Autonomic neurons of the sacral spinal cord in amyotrophic lateral sclerosis,anterior poliomyelitis and “neuronal intranuclear hyaline inclusion disease”: Distribution of sacral autonomic neurons

Summary Further evidence is presented that the Onuf's nucleus (or colonne en torsade of Laruelle) and the intermediolateral nucleus of the sacral cord share common selective vulnerability with the thoracolumbar intermediolateral nucleus in ALS, anterior poliomyelitis and neuronal intranuclear hyaline inclusion disease. Sparing of the sacral nuclei in the motor neuron diseases and neuronal loss of the nuclei in the multisystem atrophy are correlated well with normal and disturbed vesicorectal function. The clinicopathological evidence strongly supports the view that the Onuf's nucleus represents autonomic neurons much as the intermediolateral nucleus.Supported by the Research Grant awarded by the American Diabetes Association of Minnesota, USA     

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID): a study using α-internexin immunohistochemistry and principal components analysis (PCA)

Summary. Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The α-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity.     

Spatial patterns of the pathological changes in neuronal intermediate filament inclusion disease (NIFID): an α-internexin immunohistochemical study

Summary Neuronal intermediate filament inclusion disease (NIFID) is characterized by α-internexin positive neuronal cytoplasmic inclusions (NCI), swollen achromatic neurons (SN), neuronal loss, and gliosis. This study tested: 1) whether the spatial patterns of the lesions was topographically organized in areas of the frontal and temporal lobe and 2) whether a spatial relationship exists between the NCI and SN. The NCI were distributed in regular clusters and in a quarter of these areas, the clusters were 400–800 μm in diameter approximating to the size of the cells of origin of the cortico-cortical pathways. Variations in the density of the NCI were positively correlated with the SN. Hence, cortical degeneration in NIFID appears to be topographically organized and may affect the cortico-cortical projections, the clusters of NCI and SN developing within the same vertical columns of cells.     

Hemiparkinsonism-hemiatrophy syndrome – report on two cases and review of the literature

Hemiparkinsonism-hemiatrophy (HPHA) is a rare neurological syndrome. The main clinical features of HPHA consist of atrophy of one side of the body (face, trunk, limbs), ipsilateral hemiparkinsonism (bradykinesia, rigidity, tremor) and in many cases dystonia. There are no data on prevalence of HPHA as the condition is rare. The mean age of parkinsonism onset is earlier than in idiopathic Parkinson disease (43.7 years, range: 15–63). Changes in magnetic resonance imaging (MRI) (cortical, basal ganglia atrophy contralaterally to the side of clinical presentation) are described in 30% of patients. The pathogenesis of HPHA is unknown, but in many cases a history of prenatal injuries was reported.We present two male patients with HPHA – 45 and 55 years old, with left-sided parkinsonism, dystonia and hemiatrophy (to our knowledge, the first Polish cases). Both patients had no atrophic changes in MRI and levodopa treatment was ineffective. In the discussion the authors review current literature on HPHA.     

Involvement of Onuf’s nucleus in Machado–Joseph disease: a morphometric and immunohistochemical study

Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disease caused by an expansion of CAG repeats in the MJD1 gene, in which lower urinary tract dysfunction is known to be the most commonly encountered autonomic failure. However, it remains unclear whether Onuf’s nucleus (ON), which plays major roles in the micturition reflex and voluntary continence, degenerates during the disease process. In the present study, we conducted a morphometric and immunohistochemical study of ON, together with the lateral nuclear group (LNG) of the sacral anterior horns, in seven patients with MJD. When compared with controls, the number of lower motor neurons in both ON and LNG was significantly smaller in the MJD patients, the former being inversely correlated with the size of the expanded CAG repeats. Notably, MJD patients with a large CAG-repeat expansion showed an ON-predominant pattern of neuronal loss, while in the remaining patients, ON and LNG were affected to a similar degree, or rather an LNG-predominant pattern of neuronal loss was evident. Moreover, when adjusted for age, the degree of neuronal loss in both ON and LNG was significantly correlated with the extent of expansion of the CAG repeats. In MJD, the remaining lower motor neurons in ON often exhibited ataxin-3- or 1C2-immunoreactive (ir) neuronal intranuclear inclusions, while no pTDP-43-ir neuronal cytoplasmic inclusions were present in these neurons. In conclusion, the present findings strongly suggest that neuronal loss in ON, the degree of which is highly influenced by the extent of expansion of CAG repeats, is a consistent feature in MJD.     

