Gray Matter Sparing Research Articles

Acute ischaemic larger artery stroke presenting as a subcortical lesion with grey matter sparing: a case report

Large artery infarctions classically involve both white matter and grey matter in the distribution of the occluded artery. Rarely, large artery infarctions can present as isolated white matter lesions. We describe a 38-year-old, right-hand dominant woman, who presented with sudden onset right face-arm-leg weakness together with expressive aphasia. Neuroimaging demonstrated changes restricted to the white matter in the distribution of the left middle cerebral artery territory. Vascular imaging of her head and neck vessels showed irregular narrowing of the intracranial portions of the left internal carotid artery. Vasculitis was suspected due to these findings on imaging, and she was initially treated with steroids. However, due to the negative vasculitis work-up and an inadequate response, the steroids were discontinued, and she was treated with antiplatelets and statins. Early stroke rehabilitation commenced while inward.Large artery ischaemic strokes can rarely present as white matter lesions when there is adequate collateral circulation, which leads to the sparing of the grey matter.

Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery

Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days, and weeks following injury, leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD+-dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD+ depletion propagates tissue damage. Augmenting NAD+ by exogenous application of NAD+, its synthesizing enzymes, or its cellular precursors mitigates tissue damage. Nicotinamide riboside (NR) is considered to be one of the most promising NAD+ precursors for clinical application due to its ability to safely and effectively boost cellular NAD+ synthesis in rats and humans. Moreover, various preclinical studies have demonstrated that NR can provide tissue protection. Despite these promising findings, little is known about the potential benefits of NR in the context of SCI. In the current study, we tested whether NR administration could effectively increase NAD+ levels in the injured spinal cord and whether this augmentation of NAD+ would promote spinal cord tissue protection and ultimately lead to improvements in locomotor function. Our findings indicate that administering NR (500 mg/kg) intraperitoneally from four days before to two weeks after a mid-thoracic contusion-SCI injury, effectively doubles NAD+ levels in the spinal cord of Long-Evans rats. Moreover, NR administration plays a protective role in preserving spinal cord tissue post-injury, particularly in neurons and axons, as evident from the observed gray and white matter sparing. Additionally, it enhances motor function, as evaluated through the BBB subscore and missteps on the horizontal ladderwalk. Collectively, these findings demonstrate that administering NR, a precursor of NAD+, increases NAD+ within the injured spinal cord and effectively mitigates the tissue damage and functional decline that occurs following SCI.

Adult-Onset Acute Flaccid Myelitis with White Matter-predominant Longitudinally Extensive Transverse Myelitis Following Coxsackie B5 Enterovirus Infection: a case report (P8-10.001)

<h3>Objective:</h3> To describe an adult-onset case of transverse myelitis associated with enterovirus (Coxsackie B5) infection. <h3>Background:</h3> Both Acute Flaccid Myelitis (AFM) and longitudinally-extensive transverse myelitis (LETM) are more commonly associated with pediatric enteroviral infections than adult infections. However, we present an adult case of AFM due to Coxsackie B5 virus with an atypical pattern on spinal imaging. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 55-year-old male presented with acute urinary retention and lower extremity flaccid paraplegia two weeks after gastrointestinal illness. Neurologic exam revealed flaccid paralysis of bilateral lower extremities with absent lower extremity reflexes, and a sensory level to pinprick at T5. Vibration was diminished up to the ankle and proprioception was absent at the toes bilaterally. MRI thoracic spine showed T2 hyperintensity of ventral and bilateral lateral columns spanning T4-T10 levels, with notable sparing of central gray matter. MRI brain revealed four periventricular and subcortical T2/FLAIR hyperintense lesions as well as one cortical lesion. Cerebrospinal Fluid (CSF) studies demonstrated 16 WBC, 63 Glucose, and 56 Protein with one unique oligoclonal band. CSF PCR panel was positive for Enterovirus Coxsackie B5. Of note spinal angiogram, NMO, MOG, other rheumatologic and infectious usual myelitis workup was negative. The patient was treated with two days of IV steroids, five days of IV immunoglobulin therapy (IVIG), and five PLEX sessions with minimal improvement. <h3>Conclusions:</h3> We describe an adult patient presenting with Coxsackie B5-associated AFM with LETM. This patient demonstrated atypical MRI findings of T2 hyperintensity of the ventral and bilateral lateral columns spanning T4-T10 with notable sparing of central gray matter along with abnormal EMG suggesting anterior horn cell involvement. This case report highlights the importance of consideration of enterovirus as an etiology of atypical AFM with LETM in the adult population. <b>Disclosure:</b> Ms. Manouvakhova has nothing to disclose. Dr. Moghavem has nothing to disclose. Dr. Pulst-Korenberg has nothing to disclose.

