hastalığı tanılı grupta yaşla birlikte azalma eğilimi gösterirken özellikle corpus callosum genişliği, genu genişliği, splenium genişliği ve truncus en geniş kısmının genişliğinin ortalama değerlerindeki azalma istatistiki olarak da anlam ifade etmektedir (p<0,05). Parkinson hastalığı tanılı grupta bu azalmanın 81 yaş ve üzerinde daha belirgin hale geldiği görülmüştür. Parkinson hastalığı tanılı grupta corpus callosum genişliğinin yüksekliğine oranı da anlamlı düzeyde daha düşüktür (p=0,001). Açısal değerlerin analizine bakıldığında ise Parkinson hastalığı tanılı grupta açı 2, açı 4 ve açı 5 değerleri ortalamalarının anlamlı düzeyde arttığı bulunmuştur (p<0,05).
The previous chapter outlined the clinical evidence for FA in PD. In this chapter, we will discuss important imaging biomarker findings of FA in early PD with an emphasis on key findings in the Indian population. There is a lack of data for the Indian population on FA characteristics as imaging biomarkers in early PD.
Neuropsychiatric symptoms (NPSs) such as affective disorders, psychosis, behavioral changes, and cognitive impairment are common in Parkinson’s disease (PD). However, NPSs remain under-recognized and under-treated, often leading to adverse outcomes. Their epidemiology, presentation, risk factors, neural substrate, and management strategies are incompletely understood. While psychological and psychosocial factors may contribute, hallmark PD neuropathophysiological changes, plus the associations between exposure to dopaminergic medications and occurrence of some symptoms, suggest a neurobiological basis for many NPSs. A range of psychotropic medications, psychotherapeutic techniques, stimulation therapies, and other non-pharmacological treatments have been studied, are used clinically, and are beneficial for managing NPSs in PD. Appropriate management of NPSs is critical for comprehensive PD care, from recognizing their presentations and timing throughout the disease course, to the incorporation of different therapeutic strategies (ie, pharmacological and non-pharmacological) that utilize a multidisciplinary approach.
Background:
Cerebral amyloid angiopathy (CAA) often presents as cognitive impairment, but the mechanism of cognitive decline is unclear. Recent studies showed that number of microbleeds were associated with cognitive decline.
Objective:
We aimed to investigate how microbleeds contribute to cognitive impairment in association with white matter tract abnormalities or cortical thickness in CAA.
Methods:
This retrospective comparative study involved patients with probable CAA according to the Boston criteria (Aβ + CAA) and patients with Alzheimer's disease (Aβ + AD), all of whom showed severe amyloid deposition on amyloid PET. Using mediation analysis, we investigated how FA or cortical thickness mediates the correlation between the number of lobar microbleeds and cognition.
Results:
We analyzed 30 patients with Aβ + CAA (age 72.2±7.6, female 53.3%) and 30 patients with Aβ + AD (age 71.5±7.6, female 53.3%). The two groups showed similar degrees of cortical amyloid deposition in AD-related regions. The Aβ + CAA group had significantly lower FA values in the clusters of the posterior area than did the Aβ + AD group(family-wise error-corrected p < 0.05). The correlation between the number of lobar microbleeds and visuospatial function was indirectly mediated by white matter tract abnormality of right posterior thalamic radiation (PTR) and tapetum, while lobar microbleeds and language function was indirectly mediated by the abnormality of left PTR and sagittal stratum. Cortical thickness did not mediate the association between lobar microbleeds and cognition.
Conclusion:
This result supports the hypothesis that microbleeds burden leads to white matter tract damage and subsequent cognitive decline in CAA.
