Signs Of Neurological Disease Research Articles

Report of an unusual association of Oropouche Fever with Guillain-Barré syndrome in Cuba, 2024.

Oropouche virus is the aetiological agent of Oropouche fever. At present, this is currently considered one of the most important vector-borne diseases in Latin America. On 27 May 2024, the Ministry of Public Health of Cuba reported the first ever outbreak of Oropouche fever. In this report, we describe three human cases of Oropouche virus infection with symptoms and signs of neurological disease and clinical diagnosis of Guillain-Barré Syndrome. This study offers insights regarding that Oropouche virus is a causal agent of neurological disorders and it could be involved in the etiology of the Guillain-Barré Syndrome.

Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs.

Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed-specific variants are reported. Characterize the putatively causative GALC variant for GCL in a family of dogs and determine population allele frequency. Four related mixed-breed puppies with signs of neurologic disease were evaluated. Subsequently, 33 related dogs were tested for genetic markers for parentage and the identified GALC variant. Additional GALC genotyping was performed on 278 banked samples from various breeds. The 4 affected puppies had neurological exams and necropsies. DNA was isolated from blood samples. Variants in GALC were identified via Sanger sequencing. Parentage testing was performed using short tandem repeat markers. Prevalence of the GALC variant of interest was investigated in other breeds. GCL was confirmed histopathologically. A novel missense variant in GALC (NC_006590.4:g.58893972G>A) was homozygous in all affected animals (n = 4). A recessive mode of inheritance was confirmed by parentage testing as was variant linkage with the phenotype (LOD = 3.36). Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population. A novel GALC variant was identified that likely explains GCL in this cohort. The identification of multiple causal variants for GCL in dogs is consistent with findings in humans.

Functional Characterization of a Familial ALS-Associated Missense TBK1 (p-Arg573Gly) Mutation in Patient-Derived Lymphoblasts.

The goal of this work was to elucidate the pathogenic mechanism of an ALS-associated missense mutation, p.Arg573Gly (R573G), in the TBK1 gene. In particular, we seek to analyze the influence of this variant on the cellular levels and the function of TBK1 in immortalized cells from an ALS patient. The patient (Code# E7) belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or ALS. Four control individuals without signs of neurological disease were also included in this study. Our results indicate that the R375G TBK1 mutation did not affect the levels of mRNA nor the total TBK1 content; however, we observed a significant decrease in the levels of TBK1 phosphorylation, which is essential for TBK1 activity, as well as a significant reduction in the phosphorylation of p62 and RIPK1, known substrates for TBK1. Lymphoblasts from the R573G TBK1 mutation carrier patient display pathological TDP-43 homeostasis, showing elevated levels of phosphorylated TDP-43 and accumulation of the protein in the cytosolic compartment. In addition, the functional decrease in TBK1 activity observed in the E7 patient did not alter the autophagy flux, but it seems to be enough to increase ROS levels as well as the expression of pro-inflammatory cytokine IL-6.

On the Primary Influences of Age on Articulation and Phonation in Maximum Performance Tasks

Maximum performance tasks have been identified as possible domains where incipient signs of neurological disease may be detected in simple speech and voice samples. However, it is likely that these will simultaneously be influenced by the age and sex of the speaker. In this study, a comprehensive set of acoustic quantifications were collected from the literature and applied to productions of sustained [a] productions and Alternating Motion Rate diadochokinetic (DDK) syllable sequences made by 130 (62 women, 68 men) healthy speakers, aged 20–90 years. The participants were asked to produce as stable (sustained [a] and DDK) and fast (DDK) productions as possible. The full set of features were reduced to a functional subset that most efficiently modeled sex-specific differences between younger and older speakers using a cross-validation procedure. Twelve measures of [a] and 16 measures of DDK sequences were identified across men and women and investigated in terms of how they were altered with increasing age of speakers. Increased production instability is observed in both tasks, primarily above the age of 60 years. DDK sequences were slower in older speakers, but also altered in their syllable and segment level acoustic properties. Increasing age does not appear to affect phonation or articulation uniformly, and men and women are affected differently in most quantifications investigated.