Anatomical and behavioral outcomes following a graded hemi-contusive cervical spinal cord injury model in mice

BackgroundA graded hemi-contusion spinal cord injury produces complex anatomical deformation of the spinal cord parenchyma. The relationship between lesion severity and behavioral consequences in a novel contusion mouse model remains unknown. PurposeWe aimed to establish a graded cervical hemi-contusion spinal cord injury model in mice and investigate the correlation between graded anatomical damage to the spinal cord and resulting behavioral impairments. MethodsThirty-two mice were divided into groups of 1.2 mm, 1.5 mm and sham. The tip of an impactor with a diameter of 1 mm was utilized to compress the left dorsal cord of C5 by 1.2 mm or 1.5 mm at a speed of 300 mm/s. Forelimb motor function was evaluated using rearing, grooming and grip-strength tests before and after the injuries. Histologically the area of white matter sparing, gray matter sparing and lesion area were quantified at 6-week-post-injury. ResultsBehavioral assessments showed a more severe forelimb functional deficit in 1.5 mm contusion displacements relative to 1.2 mm contusion displacements after injury. The 1.2 mm hemi-contusion mainly caused damage to the dorsal fasciculus, ventral and dorsal horn, while the 1.5 mm hemi-contusion lead to additional damage extending to ventral fasciculus. Sparing of the gray and white matter at the epicenter was 36.8 ± 2.4% and 12.4 ± 2.6% in the 1.2 mm group, and 27.6 ± 4.0% and 4.1 ± 2.2% in the 1.5 mm group, respectively. Furthermore, the lesion area was 20.8 ± 3.0% and 36.0 ± 2.1% in the 1.2 mm and 1.5 mm groups, respectively. There was a significant correlation between the performance in the grooming test and white matter sparing, and between grip-test strength and gray matter sparing. ConclusionThe present study demonstrates that a hemi-contusion cervical spinal cord injury in mice can be graded by contusion displacement and that there is a correlation between anatomical and behavioral outcomes. This study provides a means for determining the severity of lesions in a contusion mouse model.

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum.

Background and ObjectivesTo assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.MethodsSixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.ResultsCompared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.DiscussionMeasures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.

Microbleed patterns in critical illness and COVID-19

BackgroundCerebral microbleeds are increasingly reported in critical ill patients with respiratory failure in need of mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO). Typically, these critical illness-associated microbleeds involve the juxtacortical white matter and corpus callosum. Recently, this pattern was reported in patients with respiratory failure, suffering from COVID-19. Materials and methodsIn this retrospective single-center study, we listed patients from March 11, 2020 to September 2, 2020, with laboratory-confirmed COVID-19, critical illness and cerebral microbleeds. Literature research was conducted through a methodical search on Pubmed databases on critical illness-associated microbleeds and cerebral microbleeds described in patients with COVID-19. Results and discussionOn 279 COVID-19 admissions, two cases of cerebral microbleeds were detected in critical ill patients with respiratory failure due to COVID-19. Based on review of existing literature critical illness-associated microbleeds tend to predominate in subcortical white matter and corpus callosum. Cerebral microbleeds in patients with COVID-19 tend to follow similar patterns as reported in critical illness-associated microbleeds. Hence, one patient with typical critical illness-associated microbleeds and COVID-19 is reported. However, a new pattern of widespread cortico-juxtacortical microbleeds, predominantly in the anterior vascular territory with relative sparing of deep gray matter, corpus callosum and infratentorial structures is documented in a second case. The possible etiologies of these microbleeds include hypoxia, hemorrhagic diathesis, brain endothelial erythrophagocytosis and/or cytokinopathies. An association with COVID-19 remains to be determined. ConclusionFurther systematic investigation of microbleed patterns in patients with neurological impairment and COVID-19 is necessary.