Mild cognitive changes, including executive dysfunction, are seen in Parkinson’s Disease (PD). Approximately 30% of individuals with PD develop Parkinson’s disease dementia (PDD). Mild cognitive impairment (MCI) has been identified as a transitional state between normal cognition and dementia. Although PD-MCI and its cognitive correlates have been increasingly studied as a risk indicator for development of PDD, investigations into the PD-MCI construct have yielded heterogeneous findings. Thus, a typical PD-MCI cognitive profile remains undefined. The present meta-analysis examined published cross-sectional studies of PD-MCI and cognitively normal PD (PD-CN) groups to provide aggregated effect sizes of group test performance by cognitive domain. Subsequently, longitudinal studies examining PD-MCI to PDD progression were meta-analyzed. Ninety-two cross-sectional articles of PD-MCI vs. PD-CN were included; 5 longitudinal studies of PD-MCI conversion to PDD were included. Random effects meta-analytic models were constructed resulting in effect sizes (Hedges’ g) for cognitive domains. Overall performance across all measures produced a large effect size (g = 0.83, 95% CI [0.79, 0.86], t2 = 0.18) in cross-sectional analyses, with cognitive screeners producing the largest effect (g = 1.09, 95% CI [1.00, 1.17], t2 = 0.19). Longitudinally, overall measures produced a moderate effect (g = 0.47, 95% CI [0.40, 0.53], t2 = 0.01), with measures of executive functioning exhibiting the largest effect (g = 0.70, 95% CI [0.51, 0.89], t2 = 0.01). Longitudinal effects were made more robust by low heterogeneity. This report provides the first comprehensive meta-analysis of PD-MCI cognitive outcomes and predictors in PD-MCI conversion to PDD. Limitations include heterogeneity of cross-sectional effect sizes and the potential impact of small-study effects. Areas for continued research include visuospatial skills and visual memory in PD-MCI and longitudinal examination of executive dysfunction in PD-MCI.
The corpus callosum is the main white matter tract between the two cerebral hemispheres and it connects both homolog and heterotopic regions in both hemispheres. The approximately 200 million axons are neatly organized from front to back with respect to which areas are connected. There are many causes for a dysfunctional corpus callosum, ranging from fetal development (agenesis) to dementia, and from stroke and head trauma to psychiatric conditions. Surgical removal of the corpus callosum for the alleviation of severe epilepsy has gained some notoriety as the “split-brain phenomenon”. Here, we summarize the different symptoms and/or syndromes that have been described in the literature. The nature of the functional impairments appears to be determined by which part(s) of the corpus callosum have been damaged, the type of damage, and the nature and localization of additional damage to the brain.
Bilingualism has been argued to have an impact on cognition and brain structure. Effects have been reported across the lifespan: from healthy children to ageing adults, including clinical (ageing) populations. It has been argued that active bilingualism may significantly contribute to the delaying of the expression of Alzheimer's disease symptoms. If bilingualism plays an ameliorative role against the expression of neurodegeneration in dementia, it is possible that it could have similar effects for other neurodegenerative disorders, including Multiple Sclerosis, Parkinson's and Huntington's Diseases. To date, however, direct relevant evidence remains limited, not least because the necessary scientific motivations for investigating this with greater depth have not yet been fully articulated. Herein, we provide a roadmap that reviews the relevant literatures, highlighting potential links across neurodegenerative disorders and bilingualism more generally.
Visual hallucinations are frequent, disabling complications of advanced Parkinson's disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson's disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson's disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson's disease hallucinators to Parkinson's disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson's disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (±3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole-brain voxel-based morphometry techniques. Clinically, the Parkinson's disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson's disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral 'what' and dorsal 'where' pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson's disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson's disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions.
Background:
Prognosis in Parkinson's disease (PD) remains poorly understood due to a lack of unbiased data on the natural history of treated PD. The CamPaIGN study has been the first to prospectively track disease evolution from diagnosis in an unselected population-representative incident cohort. We now report the 10-year follow-up data, focusing on three key irreversible milestones: postural instability (Hoehn and Yahr 3), dementia and death.
