Neurodegenerative proteinopathies associated with neuroinfections.

Infectious agents, including viruses and bacteria, are proposed to be involved in the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, these agents have capacity to evade the host immune system leading to chronic infection, inflammation, and subsequent deposition of Aß and phosphorylated-tau in the brain. Co-existing proteinopathies and age-related pathologies are common in AD and the brains of elderly individuals, but whether these are also related to neuroinfections remain to be established. This study determined the prevalence and distribution of neurodegenerative proteinopathies in patients with infection-induced acute or chronic inflammation associated with herpes simplex virus (HSV) encephalitis (n = 13) and neurosyphilis (n = 23). The mean age at death in HSV patients was 53 ± 12 years (range 24-65 years) and survival was 9 days-6 years following initial infection. The mean age at death and survival in neurosyphilis patients was 60 ± 15 years (range 36-86 years) and 1-5 years, respectively. Neuronal tau-immunoreactivity and neurites were observed in 8 HSV patients and 19 neurosyphilis patients, and in approximately half of these, this was found in regions associated with inflammation and expanding beyond regions expected from the Braak stage of neurofibrillary degeneration. Five neurosyphilis patients had cortical ageing-related tau astrogliopathy. Aß-plaques were found in 4 HSV patients and 11 neurosyphilis patients. Lewy bodies were observed in one HSV patient and two neurosyphilis patients. TDP-43 pathology was absent. These observations provide insights into deposition of neurodegenerative proteins in neuroinfections, which might have implications for COVID-19 patients with chronic and/or post-infectious neurological symptoms and encephalitis.

Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions.

The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease-related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including α-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or α-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.

Pellagra encephalopathy as a differential diagnosis for Creutzfeldt-Jakob disease.

In the present study we evaluated cases referred as suspected Creutzfeldt-Jakob disease (CJD). Five out of 59 without prion disease showed neuropathological features of pellagra encephalopathy with widespread chromatolytic neurons (age range 40-48 years at death; one woman). These patients presented with a progressive neuropsychiatric disorder lasting for 2 to 24 months. Common symptoms included gait disorder, para- or tetraspasticity, extrapyramidal symptoms, incontinence, and myoclonus. Protein 14-3-3 in the cerebrospinal fluid was examined in a single patient and was positive, allowing the clinical classification as probable sporadic CJD. Pellagra encephalopathy may be considered as a differential diagnosis of CJD including detection of protein 14-3-3.

Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy.

The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, α-synuclein, and amyloid-ß has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrP(res) detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-ß in 53.8%, amyloid angiopathy (Aß) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type α-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins.

TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea.

TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.

White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration.

Frontotemporal lobar degenerations are a group of disorders characterized by circumscribed degeneration of the frontal and temporal lobes and diverse histopathologic features. We report clinical, neuropathologic, ultrastructural, biochemical, and genetic data on 7 individuals with a 4-repeat tauopathy characterized by the presence of globular glial inclusions (GGIs) in brain white matter. Clinical manifestations were compatible with the behavioral variant of frontotemporal dementia and included motor neuron symptoms; there was prominent neuronal loss in the frontal and temporal cortex, subiculum, and amygdala. The surrounding white matter showed abundant GGIs composed of abnormal filaments present mostly in oligodendrocytes. The severity of white matter tau abnormalities correlated with a reduction in myelin and axons and with microglial activation. Western blotting of sarkosyl-insoluble tau demonstrated the presence of 2 major tau bands of 64 and 68 kd. No mutations in the microtubule-associated protein tau gene were detected in 2 affected individuals. We propose that 4-repeat tau-immunoreactive GGIs are the neuropathologic hallmark of a distinct sporadic tauopathy with variable clinical presentations that include frontotemporal dementia and occasionally upper motor neuron disease. This type of tauopathy with GGIs expands the group of neurodegenerativedisorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders.

Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age.

Dysfunction of mesocorticolimbic dopaminergic neurons is considered a common feature of all drugs of abuse, yet few investigations have evaluated the dopamine (DA) system in nonstimulant human abusers. We examined mRNA expression levels of DA transporter (DAT), tyrosine hydroxylase (TH), dopamine D2 receptor, alpha-synuclein, and nuclear receptor-related 1 (Nurr1) in discrete mesocorticolimbic and nigrostriatal subpopulations of heroin users and control subjects. The chronic use of heroin was significantly associated with decreased DAT mRNA expression localized to the paranigral nucleus (PN) and the mesolimbic division of the ventral tegmental area (VTA) with no alterations in nigrostriatal populations. Consistently, the density of DAT immunoreactivity was significantly reduced in the nucleus accumbens but not in dorsal striatum, mesolimbic and nigrostriatal efferent targets, respectively. Significant alteration of the mRNA expression of Nurr1, a transcription factor that regulates DAT expression, was also confined to the PN. Moreover, the results revealed an exaggerated reduction of Nurr1 expression with age in heroin users (r = -0.8268, p < 0.001 vs controls, r = -0.6204, p = 0.0746). TH and alpha-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D2 receptor. Evaluating midbrain mu- and kappa-opioid receptors, relevant for the action of heroin and regulation of DA neurons, revealed dysregulation of G-protein coupling selective to the VTA PN. Altogether the current findings provide direct neurobiological evidence that midbrain reward circuits have the most prominent DA and opioid impairments in human heroin abusers and that abnormal Nurr1 transcription with opiate use may exacerbate limbic dysfunction with age.