Extensive cortico-subcortical lesions in Wilson’s disease: clinico-pathological study of two cases

Wilsons disease (WD) with extensive cortico-subcortical lesions represents a rare neuropathological subgroup, the pathogenesis of which is not clearly determined. We report two new cases with identical lesions. In the families of each of the patient, there were mutations in the ATPase7B gene, especially in the family of proband 1, and in the first cousin of proband 2. These cases included massive destruction of the white matter in superior gyri, mostly frontal, extending to the deep cortex with neuronal loss and capillary proliferation. Astrocytes were of Alzheimer type 1 and 2; and type 1 were labeled by anti-metallothionein. Opalski cells were abundant and their macrophagic lineage was confirmed by immunostaining. Among the possible mechanisms proposed, the role of vascular factors and penicillamine treatment could be excluded. Cerebral copper content in white matter and putamen of case 1 was at the same level as in common WD but accumulation of unbound copper in the white matter was a distinctive feature, which suggested a pathological neurotoxic effect.     

A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease

The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein.     

A voxel-based morphometric study of cortical gray matter volume changes in Alzheimer’s disease with white matter hyperintensities

White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer’s disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p < 0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p < 0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.     

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease

Four decades after L-dopa introduction to PD therapy, the cause of Parkinson's disease (PD) remains unknown despite the intensive research and the discovery of a number of gene mutations and deletions in the pathogenesis of familial PD. Different model neurotoxins have been used as preclinical experimental models to study the neurodegenerative process in PD, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone. The lack of success in identifying the molecular mechanism for the degenerative process in PD opens the question whether the current preclinical experimental models are suitable to understand the degeneration of neuromelanin-containing dopaminergic neurons in PD. We propose aminochrome as a model neurotoxin to study the neurodegenerative processes occurring in neuromelanin-containing dopaminergic neurons in PD. Aminochrome is an endogenous compound formed during dopamine oxidation and it is the precursor of neuromelanin, a substance whose formation is a normal process in mesencephalic dopaminergic neurons. However, aminochrome itself can induce neurotoxicity under certain aberrant conditions such as (i) one-electron reduction of aminochrome catalyzed by flavoenzymes to leukoaminochrome o-semiquinone radical, which is a highly reactive neurotoxin; or (ii) the formation of aminochrome adducts with alpha-synuclein, enhancing and stabilizing the formation of neurotoxic protofibrils. These two neurotoxic pathways of aminochrome are prevented by DT-diaphorase, an enzyme that effectively reduces aminochrome with two-electrons preventing both aminochrome one-electron reduction or formation alpha synuclein protofibrils. We propose to use aminochrome as a preclinical experimental model to study the neurodegenerative process of neuromelanin containing dopaminergic neurons in PD.     

The long-term effects of febrile seizures on the hippocampal neuronal plasticity – Clinical and experimental evidence