Methods:
The cohort was collected between December 2000 and 2002. Those meeting diagnostic criteria (n=142) were followed-up until 1 January 2012. Clinical, neuropsychological and genetic testing were performed. Progression to key milestones was evaluated using Kaplan-Meier and Cox regression survival analyses.
Results:
At 10 years, 55% had died, 68% had postural instability and 46% dementia. 23% had a good outcome at 10 years (surviving free of dementia/postural instability). Death rate was comparable with the UK population (standardised mortality ratio 1.29 (0.97-1.61)). Death certificates indicated PD was a substantial contributor in only 20%, with pneumonia being the commonest cause of death. Age, non-tremor-dominant motor phenotype and comorbidity predicted earlier postural instability. Baseline predictors of dementia were age, motor impairment, 'posterior-cortical' cognitive deficits and MAPT genotype.
Conclusions:
(1) outlook in PD is heterogeneous, with most dying or developing dementia or postural instability by 10 years from diagnosis, but a quarter still doing well, with preserved mobility and intact cognition; (2) death is not directly related to PD in the majority; (3) baseline clinical and genetic variables are predictive of outcome and may be helpful in selecting patients for clinical trials.
Background:
Daytime and nighttime sleep disturbances and cognitive impairment occur frequently in Parkinson's disease (PD), but little is known about the interdependence of these non-motor complications. Thus, we examined the relationships among excessive daytime sleepiness, nighttime sleep quality and cognitive impairment in PD, including severity and specific cognitive deficits.
Methods:
Ninety-three PD patients underwent clinical and neuropsychological evaluations including the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or dementia (PDD) using recently proposed Movement Disorder Society PD-MCI and PDD criteria. Relationships between the sleep and cognitive measures and PD cognitive groups were examined.
Results:
The PD cohort included PD-NC (n = 28), PD-MCI (n = 40), and PDD (n = 25) patients. ESS scores, as a measure of daytime sleepiness, were significantly worse (p = 0.005) in cognitively impaired PD patients, particularly PDD patients. ESS scores correlated significantly with Mini-Mental State Examination scores and also with cognitive domain scores for attention/working memory, executive function, memory, and visuospatial function. In contrast, PSQI scores, as a measure of nighttime sleep quality, neither differed among cognitive groups nor correlated with any cognitive measures.
Conclusions:
Daytime sleepiness in PD, but not nighttime sleep problems, is associated with cognitive impairment in PD, especially in the setting of dementia, and attention/working memory, executive function, memory, and visuospatial deficits. The presence of nighttime sleep problems is pervasive across the PD cognitive spectrum, from normal cognition to dementia, and is not independently associated with cognitive impairment or deficits in cognitive domains.
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine. © 2008 Movement Disorder Society
To identify the factors that determine quality of life (QoL) in patients with idiopathic Parkinson's disease in a population based sample. Quality of life (QoL) is increasingly recognised as a critical measure in health care as it incorporates the patients' own perspective of their health.
All patients with Parkinson's disease seen in a population based study on the prevalence of parkinsonism were asked to complete a disease-specific QoL questionnaire (PDQ-39) and the Beck depression inventory. A structured questionnaire interview and a complete neurological examination, including the Hoehn and Yahr scale, the Schwab and England disability scale, the motor part of the unified Parkinson's disease rating scale (UPDRS part III), and the mini mental state examination were performed by a neurologist on the same day.
The response rate was 78%. The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL. Although the UPDRS part III correlated significantly with QoL scores, it did not contribute substantially to predicting their variance once depression, disability, and postural instability had been taken into account. In addition, patients with akinetic rigid Parkinson's disease had worse QoL scores than those with tremor dominant disease, mainly due to impairment of axial features.
Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease. The improvement of these features should therefore become an important target in the treatment of the disease.
