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BACKGROUND: Though mediotemporal lobe volume changes are well-known features of Alzheimer's disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN).OBJECTIVE: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club.METHODS: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n = 37; mild cognitive impairment, n = 41; Alzheimer-type dementia, n = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression.RESULTS: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume.CONCLUSION: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy.

The vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF).We assessed microvascular, parenchymal integrity, and a proxy of ISF volume alterations with intravoxel incoherent motion imaging in 21 healthy controls and 53 memory clinic patients - mainly affected by neurodegeneration (mild cognitive impairment, Alzheimer's disease dementia), vascular pathology (vascular cognitive impairment), and presumed to be without significant pathology (subjective cognitive decline).The microstructural components were quantified with spectral analysis using a non-negative least squares method. Linear regression was employed to investigate associations of these components with hippocampal and white matter hyperintensity (WMH) volumes. In the normal appearing white matter, a large f(int )(a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large f(int) value was associated with a lower hippocampal volume in the hippocampi.Large ISF volume (f(int)) was shown to be a prominent factor associated with both WMHs and neurodegenerative abnormalities in memory clinic patients and is argued to play a potential role in impaired glymphatic functioning. (C) 2021 The Author(s). Published by Elsevier Inc.

Blood–brain barrier (BBB) dysfunction is one of the pathophysiological mechanisms in cerebral small vessel disease (SVD). Previously, it was shown that BBB leakage volume is larger in patients with SVD compared with controls. In this study, we investigated the link between BBB leakage and cognitive decline over 2 years in patients with cSVD. At baseline, 51 patients with clinically overt cSVD (lacunar stroke or mild vascular cognitive impairment) received a dynamic contrast-enhanced MRI scan to quantify BBB permeability in the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical grey matter (CGM), and deep grey matter (DGM). Cognitive function in the domain executive function, information processing speed, and memory was measured in all patients at baseline and after 2 years. The association between baseline BBB leakage and cognitive decline over 2 years was determined with multivariable linear regression analysis, corrected for age, sex, educational level, baseline WMH volume, and baseline brain volume. Regression analyses showed that higher baseline leakage volume and rate in the NAWM and CGM were significantly associated with increased overall cognitive decline. Furthermore, higher baseline leakage volume in the NAWM and CGM, and higher baseline leakage rate in the CGM were significantly associated with increased decline in executive function. This longitudinal study showed that higher BBB leakage at baseline is associated with stronger cognitive decline, specifically in executive function, over 2 years of follow-up in patients with cSVD. These results emphasize the key role of BBB disruption in the pathophysiology and clinical progression of cSVD. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-021-00399-x.

Background and Purpose— Cerebral small vessel disease (SVD) is associated with cognitive impairment. This may be because of decreased microstructural integrity and microvascular perfusion, but data on these relationships are scarce. We determined the relationship between cognition and microvascular perfusion and microstructural integrity in SVD patients, using intravoxel incoherent motion imaging—a diffusion-weighted magnetic resonance imaging technique designed to determine microvascular perfusion and microstructural integrity simultaneously. Methods— Seventy-three patients with SVD and 39 controls underwent intravoxel incoherent motion imaging and neuropsychological assessment. Parenchymal diffusivity D (a surrogate measure of microstructural integrity) and perfusion-related measure fD* were calculated for the normal appearing white matter, white matter hyperintensities, and cortical gray matter. The associations between cognitive performance and D and fD* were determined. Results— In SVD patients, multivariable analysis showed that lower fD* in the normal appearing white matter and cortical gray matter was associated with lower overall cognition ( P =0.03 and P =0.002, respectively), lower executive function ( P =0.04 and P =0.01, respectively), and lower information-processing speed ( P =0.04 and P =0.01, respectively). D was not associated with cognitive function. In controls, no association was found between D , fD* , and cognition. Conclusions— In SVD patients, lower cognitive performance is associated with lower microvascular perfusion in the normal appearing white matter and cortical gray matter. Our results support recent findings that both cortical gray matter and normal appearing white matter perfusion may play a role in the pathophysiology of cognitive dysfunction in SVD. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR3786.

The phenotype of C9ORF72 repeat expansions is rapidly expanding. Originally found to be the major genetic cause of familial frontotemporal dementia with amyotrophic lateral sclerosis, several other clinical characteristics have been described more recently. Here, we report on a family diagnosed with 'degenerative schizophrenia' and harbouring a C9ORF72 repeat expansion, in which at least the index patient and an uncle showed a photoparoxysmal response during electroencephalography. Whereas epilepsy has been described in several repeat expansion disorders, photosensitivity has thus far only been reported in dentatorubral-pallidoluysian atrophy. The photoparoxysmal response may therefore be a new clinical feature of C9ORF72 repeat expansion related disease. Our observation learns that a repeat expansion disorder like C9ORF72 should be considered in patients with a combination of young-onset dementia, psychiatric symptoms and/or photosensitive epilepsy. We advocate the occasional use of EEG in the dementia workup and in particular urge to consider provocative tests such as photic stimulation.