Febrile seizures are the most common seizure disorder in childhood, but their long-term effects on the developing brains especially neuronal injury and neurocognitive function remain unresolved. Recent epidemiological studies reassure that most febrile seizures do not adversely affect global intelligence and hippocampal function, such as memory. However, there are concerns regarding those children who experience febrile seizures during the first postnatal year, having prior developmental delay and pre- or peri-natal events. Magnetic resonance imaging (MRI) studies confirmed that prolonged and focal FS can occasionally produce acute hippocampal injury that evolves into atrophy. Animal studies have revealed that the exposure of hippocampal neurons to experimental febrile seizures early in life, particularly prolonged or frequently repetitive FS, or together with brain malformation, may lead to sustained dysfunction of these cells, in spite of the absence of neuronal damage. Genetic studies suggest that the relationship between febrile seizures and subsequent epilepsy and neurocognitive dysfunction is sometimes genetic, but there are complex interactions with genetic or environmental modifiers. Therefore, there is a small group of children in whom febrile seizures-induced hippocampal injury might occur. Identification of the target population for subsequent mesial temporal sclerosis is important for prevention and early intervention.     

Expression of apolipoprotein E in ballooned neurons—Comparative immunohistochemical study on neurodegenerative disorders and infarction

Apolipoprotein E (ApoE) in neurons is suggested to play crucial roles in neuronal degeneration and regeneration. We used antibodies against ApoE and phosphorylated neurofilament (pNF) to investigate the immunohistochemical features of ballooned neurons (BNs) in infarction and in various chronic degenerative disorders, including Pick body disease, corticobasal degeneration/progressive supranuclear palsy, Alzheimer's disease, and frontotemporal dementia. BNs in these chronic degenerative processes were intensely labeled with the anti-pNF as reported, whereas BNs in infarction showed less intense pNF-like immunoreactivity (IR). In addition, BNs in infarction were characterized by an intense ApoE-like IR. This ApoE-like IR was inconsistent or less intense in BNs in the chronic degenerative processes. The rarity of ApoE-positive glial cells in the vicinity of ApoE-positive BNs suggests that accumulated ApoE in BNs is generated in the neurons. Accumulation of ApoE in BNs in infarction may be linked to a regenerative process after acute transection of axons, which seems compromised in chronic degenerative processes.     

Effects of rTMS on Parkinson’s disease: a longitudinal fMRI study

Parkinson’s disease is a movement disorder whose principal symptoms are tremor, rigidity, bradykinesia and postural instability. Initially, drugs like l-dopa or dopaminergic agonists are able to control these symptoms, but with the progress of the disease these drugs become less effective. Previous studies have reported that repetitive transcranial magnetic stimulation (rTMS) can improve these motor symptoms. The objective of this study was to investigate the neural mechanisms through which 25 Hz rTMS may improve motor symptoms in Parkinson’s disease. In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz. rTMS in 10 Parkinson’s disease patients. Fifteen rTMS sessions were performed over the primary cortex on both hemispheres (one after the other) during a 12-week period. The patients were studied using functional magnetic resonance imaging during performance of a simple tapping and a complex tapping task, 1 week before the administration of the first rTMS session and just after the last session. rTMS improved bradykinesia, while functional magnetic resonance imaging showed different cortical patterns in prefrontal cortex when patients performed the complex tapping test. Furthermore, the improvement in bradykinesia is associated with caudate nucleus activity increases in simple tapping. Finally, we observed a relative change in functional connectivity between the prefrontal areas and the supplementary motor area after rTMS. These results show a potential beneficial effect of repetitive transcranial magnetic stimulation on bradykinesia in Parkinson’s disease which is substantiated by neural changes observed in functional magnetic resonance imaging.     

The influence of methylphenidate on the power spectrum of ADHD children – an MEG study

Background

The present study was dedicated to investigate the influence of Methylphenidate (MPH) on cortical processing of children who were diagnosed with different subtypes of Attention Deficit Hyperactivity Disorder (ADHD). As all of the previous studies investigating power differences in different frequency bands have been using EEG, mostly with a relatively small number of electrodes our aim was to obtain new aspects using high density magnetoencephalography (MEG).