Atlas normalization, as commonly used by functional data analysis, provides an automated solution to the widely encountered problem of correcting for head size variation in regional and whole-brain morphometric analyses, so long as an age- and population-appropriate target atlas is used. In the present article, we develop and validate an atlas normalization procedure for head size correction using manual total intracranial volume (TIV) measurement as a reference. The target image used for atlas transformation consisted of a merged young and old-adult template specifically created for cross age-span normalization. Automated atlas transformation generated the Atlas Scaling Factor (ASF) defined as the volume-scaling factor required to match each individual to the atlas target. Because atlas normalization equates head size, the ASF should be proportional to TIV. A validation analysis was performed on 147 subjects to evaluate ASF as a proxy for manual TIV measurement. In addition, 19 subjects were imaged on multiple days to assess test-retest reliability. Results indicated that the ASF was (1) equivalent to manual TIV normalization (r = 0.93), (2) reliable across multiple imaging sessions (r = 1.00; mean absolute percentage of difference = 0.51%), (3) able to connect between-gender head size differences, and (4) minimally biased in demented older adults with marked atrophy. Hippocampal volume differences between nondemented (n = 49) and demented (n = 50) older adults (measured manually) were equivalent whether corrected using manual TIV or automated ASF (effect sizes of 1.29 and 1.46, respectively). To provide normative values, ASF was used to automatically derive estimated TIV (eTIV) in 335 subjects aged 15-96 including both clinically characterized nondemented (n = 77) and demented (n = 90) older adults. Differences in eTIV between nondemented and demented groups were negligible, thus failing to support the hypothesis that large premorbid brain size moderates Alzheimer's disease. Gender was the only robust factor that influenced eTIV. Men showed an approximately approximately 12% larger eTIV than women. These results demonstrate that atlas normalization using appropriate template images provides a robust, automated method for head size correction that is equivalent to manual TIV correction in studies of aging and dementia. Thus, atlas normalization provides a common framework for both morphometric and functional data analysis.
Several tracing studies have established a topographical distribution of fiber connections to the cortex in midsagittal cross-sections of the corpus callosum (CC). The most prominent example is Witelson's scheme, which defines five vertical partitions mainly based on primate data. Conventional MRI of the human CC does not reveal morphologically discernable structures, although microscopy techniques identified myelinated axons with a relatively small diameter in the anterior and posterior third of the CC as opposed to thick fibers in the midbody and posterior splenium. Here, we applied diffusion tensor imaging (DTI) in conjunction with a tract-tracing algorithm to gain cortical connectivity information of the CC in individual subjects. With DTI-based tractography, we distinguished five vertical segments of the CC, containing fibers projecting into prefrontal, premotor (and supplementary motor), primary motor, and primary sensory areas as well as into parietal, temporal, and occipital cortical areas. Striking differences to Witelson's classification were recognized in the midbody and anterior third of the CC. In particular, callosal motor fiber bundles were found to cross the CC in a much more posterior location than previously indicated. Differences in water mobility were found to be in qualitative agreement with differences in the microstructure of transcallosal fibers yielding the highest anisotropy in posterior regions of the CC. The lowest anisotropy was observed in compartments assigned to motor and sensory cortical areas. In conclusion, DTI-based fiber tractography of healthy human subjects suggests a modification of the widely accepted Witelson scheme and a new classification of vertical CC partitions.
Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions.
To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH).
In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors.
Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing--namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion.
Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.
Understanding the interactions among different brain regions is fundamental to our understanding of brain function. Here we describe a complete map of functional connections in the human brain derived by an automatic meta-analysis of 825 neuroimaging articles, representing 3402 experiments. The likelihood of a functional connection between regions was estimated by studying the interdependence of their "activity," as reported in each experiment, across all experiments. We obtained a dense coactivation map that recovers some fundamental principles of the brain's functional connectivity, such as the symmetric interhemispheric connections, and important functional networks, such as the fronto-parietal attention network, the resting state network and the motor network.
