Glial reactions and the clearance of amyloid β protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

Although the amyloid protein (A) E693Q mutation enhances A fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal A deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of A by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to Ax–42 (A42) and Ax–40 (A40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic A42⁺40^– granules were scattered among non-fibrillar (Congo red-negative) A deposits, i.e., clouds, fine diffuse plaques, and A42⁺40^– dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) A deposition, i.e., A42⁺40⁺ dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of A granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal A deposits may be liable to glial clearance. A sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble A oligomers in HCHWA-D brain.     

Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B–cell response

Human herpesvirus 6 (HHV–6) is one of many infectious agents that have been implicated in the pathogenesis of multiple sclerosis (MS). Intrathecal immunoglobulin (Ig) production with oligoclonal CSF bands are hallmarks of both MS and infections of the CNS. In neuroinfections the intrathecal Ig production is directed largely against the respective agent, while MS patients mount an intrathecal Ig production against different pathogens. In this study a total of 77 serum/CSF pairs were first analyzed for an intrathecal immune response against HHV–6. We found that 21% of the MS patients, but none of the control donors showed an intrathecal immunoglobulin (Ig) response against HHV–6 (p = 0.017). Patients with such an intrathecal Ig production had a significantly higher total amount of Ig (p = 0.007) and a higher cell number in the CSF (p = 0.03). In a second step, four of the MS–patients who showed a strong intrathecal Ig production against HHV–6 were examined for immune reactivity against other viruses (human herpesvirus type 1, measles virus, human cytomegalovirus, rubella virus, varicella zoster virus). All of these patients had an intrathecal Ig production against at least one other, unrelated virus. Together, our findings strongly argue that in the majority of MS patients without an intrathecal Ig response to HHV–6 (about 80 % in our study), this virus is not involved in the pathogenesis. In the other 20% the intrathecal Ig production to HHV–6 might reflect reactivation of HHV–6 or could be part of a polyspecific B cell activation.     

Critical implication of the (70–96) domain of human immunodeficiency virus type 1 Vpr protein in apoptosis of primary rat cortical and striatal neurons

The human immunodeficiency virus (HIV)-1 regulatory protein Vpr has been detected in the serum of HIV-seropositive individuals and in the cerebrospinal fluid of acquired immunodeficiency syndrome (AIDS) patients suffering from neurological disorders. Therefore, Vpr could play a critical role in the neuronal apoptosis observed postmortem in the brain of patients, often connected to a severe AIDS-related disease termed HIV-associated dementia (HAD). This suggests that the Vpr neurotoxicity already observed in vitro on hippocampal neurons could also occur in other brain structures. In this study the authors have investigated the ability of synthetic Vpr to induce apoptosis in primary cultures of rat cortical and striatal neurons. Moreover, the authors have explored the Vpr minimal proapoptotic region using synthetic Vpr fragments and mutants of the protein. Treatments of both neuronal types with Vpr, its C-terminal domain, Vpr(52-96), or a shorter fragment, Vpr(70-96), led to dose- and time-dependent cell death as determined by flow cytometry after propidium iodide labeling, phase-contrast microscopy, and TUNEL labeling. Taken together, these results support an apoptosis-induced death of these neurons. The (71-82) Vpr peptide, previously shown toxic to isolated mitochondria, was inactive on neurons. Vpr-induced neuronal apoptosis was associated with activation of caspase-3 beginning 3 h after Vpr extracellular addition and peaking 3 h later. Moreover, an hyperproduction of reactive oxygen species was observed. In addition to hippocampal neurons, the extension of the apoptotic property of Vpr to cortical and striatal neurons could account for several signs observed in HAD and is thus consistent with a possible involvement of Vpr in this syndrome.     

Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease

There is evidence that both inflammatory mechanisms and mitochondrial dysfunction contribute to Parkinson's disease (PD) pathogenesis. We investigated whether the cyclooxygenase 2 (COX-2) inhibitor rofecoxib either alone or in combination with creatine could exert neuroprotective effects in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine model of PD in mice. Both rofecoxib and creatine administered alone protected against striatal dopamine depletions and loss of substantia nigra tyrosine hydroxylase immunoreactive neurons. Administration of rofecoxib with creatine produced significant additive neuroprotective effects against dopamine depletions. These results suggest that a combination of a COX-2 inhibitor with creatine might be a useful neuroprotective strategy for PD.     

Inhibitory breakdown and dementia of the Alzheimer type: a general phenomenon?

Several recent studies have provided substantial support for the proposal that a decrease in inhibitory processing may play an important role in cognitive changes occurring in the early stages of Dementia of the Alzheimer Type (DAT). The question addressed by the present study was whether these deficits are the result of the failure of a general inhibitory mechanism, or whether DAT is associated with selective decreases in a subset of inhibitory processes. For this, a computerized battery of tasks assessing several inhibitory mechanisms was administered to 28 mild DAT patients and 28 matched elderly adults. The results showed that DAT patients failed to produce Negative Priming effects and were severely impaired in the Stroop task. However, no evidence was found for an impairment on the Go-No go task and only limited impairment on the Stop Signal task, suggesting that in the early stages of the disease, not all inhibitory mechanisms are uniformly impaired.     