Inhibition of astrocyte hemichannel improves recovery from spinal cord injury.

Spinal cord injury (SCI) causes severe disability, and the current inability to restore function to the damaged spinal cord leads to lasting detrimental consequences to patients. One strategy to reduce SCI morbidity involves limiting the spread of secondary damage after injury. Previous studies have shown that connexin 43 (Cx43), a gap junction protein richly expressed in spinal cord astrocytes, is a potential mediator of secondary damage. Here, we developed a specific inhibitory antibody, mouse-human chimeric MHC1 antibody (MHC1), that inhibited Cx43 hemichannels, but not gap junctions, and reduced secondary damage in 2 incomplete SCI mouse models. MHC1 inhibited the activation of Cx43 hemichannels in both primary spinal astrocytes and astrocytes in situ. In both SCI mouse models, administration of MHC1 after SCI significantly improved hind limb locomotion function. Remarkably, a single administration of MHC1 30 minutes after injury improved the recovery up to 8 weeks post-SCI. Moreover, MHC1 treatment decreased gliosis and lesion sizes, increased white and gray matter sparing, and improved neuronal survival. Together, these results suggest that inhibition of Cx43 hemichannel function after traumatic SCI reduces secondary damage, limits perilesional gliosis, and improves functional recovery. By targeting hemichannels specifically with an antibody, this study provides a potentially new, innovative therapeutic approach in treating SCI.

Calpastatin Overexpression Protects against Excitotoxic Hippocampal Injury and Traumatic Spinal Cord Injury.

Small molecule inhibitors of calcium-dependent proteases, calpains (CAPNs), protect against neurodegeneration induced by a variety of insults including excitotoxicity and spinal cord injury (SCI). Many of these compounds, however, also inhibit other proteases, which has made it difficult to evaluate the contribution of calpains to neurodegeneration. Calpastatin is a highly specific endogenous inhibitor of classical calpains, including CAPN1 and CAPN2. In the present study, we utilized transgenic mice that overexpress human calpastatin under the prion promoter (PrP-hCAST) to evaluate the hypothesis that calpastatin overexpression protects against excitotoxic hippocampal injury and contusive SCI. The PrP-hCAST organotypic hippocampal slice cultures showed reduced neuronal death and reduced calpain-dependent proteolysis (α-spectrin breakdown production, 145 kDa) at 24 h after N-methyl-D-aspartate (NMDA) injury compared with the wild-type (WT) cultures (n = 5, p < 0.05). The PrP-hCAST mice (n = 13) displayed a significant improvement in locomotor function at one and three weeks after contusive SCI compared with the WT controls (n = 9, p < 0.05). Histological assessment of lesion volume and tissue sparing, performed on the same animals used for behavioral analysis, revealed that calpastatin overexpression resulted in a 30% decrease in lesion volume (p < 0.05) and significant increases in tissue sparing, white matter sparing, and gray matter sparing at four weeks post-injury compared with WT animals. Calpastatin overexpression reduced α-spectrin breakdown by 51% at 24 h post-injury, compared with WT controls (p < 0.05, n = 3/group). These results provide support for the hypothesis that sustained calpain-dependent proteolysis contributes to pathological deficits after excitotoxic injury and traumatic SCI.