Vascular cognitive impairment has been related to dysfunction of the central cholinergic system. Studies exploring the putative relationship between vascular cognitive impairment and cholinergic dysfunction have largely been aimed at symptomatic cholinergic treatment rather than focusing on etiological and pathological factors. The present study characterizes chronic responses of the cholinergic system to focal cerebral infarction. Two separate experiments investigated changes in receptor responsiveness versus changes in cell number after photothrombotic infarction of the frontal cortex in rat brain. First, we conducted pharmacological magnetic resonance imaging (phMRI) together with pilocarpine injection to assess relative cerebral blood volume (CBV) responses related to cholinergic muscarinic receptor activation. PhMRI was conducted at 1 and 3 weeks after photothrombotic infarction of either the left or right frontal cortex. Second, stereological assessment was performed on choline acetyltransferase (ChAT)-immunostained sections to determine cholinergic cell body count in several basal forebrain nuclei at 4 weeks after infarction. Significant reductions in relative CBV responses were observed both inside the ischemic area at 1 and 3 weeks, and in areas distant from the lesion at 3 weeks after right-sided frontal cortical infarction. In contrast, cholinergic cell number remained unchanged. These results demonstrate that cholinergic receptor responsiveness may be significantly altered following cerebral infarction, while projecting cholinergic cells are preserved.

Magnetic resonance imaging (MRI) has been applied to visualize monocyte infiltration with the use of intravenously injected ultrasmall superparamagnetic iron oxide (USPIO). However, USPIO uptake in vivo remains elusive, and the heterogeneous enhancement patterns observed by MRI point to multiple pathophysiological events. This study focused on specific imaging of monocyte infiltration into the brain by transfusion of superparamagnetic iron oxide (SPIO)-labeled monocytes in a rat model of neuroinflammation, experimentally induced photothrombosis (PT). At day 5 after lesion induction, animals were transfused with SPIO-labeled monocytes (5 × 106 cells) or free USPIO (17 mg Fe/kg). MRI was performed 24, 72 and, 120 h later. To investigate temporal changes directly after intravenous USPIO administration, MRI was performed repeatedly up to 8 h. Relaxation measurements showed that rat monocytes were efficiently labeled in vitro using SPIO ( R2=12±0.9 s−1). After transfusion of SPIO-labeled monocytes, a significant increase in contrast enhanced area (340%±106%) in the PT lesion was observed not before 72 h. Contrast enhancement after USPIO injection increased up to 407%±39% at a much earlier point of time (24 h) and diminished thereafter. Repetitive MRI directly after USPIO injection showed significant contrast enhancement in the lesion within 2 h. Our study shows that MRI enables in vivo tracking of SPIO-labeled monocytes longitudinally. Moreover, our data suggest that contrast enhancement after injection of free USPIO does not primarily represent signals from peripherally labeled monocytes that migrated toward the inflammatory lesion. The use of SPIO-labeled monocytes provides a better tool to specifically assess the time window of monocyte infiltration.

Photochemically induced cerebral infarction has been considered a clinically relevant model for ischemic stroke. We evaluated various transgenic mice to study the role of platelet adhesion molecules in this model. Infarction to the sensorimotoric cortex was induced by erythrosin B and laser light. Infarct volumes were calculated from triphenyltetrazolium chloride stained brain slices. Thrombus formation and vessel leakage were observed in vivo by multiphoton microscopy. Mice mutant in VWF, GPIbalpha, beta3 integrin, and P-selectin did not show any significant differences in infarct volume compared to wild type (WT). This is in contrast to the intraluminal middle cerebral artery occlusion model in which alphaIIbbeta3 integrin, GPIbalpha, and P-selectin are known to modulate infarct size. Multiphoton microscopy showed that small, non-occlusive embolizing platelet thrombi formed in the photochemically injured brains. Massive vessel leakage was observed within 25 min of laser injury. Interestingly, we observed a significant increase in infarct size with aging, accordant with heightened fragility of the blood brain barrier (BBB) in older mice. This model of photochemically induced stroke is closer to a BBB injury model than a thrombotic stroke model in which platelets and their adhesion molecules are crucial. This model will be useful to study mechanisms regulating BBB permeability.

The syndrome of hemispatial neglect is defined as an inability to report, respond or orient to stimuli contralateral to a cerebral lesion despite intact elementary sensory or motor function. This syndrome is typically observed after lesions of the right cerebral cortex, and has been associated with impairment of attention. We studied whether visual attention performance is impaired after right-hemisphere infarction in rats. Using a behavioural paradigm measuring spatial visual attention, we tested the effects of photothrombotic infarction to either the frontal cortex or the parietal cortex on attention performance. Since the cholinergic system is known to modulate attention performance, we additionally evaluated the role of cholinergic receptor blockade with scopolamine in our task paradigm. Our results show a transient response bias immediately after cortical infarction, with a decrease in contralesional responses and an increase in contralesional omissions after frontal infarction. Parietal infarction and systemic administration of scopolamine also resulted in a decrease in correct responses and an increase in omissions, but without a difference in side responding. In conclusion, right frontal infarction induces a transient impairment in contralesional spatial visual attention that we explain as left-sided neglect. Right parietal infarction and cholinergic blockade shows non-lateralized deficits in spatial visual attention, suggestive of global attentional impairment. We postulate that both effects of cortical infarction on attention performance may be related to cholinergic dysfunction. Our study confirms the role of frontal and parietal cortices in attention performance in rats, and corroborates the theory that attention performance is impaired in hemispatial neglect in human stroke patients.