Background
The optimal properties of a comprehensive (level II) neuropsychological battery for determining Parkinson's disease mild cognitive impairment (PD-MCI) by Movement Disorder Society (MDS) Task Force criteria remain unresolved.Methods
Seventy-six nondemented PD patients underwent PD-MCI classification using a consensus diagnosis and level II criteria. We examined the optimal number of tests in each of the five designated cognitive domains, identified the best tests within each domain, and determined the best overall battery for PD-MCI level II diagnosis.ResultsA battery with two tests per domain provided a highly practical, robust diagnostic assessment. Level II testing with the two best tests and impairment defined as 2 standard deviations below norms was highly sensitive and specific for PD-MCI diagnosis.Conclusions
Our findings strongly support the MDS Task Force Level II testing recommendations, provide a framework for creating an optimal, efficient neuropsychological test battery for PD-MCI diagnosis, and offer specific test recommendations. © 2014 International Parkinson and Movement Disorder Society
Objective:
Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes.
Methods:
High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model.
Results:
There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal-dominant atrophy subtype (n = 52, ∼ 34.2%), (2) parietal-dominant subtype (n = 28, ∼ 18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼ 47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features.
Conclusions:
This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.
The recently proposed Movement Disorder Society (MDS) Task Force diagnostic criteria for mild cognitive impairment in Parkinson's disease (PD-MCI) represent a first step toward a uniform definition of PD-MCI across multiple clinical and research settings. However, several questions regarding specific criteria remain unanswered, including optimal cutoff scores by which to define impairment on neuropsychological tests. Seventy-six non-demented PD patients underwent comprehensive neuropsychological assessment and were classified as PD-MCI or PD with normal cognition (PD-NC). The concordance of PD-MCI diagnosis by MDS Task Force Level II criteria (comprehensive assessment), using a range of standard deviation (SD) cutoff scores, was compared with our consensus diagnosis of PD-MCI or PD-NC. Sensitivity, specificity, and positive and negative predictive values were examined for each cutoff score. PD-MCI subtype classification and distribution of cognitive domains impaired were evaluated. Concordance for PD-MCI diagnosis was greatest for defining impairment on neuropsychological tests using a 2 SD cutoff score below appropriate norms. This cutoff also provided the best discriminatory properties for separating PD-MCI from PD-NC compared with other cutoff scores. With the MDS PD-MCI criteria, multiple domain impairment was more frequent than single domain impairment, with predominant executive function, memory, and visuospatial function deficits. Application of the MDS Task Force PD-MCI Level II diagnostic criteria demonstrates good sensitivity and specificity at a 2 SD cutoff score. The predominance of multiple domain impairment in PD-MCI with the Level II criteria suggests not only influences of testing abnormality requirements, but also the widespread nature of cognitive deficits within PD-MCI. © 2013 Movement Disorder Society.
The overarching objective of the thesis was to investigate the morphological changes in the corpus callosum (CC) in aging and dementia in relation to its role in cognitive and motor decline. The CC is the largest white matter tract in the brain, containing upwards of 200 million axons, and is believed important for communication and interaction between the two cerebral hemispheres. Historically, the role of white matter, including the CC, in relation to cognitive function has often been eclipsed by the predominance of the cortex, and led to a "corticocentric" view of the brain and cognitive function. However, from the 1960s and onwards, the role of lesions in the white matter in the appearence of cognitive deficits and diseases such as dementia has become increasingly evident. Many studies have indicated that AD is associated with CC atrophy, but the precise pattern of subregional CC atrophy in different disease stages remains undetermined. In study I, we establish that atrophy is present primarily in the posterior CC early in AD, and that atrophy of the CC is associated with faster disease progression. This finding supports a model where posterior atrophy is the earliest changes in the CC in AD patients, with atrophy of anterior CC being a later pathological event. To further elucidate the role of CC atrophy in dementia, we examined a population of 329 elderly subjects, and found that a higher rate of tissue loss in posterior CC is associated with an increased risk of dementia. This study represents the first to examine CC in elderly subjects longitudinally. In the same cohort, we investigated whether impairment in specific cognitive domains was associated with CC tissue loss. Previous studies had shown that processing speed and executive functions may be particularly reliant on the CC. Our findings indicated that CC tissue loss leads to selective impairment of processing speed but not memory or executive function deficits. Finally, CC tissue loss was also associated with impairment of motor function. Overall, the present findings confirm and extend the role of the CC in dementia and age-associated cognitive and motor deficits.