The effect of 808\u2009nm and 905\u2009nm wavelength light on recovery after spinal cord injury

We investigated the effect of a Multiwave Locked System laser (with a simultaneous 808 nm continuous emission and 905 nm pulse emission) on the spinal cord after spinal cord injury (SCI) in rats. The functional recovery was measured by locomotor tests (BBB, Beam walking, MotoRater) and a sensitivity test (Plantar test). The locomotor tests showed a significant improvement of the locomotor functions of the rats after laser treatment from the first week following lesioning, compared to the controls. The laser treatment significantly diminished thermal hyperalgesia after SCI as measured by the Plantar test. The atrophy of the soleus muscle was reduced in the laser treated rats. The histopathological investigation showed a positive effect of the laser therapy on white and gray matter sparing. Our data suggests an upregulation of M2 macrophages in laser treated animals by the increasing number of double labeled CD68+/CD206+ cells in the cranial and central parts of the lesion, compared to the control animals. A shift in microglial/macrophage polarization was confirmed by gene expression analysis by significant mRNA downregulation of Cd86 (marker of inflammatory M1), and non-significant upregulation of Arg1 (marker of M2). These results demonstrated that the combination of 808 nm and 905 nm wavelength light is a promising non-invasive therapy for improving functional recovery and tissue sparing after SCI.

Repositioning Flubendazole for Spinal Cord Injury

We previously reported the serendipitous observation that fenbendazole, a benzimidazole anthelmintic, improved functional and pathological outcomes following thoracic spinal cord contusion injury in mice when administered pre-injury. Fenbendazole is widely used in veterinary medicine. However, it is not approved for human use and it was uncertain if only post-injury administration would offer similar benefits. In the present study we evaluated post-injury administration of a closely related, human anthelmintic drug, flubendazole, using a rat spinal cord contusion injury model. Flubendazole, administered i.p. 5 or 10 mg/kg day, beginning 3 h post-injury and daily thereafter for 2 or 4 weeks, resulted in improved locomotor function after contusion spinal cord injury (SCI) compared with vehicle-treated controls. Histological analysis of spinal cord sections showed that such treatment with flubendazole also reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing. Flubendazole inhibited the activation of glial fibrillary acidic protein (GFAP); suppressed cyclin B1 expression and Bruton tyrosine kinase activation, markers of B cell activation/proliferation and inflammation; and reduced B cell autoimmune response. Together, these results suggest the use of the benzimidazole anthelmintic flubendazole as a potential therapeutic for SCI.

Development of a Model of Hemispheric Hypodensity ("Big Black Brain").

Subdural hematoma (SDH) is the most common finding after abusive head trauma (AHT). Hemispheric hypodensity (HH) is a radiological indicator of severe brain damage that encompasses multiple vascular territories, and may develop in the hemisphere(s) underlying the SDH. In some instances where the SDH is predominantly unilateral, the widespread damage is unilateral underlying the SDH. To date, no animal model has successfully replicated this pattern of injury. We combined escalating severities of the injuries and insults commonly associated with HH including SDH, impact, mass effect, seizures, apnea, and hypoventilation to create an experimental model of HH in piglets aged 1 week (comparable to human infants) to 1 month (comparable to human toddlers). Unilateral HH evolved over 24 h when kainic acid was applied ipsilateral to the SDH to induce seizures. Pathological examination revealed a hypoxic-ischemic injury-type pattern with vasogenic edema through much of the cortical ribbon with relative sparing of deep gray matter. The percentage of the hemisphere that was damaged was greater on the ipsilateral versus contralateral side and was positively correlated with SDH area and estimated seizure duration. Further studies are needed to parse out the pathophysiology of this injury and to determine if multiple injuries and insults act synergistically to induce a metabolic mismatch or if the mechanism of trauma induces severe seizures that drive this distinctive pattern of injury.

Pharmacological Stimulation of Mitochondrial Biogenesis Using the Food and Drug Administration-Approved β2-Adrenoreceptor Agonist Formoterol for the Treatment of Spinal Cord Injury.

