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Claustral structural connectivity and cognitive impairment in drug naïve Parkinson’s disease

DOI:10.1007/s11682-018-9907-z
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Alessandro Arrigo at Università Vita-Salute San Raffaele
Alessandro Arrigo
Alessandro Calamuneri at Centro Neurolesi Bonino Pulejo, Messina
Alessandro Calamuneri
Demetrio Milardi
Demetrio Milardi
Demetrio Milardi
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Enricomaria Mormina at Università degli Studi di Messina
Enricomaria Mormina
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Abstract and Figures

The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between claustrum and Parkinson’s Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI, claustral structural network changes in drug naïve PD patients, with the goal to understand whether such changes may contribute to cognitive decline in PD. 15 drug naïve PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model. Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation between MoCA and density of pathways connecting ipsilaterally claustrum to left (r = 0.578, p = 0.021) and right (r = 0.640, p = 0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naïve PD patients.
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ORIGINAL RESEARCH
Claustral structural connectivity and cognitive impairment in drug naïve
Parkinson’s disease
Alessandro Arrigo
1
&Alessandro Calamuneri
2,3
&Demetrio Milardi
2,4
&Enricomaria Mormina
3,4
&Michele Gaeta
4
&
Francesco Corallo
2
&Viviana Lo Buono
2
&Gaetana Chillemi
2
&Silvia Marino
2
&Alberto Cacciola
2,4
&
Giuseppe Di Lorenzo
2
&Giuseppina Rizzo
4
&Giuseppe Pio Anastasi
4
&Angelo Quartarone
2,4,5,6
Published online: 18 June 2018
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between
claustrum and Parkinson’s Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-
synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI,
claustral structural network changes in drug naïve PD patients, with the goal to understand whether such changes may contribute to
cognitive decline in PD. 15 drug naïve PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T
scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model.
Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired
subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared
to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation
between MoCA and density of pathways connecting ipsilaterally claustrum to left (r=0.578,p= 0.021) and right (r=0.640,p=
0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naïve PD patients.
Keywords Claustrum .Connectivity .Diffusion MRI .Parkinson’s disease .Cognitive assessment; Tractography
Introduction
The histopathological hallmark of both Parkinson’s disease
(PD) and Lewy Body Dementia (LBD) is the presence of
alpha-synuclein (alpha-Syn) positive intraneuronal inclusions
known as Lewy bodies and Lewy neurites. Although their
presence in the substantia nigra is pathognomonic for PD,
alpha-Syn pathological lesions have been reported in several
extranigral regions as well. In a very elegant study Kalaitzakis
and associates have evaluated the alpha-Syn, tau and
amyloid-βeta (Aβ) pathologies in claustrum of 20 PD cases
without dementia, 12 PD cases with dementia (PDD) and 7
cases with dementia with LBD (Kalaitzakis et al. 2009). An
alpha-Syn positivity has been observed in 75% of PD cases
without dementia and in 100% of PDD and LBD cases. On the
other hand, Aβpathology has been observed in claustrum in
25% of PD, 58% of PDD and 100% of LBD cases. The au-
thors concluded that pathology in the claustrum was strongly
related to the presence of dementia in PD and LBD.
Claustrum is a thin layer of subcortical gray matter (GM)
placed in the deep part of both the cerebral lobes.
Alessandro Arrigo and Alessandro Calamuneri PhD equally contributed
to the present work and are considered co-first authors.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11682-018-9907-z) contains supplementary
material, which is available to authorized users.
*Alessandro Calamuneri
alecalamuneri@gmail.com
1
Department of Ophthalmology, IRCCS Ospedale San Raffaele,
University Vita-Salute San Raffaele, Milan, Italy
2
IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113 –Contrada
Casazza, 98124 Messina, Italy
3
Department of Clinical and Experimental Medicine, University of
Messina, Messina, Italy
4
Department of Biomedical Sciences and Morphological and
Functional Images, University of Messina, Messina, Italy
5
NYU-Langone School of Medicine, New York, NY, USA
6
The Fresco Institute for Parkinson’s & Movement Disorders, New
York, NY, USA
Brain Imaging and Behavior (2019) 13:933–944
https://doi.org/10.1007/s11682-018-9907-z
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... In patients with Parkinson's disease, there is a decrease in claustral connectivity with cortical regions involved in visual-motor and auditory processing. There is a decrease in the density of connections with the parietal, upper temporal and postcentral cortical regions as well as the middle temporal gyrus, pars opercularis, pars triangularis, and pars orbitalis of the frontal gyrus [75]. Functional and anatomical disorders in claustrum are therefore associated with progressive dementia in Parkinson's disease [75]. ...
... There is a decrease in the density of connections with the parietal, upper temporal and postcentral cortical regions as well as the middle temporal gyrus, pars opercularis, pars triangularis, and pars orbitalis of the frontal gyrus [75]. Functional and anatomical disorders in claustrum are therefore associated with progressive dementia in Parkinson's disease [75]. Atrophic lesions in the claustrum may be a manifestation of pathophysiological changes in patients with Parkinson's disease [76,77]. ...