Reaction time performance reflects the speed of information processing, both in humans and lower vertebrates like the rat. The present study compared reaction time performance in rats following unilateral infarction to the frontal cortex. The objective was to model cognitive impairment as it is seen in humans after stroke. Rats were trained in a reaction time paradigm, after which unilateral cortical infarction was induced photochemically. Reaction time performance was differentially affected after unilateral infarction to either the left or right frontal cortex, whereas sham operation did not result in a significant alteration in reactivity. An overall increase in reaction time of about 10% was present at 4 weeks after frontal infarction. In addition, a lateralized reaction time deficit occurred very early after right frontal infarction as an increase of 10-15% in trials directed towards the contralesional side. Additional analyses showed that these reaction time deficits can be explained differently: the former as a gradual and general decrease in the speed of information processing, whereas the latter shows specific impairment to initiate a contralateral motor response. The former matches well with the mental slowing observed in stroke patients, whereas the latter resembles a neglect phenomenon. We conclude that measuring reaction time performance after frontal cortical infarction in rats could offer a useful tool to model particular human cognitive impairments following cerebral infarction.

The potential of the adult brain to reorganize after ischemic injury is critical for functional recovery and provides a significant target for therapeutic strategies to promote brain repair. Despite the accumulating evidence of brain plasticity, the interaction and significance of morphological and physiological modifications in post-stroke brain tissue remain mostly unclear. Neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) enable in vivo assessment of the spatial and temporal pattern of functional and structural changes inside and outside ischemic lesion areas. This can contribute to the elucidation of critical aspects in post-stroke brain remodeling. Task/stimulus-related fMRI, resting-state fMRI, or pharmacological MRI enables direct or indirect measurement of neuronal activation, functional connectivity, or neurotransmitter system responses, respectively. DTI allows estimation of the structural integrity and connectivity of white matter tracts. Together, these MRI methods provide an unprecedented means to (a) measure longitudinal changes in tissue structure and function close by and remote from ischemic lesion areas, (b) evaluate the organizational profile of neural networks after stroke, and (c) identify degenerative and restorative processes that affect post-stroke functional outcome. Besides, the availability of MRI in clinical institutions as well as research laboratories provides an optimal basis for translational research on stroke recovery. This review gives an overview of the current status and perspectives of fMRI and DTI applications to study brain reorganization in experimental stroke models.

The central cholinergic system is involved in several cognitive functions such as attention, consciousness, learning and memory. Functional imaging of this neurotransmitter system may provide novel opportunities in the diagnosis and evaluation of cognitive disorders. The aim of this study was to investigate the spatial and temporal activation patterns of muscarinic acetylcholine receptor (mAChR) stimulation in rat brain with pharmacological magnetic resonance imaging (phMRI). We performed blood oxygenation level-dependent (BOLD) MRI and contrast-enhanced cerebral blood volume (CBV)-weighted MRI combined with injection of pilocarpine, a non-selective mAChR agonist. BOLD and CBV responses were assessed after pretreatment with methyl-scopolamine in order to block peripheral muscarinic effects. Region-of-interest analysis in individual animals and group-level independent component analysis failed to show significant BOLD signal changes following pilocarpine injection. However, with contrast-enhanced CBV-weighted MRI, positive CBV responses were detected in the cerebral cortex, thalamus, and hippocampus whereas a negative CBV response was observed in the striatum. Thus, pilocarpine-induced significant activation responses in brain regions that are known to have a high density of muscarinic receptors. Our study demonstrates that phMRI of mAChR stimulation in rats allows functional assessment of the cholinergic system in vivo.

The photothrombotic model for stroke was originally described as a focal cortical infarction resulting from occlusive thrombosis. However, subsequent studies have shown evidence for extravasation of water and proteins using ex vivo techniques. The aim of the present study was to determine the role of vascular leakage in the pathophysiology of photochemically induced infarction in vivo. At several times points after infarct induction, analysis of blood flow and vascular leakage was performed using intravital microscopy and fluorescent labelling of blood plasma. In the first hour following infarct induction, massive vascular leakage of the plasma label occurred inside the lesion core that was destined to become infarcted. Flow had stopped completely in this area at 4 h after illumination. On the day following infarct induction substantial leakage was still present in the penumbral area, defined as the area immediately surrounding the lesion core where reduced flow velocities were observed. Thus, together with the formation of occlusive thrombi, vascular leakage is an important factor in the pathophysiology of photothrombotic stroke.

A 73-year-old man was referred to the outpatient clinic with a 2-week history of headache and apathy. Neurologic examination revealed mild left-sided facial, arm, and leg paresis. Head CT appeared to show a right frontal lobe tumor with finger-like vasogenic edema. Instead, MRI revealed a subacute lobar hemorrhage with perihematomal edema (figure). On follow-up imaging, no underlying cause was found.