Methods

35 children (6 female, 29 male) participated in this study. Mean age was 11.7 years (± 1.92 years). 17 children were diagnosed of having an Attention-Deficit/Hyperactivity Disorder of the combined type (ADHDcom, DSM IV code 314.01); the other 18 were diagnosed for ADHD of the predominantly inattentive type (ADHDin, DSM IV code 314.0). We measured the MEG during a 5 minute resting period with a 148-channel magnetometer system (MAGNES? 2500 WH, 4D Neuroimaging, San Diego, USA). Power values were averaged for 5 bands: Delta (D, 1.5–3.5 Hz), Theta (T, 3.5–7.5 Hz), Alpha (A, 7.5–12.5 Hz), Beta (B, 12.5–25 Hz) and Global (GL, 1.5–25 Hz).). Additionally, attention was measured behaviourally using the D2 test of attention with and without medication.

Results

The global power of the frequency band from 1.5 to 25 Hz increased with MPH. Relative Theta was found to be higher in the left hemisphere after administration of MPH than before. A positive correlation was found between D2 test improvement and MPH-induced power changes in the Theta band over the left frontal region. A linear regression was computed and confirmed that the larger the improvement in D2 test performance, the larger the increase in Theta after MPH application.

Conclusion

Main effects induced by medication were found in frontal regions. Theta band activity increased over the left hemisphere after MPH application. This finding contradicts EEG results of several groups who found lower levels of Theta power after MPH application. As relative Theta correlates with D2 test improvement we conclude that MEG provide complementary and therefore important new insights to ADHD.     

Impact of multiple traumatic experiences on the persistence of depressive symptoms – a population-based study

The objective of this population-based study was to determine whether traumatic experiences in general, and multiple traumatic experiences in particular, are associated with persistent self-rated depressive symptoms in adult Finnish subjects over 2?years of follow-up. The study sample included 1405 subjects aged 25–64?years. Subjects (n=217) who were depressed both at baseline in 1999 and on follow-up 2?years later in 2001 (having persistent depressive symptoms) were compared with subjects (n=987) having no depressive symptoms either at baseline or on follow-up. All six categories of traumatic experiences (wartime experience, natural disaster, life-threatening accident, victim of violent crime, domestic violence and childhood sexual abuse) pertained to the respondents’ whole life span. Odds ratios, adjusted for significant covariates, were obtained from multiple logistic regression models that estimated the likelihood of persistent depressive symptoms in different trauma categories. Persistent depressive symptoms had a significant positive graded relationship with the number of traumatic experiences. The adjusted odds of persistent depression was 6.05 (95% CI 1.76–20.7) for men and 6.99 (95% CI 2.69–18.2) for women in those with three or more traumatic experiences compared with those with no such experiences at all. Multiple traumatic experiences substantially increase the likelihood of persistent depressive symptoms. Mental health intervention, as early as possible, may serve to prevent the chronicity of depressive reactions among victims of multiple traumas.     

Effect of type-2 astrocytes on the viability of dorsal root ganglion neurons and length of neuronal processes简

The role of type-2 astrocytes in the repair of central nervous system injury remains poorly un- derstood. In this study, using a relatively simple culture condition in vitro, type-2 astrocytes, differentiated from oligodendrocyte precursor cells by induction with bone morphogenetic pro- tein-4, were co-cultured with dorsal root ganglion neurons. We examined the effects of type-2 astrocytes differentiated from oligodendrocyte precursor cells on the survival and growth of dorsal root ganglion neurons. Results demonstrated that the number of dorsal root ganglion neurons was higher following co-culture of oligodendrocyte precursor cells and type-2 astrocytes than when cultured alone, but lower than that of neurons co-cultured with type-1 astrocytes. The length of the longest process and the length of all processes of a single neuron were shortest in neurons cultured alone, followed by neurons co-cultured with type-2 astroc~es, then neurons co-cultured with oligodendrocyte precursor cells, and longest in neurons co-cultured with type-1 astrocytes. These results indicate that co-culture with type-2 astrocytes can increase neuronal survival rate and process length. However, compared with type-1 astrocytes and oligodendrocyte precursor cells, the promotion effects of type-2 astrocytes on the growth of dorsal root ganglion neurons were weaker.