Detection of peri-synaptic amyloid-β pyroglutamate aggregates in early stages of Alzheimer's disease and in AβPP transgenic mice using a novel monoclonal antibody

The neurodegenerative pathology in patients with Alzheimer's disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-β (Aβ) species. Among them, recent studies indicate that the pyroglutamate modification of Aβ (pE(3)Aβ) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aβ aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aβ across the spectrum of AD and in the brains of amyloid-β protein precursor (AβPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated D129) that specifically recognizes pE(3)Aβ and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AβPP tg mice. We found that in early stages of AD and young AβPP tg mice pE(3)Aβ was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AβPP tg mice, pE(3)Aβ was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aβ might contribute to early cognitive dysfunction in AD.     

Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature

Background

Patients with multiple sclerosis (MS) frequently have an intrathecal production of antibodies to different common viruses, which can be detected by elevated antiviral antibody indices (AIs). There is a strong and consistent association of MS and Epstein–Barr virus (EBV) infection.

Objective

To systematically compare the frequencies of intrathecal antibody production to EBV, measles virus, rubella virus, varicella zoster virus (VZV) and herpes simplex virus (HSV) in patients with MS.

Methods

Review of the English and German literature on the frequencies of intrathecal immunoglobulin (Ig)G antibody production, as defined by an elevated AI, to EBV, measles virus, rubella virus, VZV and HSV in adult and pediatric patients with MS.

Results

In nine original studies identified, the frequencies of an intrathecal production of antibodies to Epstein–Barr nuclear antigen-1 (33/340, 9.7%), EBV viral capsid antigen (12/279, 4.3%) and antigens from EBV-infected cell lines (14/90, 15.6%) in adult patients with MS were clearly lower (p ≤ 0.03 for all pairwise comparisons) than the frequencies of an intrathecal production of antibodies to measles virus (612/922, 66.4%), rubella virus (521/922, 56.5%), VZV (470/922, 51%; data from 17 original studies) and HSV (78/291, 26.8%; data from 6 original studies). Though based on a lower number of original studies and patients, findings in children with MS were essentially similar. As in adults and children with MS the seroprevalence of EBV is higher than the seroprevalences of the other investigated viruses, the lower frequency of elevated EBV AIs became even more pronounced after correction of the frequencies of elevated antiviral AIs for the seroprevalences of the respective viruses.

Conclusions

Given the very high seroprevalence of EBV in MS, the frequency of intrathecally produced antibodies to EBV in patients with MS is paradoxically low compared to that of other common viruses. These findings are compatible with the recently proposed hypothesis that in individuals going on to develop MS antiviral antibody-producing cells may invade the brain predominantly at the time of and triggered by acute primary EBV infection, before anti-EBV IgG producing cells have yet occurred.

     

Evolution of Charcot–Marie–Tooth disease type 1A duplication: a 2-year clinico-electrophysiological and lower-limb muscle MRI longitudinal study

The objective of this study was to analyze Charcot–Marie–Tooth disease type 1A (CMT1A) evolution. We conducted a 2-year longitudinal study in 14 CMT1A patients and 14 age- and sex-matched controls. In the patients, we performed neurological examination with hand-held dynamometry, electrophysiology, and lower-limb muscle MRI, both at baseline and 2 years later, while controls were examined at baseline only. Patients’ ages ranged from 12 to 51 years. Outstanding manifestations on initial evaluation included pes cavus, areflexia, lower-limb weakness, and foot hypopallesthesia. In evaluating muscle power, good correlation was observed between manual testing and dynamometry. Compared to controls, Lunge, 10-Meter-Walking, and 9-Hole-Peg tests were impaired. Their CMT neuropathy score and functional disability scale showed that patients exhibited mild phenotype and at most slight walking difficulty. Electrophysiology revealed marked nerve conduction slowing and variable compound muscle action potential amplitude reduction. On lower-limb muscle MRI, there was distally accentuated fatty infiltration accompanied by edema in calf muscles. All these clinico-electrophysiological and imaging findings remained almost unaltered during monitoring. Using multivariate analysis, no significant predictors of progression associated to the disease were obtained. We conclude that in the 2-year period of study, CMT1A patients showed mild progression with good concordance between clinico-electrophysiological and imaging findings.     

Clinical spectrum and gender differences in a large cohort of Charcot–Marie–Tooth type 1A patients

IntroductionHeterogeneous clinical presentation and gender differences were reported in Charcot–Marie–Tooth disease type 1A (CMT1A).MethodsThis report examined demographic and clinical data collected during a randomised controlled trial, to describe the clinical spectrum of a large and well-defined cohort of CMT1A patients.ResultsAmong the 189 symptomatic patients screened, three patients (1.6%) reported first symptoms in the upper limbs, which may be misleading when establishing the clinical diagnosis. The quality of life (QoL) of patients was significantly deteriorated compared to the standard population, and slightly better compared to multiple sclerosis patients. According to the literature, patients reported several disorders which may be associated with CMT1A, including auditory dysfunction (7.9%), Carpal Tunnel Syndrome (CTS) (7.9%) or sleep apnoea (4.2%). Compared to available data, we reported more patients with CTS and fewer patients with sleep apnoea. Women were more affected by CTS than men (11% and 2.8%, respectively). Women also reported an earlier onset of symptoms than men (8.6 ± 9.5 years and 13.1 ± 14 years, respectively), higher deterioration of their QoL and higher disability of their upper limb, assessed by Overall Neuropathy Limitation Scale (p = 0.023).ConclusionsThis information will be useful for better understanding of this disease and for designing future clinical studies.     