[Human prion diseases: the Hungarian experience]. / Emberi prionbetegségek: magyarországi tapasztalatok.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease is the most frequent human prion disease. Genetic forms are associated with mutations in the human prion protein gene (PRNP) and thought to comprise 5-15% of cases. Acquired forms include iatrogenic and variant Creutzfeldt-Jakob disease. The latter is associated with the bovine spongiform encephalopathy. We recently reported the high incidence of genetic Creutzfeldt-Jakob disease in Hungary. MATERIALS AND METHODS: In the present study we summarize the results of a widened investigation comprising Creutzfeldt-Jakob disease cases collected in the National Institute of Psychiatry and Neurology, Hungary in the last 12 years. We examined the disease forms and their geographical distribution. RESULTS: Our study involved 155 patients. The four major results are as follows: 1. In Hungary we detected only sporadic and genetic forms of human prion disease, while iatrogenic and variant Creutzfeldt-Jakob disease were not observed. 2. The proportion of genetic prion disease (E200K mutation), similarly to Slovakia, is higher than reported worldwide. Our observations indicate that at least every third case is genetic Creutzfeldt-Jakob disease. The mean incidence of genetic Creutzfeldt-Jakob disease (0.42/million) is unusually high. Especially the year 2006 was striking when the incidence of genetic Creutzfeldt-Jakob disease was 1.4/million. 3. More than half of genetic Creutzfeldt-Jakob disease cases lack a positive family history. 4. Some counties and the eastern part of Hungary shows elevated incidence of human prion disease. CONCLUSIONS: Differences in the geographical distribution may be related to migration and historical relationship with the Slovakian population. Based on the increased incidence of E200K mutation, genetic testing of the PRNP is recommended in all cases with atypical neuropsychiatric disorder or suspicion of prion disease.

Neuropathology of white matter disease in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is associated with point mutations in the mitochondrial DNA (mtDNA), coding for a mitochondrial respiratory chain complex I subunit. It is characterized by bilateral, usually sequential, optic neuropathy and may co-occur with multiple sclerosis-like white matter lesions. Despite repeated clinical reports including MRI and histopathological examination of the visual system, neuropathological descriptions of LHON associated with multiple sclerosis-like syndrome are lacking. We present here the case of a female patient with a point mutation at nucleotide position T14484C, who suffered from relapsing episodes of visual loss of both eyes and consecutively developed Hashimoto thyroiditis as well as widespread demyelinating CNS lesions outside the visual system. She died of bronchopneumonia at the age of 44 years, after a disease duration of 19 years, with progressive deterioration, epileptic seizures and immobility. Immunohistochemical analysis on formalin-fixed and paraffin-embedded tissue reveals a spectrum of neuropathological changes, including actively and inactively demyelinating plaques in the white matter and optic nerve, vacuolation and cystic necrosis with CD8-positive T cells in the frontal lobe, axonal damage, and vacuolation of white matter. Tissue destruction is associated with upregulation of mitochondrial manganese superoxide dismutase within the lesions and an increase in the expression of inducible nitric oxide synthase within macrophages and microglia. This variable phenotype of extraoptic LHON disease suggests that mtDNA mutations may affect the nervous system on a common metabolic basis and occasionally may aggravate or initiate autoimmune pathology.

Creutzfeldt-Jakob disease in Hungary.

Human prion diseases or transmissible spongiform encephalopathies are progressive fatal neuropsychiatric diseases. In addition to the evaluation of clinical features, a common diagnostic procedure includes examination of the protein 14-3-3 in the cerebrospinal fluid, performing EEG to detect periodic sharp wave complexes with triphasic morphology, and cranial MRI to demonstrate high signal intensity in the basal ganglia or thalamus. The definite diagnosis requires a neuropathological examination. The analysis of the prion protein gene (PRNP) is initiated mainly after suspicion of a positive family history or an atypical presentation. In Hungary collecting data and setting up the neuropathological diagnosis in suspect prion disease cases originates from the late 1960s. Systematic surveillance was established in 1994 and since 2001 reporting of Creutzfeldt-Jakob disease has been compulsory. According to our database, the incidence of genetic prion disease is increased in Hungary. The most frequent mutation in the PRNP is at codon 200. This might be linked to migration from the Slovakian focus. Acquired forms of prion disease were not detected in our country. The surveillance system is based on referrals from clinicians and pathologists and the aim is to perform the neuropathological examination and analysis of the PRNP on the majority of suspect cases.