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... This is in line with the enrichments we found regarding addiction and depression (bipolar) gene sets in the IC and claustrum, as well as dopamine activity in the IC. Although we did not observe any gene sets indicating an association with Parkinson's disease and schizophrenia, studies have implicated the IC and claustrum in these diseases (Kalaitzakis et al., 2009;Cascella et al., 2011;Chen et al., 2016;Criaud et al., 2016;Arrigo et al., 2018;Joutsa et al., 2018). ...
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... During the last decades, the progress of magnetic resonance imaging (MRI) has allowed the development of neuroimaging approaches as an alternative modality to assess morphological neuronal connectivity patterns in living humans. Diffusion-weighted magnetic resonance imaging (DWI) and tractography have been successfully employed to model and infer white matter bundles' trajectory of white matter bundles together with their microstructural properties ( Milardi et al., 2016bMilardi et al., , 2017Cacciola et al., 2017a,c;Calamuneri et al., 2018;Rizzo et al., 2018;Arrigo et al., 2019). Despite these techniques have lower spatial resolution than chemical and virus tract-tracing and they are not able to estimate the directionality of neural pathways, they do provide the only chance to explore anatomical connectivity in vivo and non-invasively in the human brain (Chung et al., 2011). ...
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... Along with its inability to detect signal directionality and presence of synapses 81,82 , and a recent paper underlined that tractographic reconstruction is prone to high rates of false positive tracts, when compared to ground truth tracts obtained from a simulated human brain dataset 83 . Despite its intrinsic limitations, tractography remains the only way to study structural connectivity in humans in vivo [84][85][86][87][88][89][90][91][92][93][94][95][96][97] . Moreover, it should be considered that the present study is based on a consolidated anatomical foundation and globally replicates what has already been found out in other species. ...
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... Based on our recent studies, we propose that the CLA plays a role in SN-related neuropsychiatric disorders (Kalaitzakis et al., 2009;Cascella et al., 2011;Smith and Alloway, 2014;Wegiel et al., 2014;Patru and Reser, 2015;Bernstein et al., 2016;Smith et al., 2017). A recent fMRI study of Parkinson's disease patients has found significant decreases in the functional connectivity of the CLA compared to age-matched control patients, especially ''with areas mainly involved in visuomotor and attentional systems'' (Arrigo et al., 2018). Due to their similar anatomical and functional connections with Cg cortex and the BLA, both the insula and CLA could play a role in regulating levels of vigilance through the SN, which underlie a host of affective disorders. ...
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... On the other hand, diffusion-weighted imaging (DWI) and tractography represent powerful tools to trace structural connections non-invasively and in vivo (Cacciola et al. 2016(Cacciola et al. , 2017a(Cacciola et al. , c, d, 2018(Cacciola et al. , 2019Milardi et al. 2016aMilardi et al. , b, 2017Arrigo et al. 2018;Calamuneri et al. 2018), by estimating diffusion properties of magnetically labeled water molecules along myelinated axons (Basser et al. 1994;Henderson 2012). Several tractography studies explored the structural connectivity of PAG in humans (Sillery et al. 2005;Hadjipavlou et al. 2006;Owen et al. 2007Owen et al. , 2008Ezra et al. 2015), though only a few characterized either direct or indirect pathways between the PAG and cerebellum (Sillery et al. 2005;Hadjipavlou et al. 2006;Owen et al. 2008). ...
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Article
  • Sep 1981
The cat's dorsocaudal claustrum was studied in Golgi preparations, by electron microscopy, and by anterograde and retrograde tracer techniques. It receives a convergent retinotopic projection from several visual cortical ares, including areas 17, 18, 19, 21a and PMLS (posteromedial lateral suprasylvian area). The projection arises from spiny dendrite cells (pyramidal and fusiform) in the middle of cortical layer VI. As shown by a double label experiment, they form a separate population from those projecting to the lateral geniculate nucleus. There are also inputs from the lateral hypothalamus, from the nucleus centralis thalami, and probably from the locus coeruleus, but not from the sensory nuclei of the thalamus. Non-visual cortical areas do not project to the visual claustrum, but many of them are connected to other parts of the nucleus. For example, the splenial (cingulate) gyrus projects to a claustral zone just ventral to the visual area, and regions anterior to the visual area are connected with somatosensory and auditory cortex. The commonest cell type in the claustrum is a large spiny dendrite neuron whose axon leaves the nucleus after giving off local collaterals. Small spine-free cells, with beaded dendrites and a locally arborizing axon, are found also. Electron microscopy of the claustrum after ablation of the visual cortex showed degenerating type 1 axon terminals synapsing on spines and beaded dendrites, suggesting a direct cortical input to both cell types. The visual claustrum projects back to the visual cortex, to the same areas from which it receives an input. The return projection is predominantly ipsilateral, but there is, in addition, a small crossed projection. The claustrocortical axons terminate in all cortical layers but most heavily in layers IV and VI. The majority of the cells in the visual claustrum project to the cortex, and retinotopy is maintained throughout the entire corticoclaustral loop. No subcortical projections from the claustrum could be identified.
“Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician
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Mini-mental state-practical method for grading cognitive state of patients for clinicians
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Members of the UPDRS Development Committee Unified Parkinson's Disease Rating Scale, in Recent developments in Parkinson's disease
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  • Jan 1987