Delayed myelination is not a constant feature of Allan–Herndon–Dudley syndrome: Report of a new case and review of the literature

Introduction: Allan–Herndon–Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. Case report: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17 months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14 months, were normal. Discussion: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan–Herndon–Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.     

A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot–Marie–Tooth type 2D in a Chinese family

Abstract

Objective:

To explore the clinical features of a novel glycyl-tRNA synthetase (GARS) gene mutation in a family with Charcot–Marie–Tooth disease type 2D (CMT2D).

Methods:

Exome capture with the next-generation sequencing technique was used to detect gene mutations. The mutations were verified by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing.

Results:

In this pedigree, eight members were affected; seven males and one female. The affected members initially manifested with the onset of hand muscle weakness and atrophy in adolescence followed by gradual development of distal lower limb involvement and minor sensory involvement. Electrophysiological studies revealed that this disease mainly involves axonal damage. Genetic detection showed that all affected family members had a heterozygous missense mutation, c.999G>T (p.E333D), of the GARS gene.

Conclusions:

The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population.     

Functions of the CB1 and CB2 Receptors in Neuroprotection at the Level of the Blood–Brain Barrier

The cannabinoid (CB) receptors are the main targets of the cannabinoids, which include plant cannabinoids, endocannabinoids and synthetic cannabinoids. Over the last few years, accumulated evidence has suggested a role of the CB receptors in neuroprotection. The blood–brain barrier (BBB) is an important brain structure that is essential for neuroprotection. A link between the CB receptors and the BBB is thus likely, but this possible connection has only recently gained attention. Cannabinoids and the BBB share the same mechanisms of neuroprotection and both protect against excitotoxicity (CB₁), cell death (CB₁), inflammation (CB₂) and oxidative stress (possibly CB independent)—all processes that also damage the BBB. Several examples of CB-mediated protection of the BBB have been found, such as inhibition of leukocyte influx and induction of amyloid beta efflux across the BBB. Moreover, the CB receptors were shown to improve BBB integrity, particularly by restoring the tightness of the tight junctions. This review demonstrated that both CB receptors are able to restore the BBB and neuroprotection, but much uncertainty about the underlying signaling cascades still exists and further investigation is needed.     

Method availability and the prevention of suicide – a re-analysis of secular trends in England and Wales 1950–1975

  Background: In England and Wales in the 1960s there were marked declines in suicide rates. These reductions were partly attributable to the detoxification of the domestic gas supplies; however, their extent varied by age and gender, with the most striking effects seen in older men. The objective of this study was to investigate method-specific trends in suicide between 1950 and 1975 to elucidate possible explanations for the patterns seen in different demographic groups. Methods: An analysis of age-standardised method-specific suicide rates for England and Wales between 1950 and 1975 was carried out using routinely available mortality and population statistics. Results: As has previously been shown, there were marked reductions in suicides by gassing in men and women of all ages between 1960 and 1975. In women and younger men, the effects of these reductions on overall suicide rates were partially offset by rises in drug overdose deaths (method substitution), but there were no immediate increases in the use of other suicide methods. In contrast, in older men, reductions in suicide by gassing were accompanied by only a slight increase in overdose suicides as well as reductions in rates of suicide using all other methods. The modest rise in overdose fatalities in older men occurred despite the fact that they were more often prescribed barbiturates and tricyclic antidepressants than younger men. Conclusions: Accessibility to and the lethality of particular methods of suicide may have profound effects on overall suicide rates. Such effects appear to depend upon the popularity of the method and the extent to which alternative methods that are acceptable to the individual are available. Social and psychological interpretations of fluctuations in suicide rates should only be made after assessing the possible contribution to these of changes in method availability and lethality. Accepted: 5 June 2000     

Isolated intracranial Rosai–Dorfman disease in a child,a case report and review of the literature

Background

Rosai–Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy (SHML), usually affects young adults and commonly presents with massive painless cervical lymphadenopathy. Extranodal disease is present in a third of patients, and it is recognised that this can involve the central nervous system. Intracranial RDD is rare in adults and fewer than 10 paediatric cases have been reported.

Case

A 10-year-old boy with isolated intracranial RDD presents with a painless forehead mass. The management is discussed and the literature reviewed.

Conclusion

This case of isolated intracranial RDD highlights the importance of considering RDD in the differential of paediatric intracranial mass lesions and outlines the diagnostic and treatment challenges faced when managing this rare condition.