Study of Clinical Profile of Neonatal Seizures in Level III NICU

Background: During the neonatal age, seizures are the most distinctive sign of neurological disease. Convulsive symptoms are the most promi- nent forms of neonatal neurological disorders. The goal of this research was to have a better view of the epidemiology, etiology, incidence, forms and mortality of neonatal seizures in our hospital. This research was undertaken to evaluate the prevalence, forms of neonatal seizures, etiology, occurrence period and correlation with etiology, and to establish the mortality correlated with neonatal seizures. For research the etiology and its etiological connection, the occurrence of neonatal seizures. Subjects and Methods: A comprehensive history was collected for the antenatal, natal, postnatal and family history. Age of initiation, form, duration and amount of seizures, consciousness before and after the seizures were taken. Comprehensive neonate examination was performed after detailed history. Relevant investigations were carried out depending upon clinical presentation. Results: In our analysis of 200 neonatal seizures, 194 had one of the four classically identified neonatal seizures. Multifocal clonic seizures were among the most common type of seizures 36% (72 cases) followed by subtle 27% (54 cases), GTS 26% (52 cases), Myoclonic 7% (15 cases), mixed type of seizures 3% (6 cases) and focal clonic seizures 1% (2 cases). Conclusion: Because neonatal seizures are most frequently due to birth asphyxia, better antenatal and perinatal care reduces birth asphyxia and if mothers are identified as high-risk. The impact of neonatal seizures is thereby minimized. Subtle seizures are the most frequent form of psychiatric seizure; thus, close monitoring of newborns at risk is important.

IL-22 hinders antiviral T cell responses and exacerbates ZIKV encephalitis in immunocompetent neonatal mice

BackgroundThe Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of nervous system injuries and congenital defects. However, host immunity- and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays, a role in ZIKV infection is unknown.MethodsThe cellular source of IL-22 was identified in IFNAR-/- mice and wild-type (WT) neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old WT and IL-22-/- mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, glial cells were cultured in vitro and infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression, and viral loads.ResultsWe found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to exhibit weight loss, staggered steps, bilateral hind limb paralysis, and weakness at 10 days post-infection (dpi) and ultimately succumbed to infection at 16–19 dpi. IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly improved clinical signs of neurological disease and mortality. ZIKV infection also induced the activation of microglia and astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a negligible effect on glial cells in vitro, IL-22-/- mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain.ConclusionsOur data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

Comparison of 2 collection methods for cerebrospinal fluid analysis from standing, sedate adult horses

BackgroundCerebrospinal fluid (CSF) analysis is an important component of the evaluation of horses with neurologic disease. Lumbosacral (LS) centesis is routine, but CSF is also collected from the space between the first and second cervical vertebrae (C1‐C2).ObjectivesTo compare collection times, CSF cytology results, and equine protozoal myelitis (EPM) titers of CSF collected from the C1‐C2 and LS sites.AnimalsFifteen university‐owned adult horses with no evidence of neurologic disease, and 9 horses with signs of neurologic disease: 3 university‐owned and 6 client‐owned.MethodsProspective study. Cerebrospinal fluid collection from the LS space and C1‐C2 space of each horse was performed in randomized order. Continuous data were analyzed using mixed‐effects linear models and count data using mixed‐effects negative binomial regression. Statistical significance was set at P < .05.ResultsCerebrospinal fluid collected from the C1‐C2 site had a significantly lower mean protein concentration (49 [95% CI: 43‐55.8] mg/dL C1‐C2 versus 52.1 [95% CI: 45.7‐59.3] mg/dL LS; P = .03) and red blood cell count (6 [95% CI: 2‐16] cells/μL versus 33 [95% CI: 13‐81] cells/μL; P = .02). Collection time, total nucleated cell count, EPM titers, and serum:CSF EPM titer ratios were not significantly different between collection sites.Conclusions and Clinical ImportanceCerebrospinal fluid from the C1‐C2 space provides an acceptable alternative to LS CSF collection with decreased likelihood of clinically important blood contamination of samples.

The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII

Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8–25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003-CL301; NCT02377921), receiving 24–48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (GAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blind-start study.Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to non-compliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. Out of the eleven subjects who tested positive for anti-drug antibodies at any time during the blind-start or extension study, including the baseline assessment in the blind-start study, seven subjects tested positive for neutralizing antibodies and all seven continued to demonstrate a reduction in urinary GAG levels. There was no association between antibody formation and infusion associated reactions.Subjects receiving continuous vestronidase alfa treatment showed a sustained urinary GAG reduction and clinical response evaluated using a multi-domain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reduction in fatigue was also maintained in the overall population. As ERT is not expected to cross the blood brain barrier, limiting the impact on neurological signs of disease, and not all subjects presented with neurological symptoms, outcomes related to central nervous system pathology are not focused on in this report.Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.

Bioluminescence Imaging of Neuroinflammation in a Mouse Model of Parkinson's Disease.