We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.
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. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
Objectives:
To characterize different stages of Parkinson disease (PD)-related cognitive decline using diffusion tensor imaging (DTI) and investigate potential relationships between cognition and microstructural integrity of primary white matter tracts.
Methods:
Movement Disorder Society criteria were used to classify 109 patients with PD as having normal cognition (PD-N, n = 63), mild cognitive impairment (PD-MCI, n = 28), or dementia (PD-D, n = 18), and were compared with 32 matched controls. DTI indices were assessed across groups using tract-based spatial statistics, and multiple regression was used to assess association with cognitive and clinical measures.
Results:
Relative to controls, PD-N showed some increased mean diffusivity (MD) in corpus callosum, but no significantly decreased fractional anisotropy (FA). Decreased FA and increased MD were identified in PD-MCI and PD-D relative to controls. Only small areas of difference were observed in PD-MCI and PD-D compared with PD-N, while DTI metrics did not differ significantly between PD-MCI and PD-D. Executive function, attention, memory, and a composite measure of global cognition were associated with MD, primarily in anterior white matter tracts; only attention was associated with FA. These differences were independent of white matter hyperintensity load, which was also associated with cognition in PD.
Conclusions:
PD is associated with spatially restricted loss of microstructural white matter integrity in patients with relatively normal cognition, and these alterations increase with cognitive dysfunction. Functional impairment in executive function, attention, and learning and memory appears associated with microstructural changes, suggesting that tract-based spatial statistics provides an early marker for clinically relevant cognitive impairment in PD.
Dementia is a frequent and disabling complication of Parkinson's disease (PD). Clinicians and researchers lack a biomarker capable of tracking the structural and functional changes that underlie the evolution of cognitive dysfunction in PD. Magnetic resonance imaging (MRI) has been adopted as a biomarker in natural history and interventional studies of Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), but its utility as a biomarker for PD and Parkinson's disease dementia (PDD) is unclear. In this review, the authors summarize the studies that have used MRI to investigate cognitive decline in PD, outline limitations of those studies, and suggest directions for future research. PD dementia is associated with extensive cortical atrophy, which may be quantified with structural MRI. More promisingly, patterns of atrophy may be present in those who have PD with MCI (PD-MCI). Subcortical white matter tract degeneration is detectable early in the disease with diffusion tensor imaging and may precede changes observed on conventional structural MRI. Although less well studied, other MR techniques, such as functional MRI, MR perfusion imaging with arterial spin labeling, and MR spectroscopy, have demonstrated differences in activation and metabolism between PD and PDD. In this review, the ability to compare studies was limited by the heterogeneity of study populations, cognitive testing methods, and imaging protocols. Future work should adopt agreed scan protocols, should be adequately powered, and should use carefully phenotyped patients to fully maximize the contribution of MRI as a biomarker for PDD. © 2013 Movement Disorder Society.