A hallmark of the progressive cascade of damage referred to as secondary spinal cord injury (SCI) is vascular disruption resulting in decreased oxygen delivery and loss of mitochondria homeostasis. While therapeutics targeting restoration of single facets of mitochondrial function have proven largely ineffective clinically post-SCI, comprehensively addressing mitochondrial function via pharmacological stimulation of mitochondrial biogenesis (MB) is an underexplored strategy. This study examined the effects of formoterol, a mitochondrial biogenic Food and Drug Administration-approved selective and potent β2-adrenoreceptor (ADRB2) agonist, on recovery from SCI in mice. Female C57BL/6 mice underwent moderate SCI using a force-controlled impactor-induced contusion model, followed by daily formoterol intraperitoneal administration (0.1 mg/kg) beginning 1 h post-SCI. The SCI resulted in decreased mitochondrial protein expression, including PGC-1α, in the injury and peri-injury sites as early as 3 days post-injury. Formoterol treatment attenuated this decrease in PGC-1α, indicating enhanced MB, and restored downstream mitochondrial protein expression to that of controls by 15 days. Formoterol-treated mice also exhibited less histological damage than vehicle-treated mice 3 days after injury-namely, decreased lesion volume and increased white and gray matter sparing in regions rostral and caudal to the injury epicenter. Importantly, locomotor capability of formoterol-treated mice was greater than vehicle-treated mice by 7 days, reaching a Basso Mouse Scale score two points greater than that of vehicle-treated SCI mice by 15 days. Interestingly, similar locomotor restoration was observed when initiation of treatment was delayed until 8 h post-injury. These data provide evidence of ADRB2-mediated MB as a therapeutic approach for the management of SCI.

The Effect of Human Mesenchymal Stem Cells Derived from Wharton's Jelly in Spinal Cord Injury Treatment Is Dose-Dependent and Can Be Facilitated by Repeated Application.

Human mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) were used for the treatment of the ischemic-compression model of spinal cord injury in rats. To assess the effectivity of the treatment, different dosages (0.5 or 1.5 million cells) and repeated applications were compared. Cells or saline were applied intrathecally by lumbar puncture for one week only, or in three consecutive weeks after injury. Rats were assessed for locomotor skills (BBB, rotarod, flat beam) for 9 weeks. Spinal cord tissue was morphometrically analyzed for axonal sprouting, sparing of gray and white matter and astrogliosis. Endogenous gene expression (Gfap, Casp3, Irf5, Cd86, Mrc1, Cd163) was studied with quantitative Real-time polymerase chain reaction (qRT PCR). Significant recovery of functional outcome was observed in all of the treated groups except for the single application of the lowest number of cells. Histochemical analyses revealed a gradually increasing effect of grafted cells, resulting in a significant increase in the number of GAP43+ fibers, a higher amount of spared gray matter and reduced astrogliosis. mRNA expression of macrophage markers and apoptosis was downregulated after the repeated application of 1.5 million cells. We conclude that the effect of hWJ-MSCs on spinal cord regeneration is dose-dependent and potentiated by repeated application.

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.

Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury

Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury (SCI). The objectives of the study were to evaluate the distinct roles of ERK2 vs. ERK1/2 and ERK1/2-calpain 1–NF-κB signal transduction in the tissue damage and astrogliosis/astroglial scar formation following SCI in rats. RNAi approaches, pharmacological intervention (U0126), Western blot analysis, immunofluorescence analysis, and histological assessment were used to target ERK1/2-calpain 1-NF-κB signal transduction pathway for neuroprotection. Histological staining analysis demonstrated that selectively reducing pERK2 using ERK2 siRNA, but not inhibition of pERK1/2 with U0126, significantly reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing in spinal cord two weeks after contusive SCI. An ERK1/2-calpain 1-NF-κB signal transduction pathway was involved in the astroglial scar formation after SCI. Blockade of ERK1/2 by U0126 decreased calpain 1 expression 4 h following SCI. Selective calpain 1 reduction by lentiviral shRNA attenuated astroglial NF-κB activity and astroglial scar formation after SCI in rats. Taken together, these results demonstrate the involvement of individual ERK2 and calpain 1 signaling pathways in tissue damage and astrogliosis/astroglial scar formation in animal models of SCI. Therefore, targeting individual ERK and its downstream signal transduction of calpain 1-NF-κB may provide greater potential as novel therapeutics for minimizing tissue damage and astroglial scar formation following SCI.