A chronic Alzheimer's model evoked by mitochondrial poison sodium azide for pharmacological investigations.

Alzheimer's disease (AD) is a neurodegenerative disorder and accounts for 50-70% of all dementia cases affecting more than 12 million people worldwide. The primary cause of the disease is presently unknown; however, much evidence suggests the involvement of mitochondrial damage. Selective reduction of complex IV activity is present in post-mortem AD brains. Inhibition of this complex could be evoked by chronic sodium azide (NaN(3)) administration in animals. Partial inhibition of the mitochondrial respiratory chain produces free radicals, diminishes aerobic energy metabolism and causes excitotoxic damage creating a deleterious spiral causing neurodegeneration, a pathological process considered to underlie AD. In the present study SPRD rats were treated by various doses of NaN(3) (24-51 mg/kg per day) for 31 days via subcutaneously implanted osmotic minipumps. We have found the proper dose and duration of NaN(3) treatment which was able to cause easily detectable and reproducible cognitive changes. Animals receiving Na-azide doses under 45 mg/kg daily did not show cognitive deficits, but minor histopathological changes were already present. Doses above 45 mg/kg per day proved to be toxic in 4-week-long application causing mortality. NaN(3) dose of 45 mg/kg per day caused cognitive deficit in Morris water maze and passive avoidance tests and a decrease of spontaneous exploratory activity in open field. Histopathological but not biochemical changes were present: dendritic thickening, nerve cell loss, corkscrew-like dendrites and pycnotic nerve cells. The cognitive, behavioural and histopathological features were reproducible. The chronic Na-azide-induced mitochondrial poisoning is suitable for producing AD-like symptoms in rats and testing neuroprotective drug candidates by preventive or curative applications.

The expression of PARP, NF-kappa B and parvalbumin is increased in Parkinson disease.

Immunohistochemical techniques revealed a significant increase of poly(ADP-ribose) polymerase (PARP)-containing nuclei in the dopaminergic neurons of the substantia nigra (SN) in Parkinson disease and in diffuse Lewy body disease as compared with a group of patients with other neurodegenerative diseases and normal controls. The nuclear translocation of nuclear factor kappa B (NF-kappa B) was also noted in the same cells. The over-activation of PARP and the transcriptional activation of NF-kappa B can contribute to the pathomechanism of the disease specific lesion of the neurons in the SN. However, in another subgroup of dopaminergic cells of the SN an increased parvalbumin content was detected reflecting a natural protective mechanism against the putative increase of intracellular calcium caused by excitotoxic injury and oxidative stress.

Serum IgG and IgM ganglioside GM1 antibodies in patients with multiple sclerosis.

INTRODUCTION: In order to obtain more information concerning the pathogenic significance of ganglioside GM1 in multiple sclerosis serum polyclonal IgG and IgM antibodies to GM1 were evaluated in multiple sclerosis patients with relapsing-remitting and secondary progressive forms of the disease. PATIENTS AND METHODS: The evaluated sera were from 55 patients with clinically definite multiple sclerosis and from 20 healthy subjects. Forty-two of patients were with relapsing-remitting and 13 with secondary progressive multiple sclerosis. Antibodies to GM1 were measured using a modification of the enzyme-linked immunosorbent assay technique of Mizutamari et al (1994). RESULTS: A statistically significant difference of serum IgG antibody titres to GM1 was found between the healthy subjects and the multiple sclerosis patients with relapsing-remitting form of the disease (p = 0.04), as well as of serum IgG antibody titres to GM1 between the patients with relapsing-remitting multiple sclerosis in relapse and in remission (p = 0.01). CONCLUSION: Bearing in mind the heterogeneity of multiple sclerosis, the pathogenic significance of serum antibodies to GM1 should be interpreted concerning the precise clinical form of the disease and not the whole group of MS patients. The findings in this study argue for the possible involvement of ganglioside GM1 in the pathogenesis of demyelination in relapsing-remitting multiple sclerosis.

Virological, Neurological and Histological Investigations of a Child Born to a Mother with AIDS.

HIV-1 was isolated from a child at 6 and 9 months of age, proving the vertical transmission of infection from the mother with AIDS. The p24 antigen test of the plasma at 9 months of age was positive as well. A positive PCR reaction was detected in J34 cells, infected with the supernatant of the peripheral blood lymphocytes of the child. According to phenotypic characterization, the virus proved to be a SI (syncytium inducing) isolate, growing in PBL, MT2, J34 and other T and monocytic cell lines. The isolate was AZT sensitive. Two methods were applied for genotypic characterization: 1. Heteroduplex mobility assay (HMA), 2. Sequence analysis of a part of the env gene. On the basis of both of these methods, this virus belongs to the B subtype of HIV-1, which is prevalent mainly in Europe and in the USA. The neurological status of the child was followed regularly. At autopsy the presence of p24 antigen was detected in glial cells of the frontal cortex, proving the presence of the virus in the brain. A retardation of the development of the central nervous system could be observed as well.