Voxel-based morphometry (VBM) studies have provided cumulative evidence of gray matter (GM) atrophy in patients with Parkinson's disease with dementia (PDD) relative to healthy controls (HC). However, not all the studies reported entirely consistent findings. A systematic search for VBM studies of PDD patients and HC subjects published in PubMed and Embase databases from January 2000 to June 2012 was conducted. Meta-analysis was performed by using a newly improved voxel-based meta-analytic technique, effect size signed differential mapping, to quantitatively explore the GM abnormalities between PDD patients and HC subjects. A total of 6 cross-sectional VBM studies involving 105 PDD patients and 131 HC subjects met the inclusion criteria. Considerable regional GM decrease was detected in the medial temporal lobe (MTL) and basal ganglia. The findings of the present study remained largely unchanged in the entire brain jackknife sensitivity analyses. Meta-regression showed dementia severity correlated with the left MTL. The present meta-analysis provided evidence of PDD-related GM atrophy, which suggested MTL and basal ganglia were implicated in PDD. This finding could give us further insight about the pathophysiological basis revealed by structure abnormalities in PDD.
Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed. © 2007 Movement Disorder Society
Cross-sectional studies have suggested that corpus callosum (CC) atrophy is related to impairment in global cognitive function, mental speed, and executive functions in the elderly. Longitudinal studies confirming these findings have been lacking. We investigated whether CC tissue loss is associated with change in cognitive performance over time in subjects with age-related white matter lesions (WML). Two-hundred-fifty-three subjects, aged 65-84 years, were evaluated by using repeated MRI and neuropsychological evaluation at baseline and after 3 years. The effect of overall and regional CC tissue loss on cognitive decline was analyzed with hierarchical linear regression models. After controlling for age, sex, education, and baseline cognitive performance, the rates of tissue loss in the total CC area, and in rostrum/genu and midbody subregions were significantly associated with decline in a compound measure of cognitive speed and motor control, but not in those of executive functions, memory, or global cognitive function. Total CC area and midbody remained significant predictors of speed also after adjusting for baseline WML volume, WML progression, and global brain atrophy. However, the relationship between anterior CC and speed performance was mediated by WML volume. In conclusion, the overall and regional rate of CC tissue loss parallels longitudinal slowing of psychomotor performance. The adverse effect of CC tissue loss on psychomotor function may be driven by altered interhemispheric information transfer between homologous cortical areas.
Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
Histological studies on nonhuman primates have shown a rich topography of homotopic (i.e., going to the same regions) or heterotopic (i.e., going to different regions) callosal projections. Unfortunately, a complete within-subject mapping of commissural projections in humans has been limited due to the inability of typical imaging methods to detect lateral projections in posterior cortical regions. Here, we set out to map callosal projection connectivity, at the single subject level (N=6), by combining high angular resolution diffusion weighted imaging and a novel multi-stage, region-of-interest (ROI) based fiber tracking approach. With these methods we were able to obtain a consistent increase in coverage of lateral projections to posterior cortical regions. Using 70 automatically segmented ROIs in each hemisphere and permutation statistics, we characterized significant interhemispheric connectivity patterns within each subject and observed: (1) consistent projections to frontal, parietal and occipital, but not temporal, areas, (2) a greater relative proportion of homotopic than heterotopic connections, and (3) commissural projections to the basal ganglia and thalamus that are consistent with human and nonhuman primate neuroanatomical literature. These results illustrate the first full connectivity analysis of the human corpus callosum, revealing several patterns consistent with histological findings in the nonhuman primate.
The interhemispheric connections of the cortical areas of the human brain are distributed within the corpus callosum according to a topographic order which is being studied in detail by novel imaging techniques. Total section of the corpus callosum is followed by a variety of interhemispheric disconnection symptoms each of which can be attributed to the interruption of fibers in a specific callosal sector. Disconnection symptoms deriving from posterior callosal sections, disconnecting parietal, temporal and occipital lobes across the midline, are more apparent than those following anterior callosal sections disconnecting the frontal lobes. In spite of the massive bulk of the frontal callosal connections in man, ascertained consequences of their interruption are limited to disorders of motor control, with particular regard to bimanual coordination. Technical advances in brain imaging and the design of appropriate tests are expected to reveal so far undetected deficits in the domain of executive and higher cognitive functions, resulting from callosal disconnection of the prefrontal cortices.