The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features.

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.

Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.

The effect of hypothermia on sensory-motor function and tissue sparing after spinal cord injury

Background contextIn recent years, hypothermia has been described as a therapeutic approach that leads to potential protective effects via minimization of secondary damage consequences, reduction of neurologic deficit, and increase of motor performance after spinal cord injury (SCI) in animal models and humans. PurposeThe objective of this study was to determine the therapeutic efficacy of hypothermia treatment on sensory-motor function and bladder activity outcome correlated with the white and gray matter sparing and neuronal survival after SCI in adult rats. Study designA standardized animal model of compression SCI was used to test the hypothesis that hypothermia could have a neuroprotective effect on neural cell death and loss of white and/or gray matter. MethodsAnimals underwent spinal cord compression injury at the Th8–Th9 level followed by systemic hypothermia of 32.0°C with gradual re-warming to 37.0°C. Motor function of hind limbs (BBB score) and mechanical allodynia (von Frey hair filaments) together with function of urinary bladder was monitored in all experimental animals throughout the whole survival period. ResultsPresent results showed that hypothermia had beneficial effects on urinary bladder activity and on locomotor function recovery at Days 7 and 14 post-injury. Furthermore, significant increase of NeuN-positive neuron survival within dorsal and ventral horns at Days 7, 14, and 21 were documented. ConclusionsOur conclusions suggest that hypothermia treatment may not only promote survival of neurons, which can have a significant impact on the improvement of motor and vegetative functions, but also induce mechanical allodynia.

Calpain 1 knockdown improves tissue sparing and functional outcomes after spinal cord injury in rats.

To evaluate the hypothesis that calpain 1 knockdown would reduce pathological damage and functional deficits after spinal cord injury (SCI), we developed lentiviral vectors encoding calpain 1 shRNA and eGFP as a reporter (LV-CAPN1 shRNA). The ability of LV-CAPN1 shRNA to knockdown calpain 1 was confirmed in rat NRK cells using Northern and Western blot analysis. To investigate the effects on spinal cord injury, LV-CAPN1shRNA or LV-mismatch control shRNA (LV-control shRNA) were administered by convection enhanced diffusion at spinal cord level T10 in Long-Evans female rats (200-250 g) 1 week before contusion SCI, 180 kdyn force, or sham surgery at the same thoracic level. Intraspinal administration of the lentiviral particles resulted in transgene expression, visualized by eGFP, in spinal tissue at 2 weeks after infection. Calpain 1 protein levels were reduced by 54% at T10 2 weeks after shRNA-mediated knockdown (p<0.05, compared with the LV-control group, n=3 per group) while calpain 2 levels were unchanged. Intraspinal administration of LV-CAPN1shRNA 1 week before contusion SCI resulted in a significant improvement in locomotor function over 6 weeks postinjury, compared with LV-control administration (p<0.05, n=10 per group). Histological analysis of spinal cord sections indicated that pre-injury intraspinal administration of LV-CAPN1shRNA significantly reduced spinal lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing (p<0.05, n=10 per group). Together, results support the hypothesis that calpain 1 activation contributes to the tissue damage and impaired locomotor function after SCI, and that calpain1 represents a potential therapeutic target.

The brain basis of musicophilia: evidence from frontotemporal lobar degeneration

Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia, and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional gray matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p < 0.05 corrected for regional comparisons); at a relaxed significance threshold (p < 0.001 uncorrected across the brain volume) musicophilia was associated with additional relative sparing of regional gray matter in other temporal lobe and prefrontal areas and atrophy of gray matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social) stimuli, with some specificity for particular neurodegenerative pathologies.