In Parkinson's disease (PD) and related disorders pathological alpha-synuclein has been discussed to propagate via a prion-like mechanism in the CNS. The application of exogenous alpha-synuclein fibrils via injection to animal models of PD has been shown to be a useful method to study prion-like propagation of pathological alpha-synuclein and of transmission pathways that play a critical role in recapitulating characteristics of synucleinopathies. Using bigenic mice expressing mutant human alpha-synuclein in neurons and firefly luciferase in astrocytes we showed that transmission via the tongue and the peritoneum represent entrance points for pathological alpha-synuclein to invade the CNS. Here we present a method to quantify astrogliosis by bioluminescence imaging in an animal model of PD. This method allows noninvasive tracking of the neuroinflammatory process that often precedes neurological signs of disease and represents an alternative to behavioral or histological and biochemical analysis to detect disease.

Human and Equine Infection with Alphaviruses and Flaviviruses in Panamá during 2010: A Cross-Sectional Study of Household Contacts during an Encephalitis Outbreak.

Members of the genera Alphavirus (family Togaviridae) and Flavivirus (family Flaviridae) are important zoonotic human and equine etiologic agents of neurologic diseases in the New World. In 2010, an outbreak of Madariaga virus (MADV; formerly eastern equine encephalitis virus) and Venezuelan equine encephalitis virus (VEEV) infections was reported in eastern Panamá. We further characterized the epidemiology of the outbreak by studying household contacts of confirmed human cases and of equine cases with neurological disease signs. Serum samples were screened using a hemagglutination inhibition test, and human results were confirmed using plaque reduction neutralization tests. A generalized linear model was used to evaluate the human MADV and VEEV seroprevalence ratios by age (in tercile) and gender. Overall, antibody prevalence for human MADV infection was 19.4%, VEEV 33.3%, and Mayaro virus 1.4%. In comparison with individuals aged 2-20 years, people from older age groups (21-41 and > 41 years) were five times more likely to have antibodies against VEEV, whereas the MADV prevalence ratio was independent of age. The overall seroprevalence of MADV in equids was 26.3%, VEEV 29.4%, West Nile virus (WNV) 2.6%, and St. Louis encephalitis virus (SLEV) was 63.0%. Taken together, our results suggest that multiple arboviruses are circulating in human and equine populations in Panamá. Our findings of a lack of increase in the seroprevalence ratio with age support the hypothesis of recent MADV exposure to people living in the affected region.

A quantitative EEG and MRI analysis of intermittent temporal slowing in the elderly

ObjectiveWhereas the correlation between diffuse slowing of EEG activity and neurodegenerative diseases such as Alzheimer’s disease is well established, intermittent slowing over the temporal regions, which is a frequent finding in the elderly, does not have a specific clinical correlate. In this study, we compared quantitative EEG parameters between patients with temporal slowing with no signs of neurological disease and controls to evaluate cortical function in the temporal lobes and other cerebral regions. We also compared the width of the temporal lobes on magnetic resonance imaging (MRI). MethodsMean dominant frequency and relative power in delta, theta, alpha, and beta frequency bands were examined in 20 patients older than 60 years with intermittent temporal slowing and 20 age-matched controls without significant lesions on MRI or medical conditions known to affect the EEG. Furthermore, the correlation between the frequency of temporal slowing and the mean dominant frequency and the width of the medial temporal lobes on MRI were examined. ResultsMean dominant frequency and the relative power in the beta frequency band was lower in patients with temporal slowing than in controls in all of the cortical regions examined. No significant correlation was found between the frequency of slowing and the mean dominant frequency. There was no significant difference in the width of the medial temporal lobes. ConclusionsIntermittent temporal slowing was correlated with diffusely reduced mean dominant frequency and a shift in relative power to lower frequency bands. SignificanceThe results suggest that subclinical diffuse cerebral pathology may be present in subjects with intermittent temporal slowing, but prospective studies including tests of cognitive function, cerebral perfusion, metabolic status, and advanced neuroimaging should be conducted.

Neurologisch onderzoek bij paarden in de praktijk

Een grondig neurologisch onderzoek is aangewezen wanneer een paard tekenen vertoont van zenuwstoornissen maar ook in gevallen waarbij het belangrijk is te bevestigen dat een paard neurologisch normaal is. Het voornaamste doel van het neurologisch onderzoek is uitmaken of er neurologische afwijkingen zijn en in tweede instantie wordt getracht de primaire oorzaak en lokalisatie hiervan te achterhalen. Een gestandaardiseerde van-kop-tot-staartbenadering vermijdt dat er afwijkingen over het hoofd gezien worden. Daarom start het onderzoek steeds met het afnemen van een goede anamnese, observatie van het paard met aandacht voor het bewustzijn, gedrag, houding en stand en met een klinisch onderzoek. Vervolgens worden de kopzenuwen getest door middel van onder andere dreig-, pupil- en ooglidreflex. De hals, romp, ledematen en staart worden onderzocht om asymmetrieën of toegenomen of verminderde sensatie aan het licht te brengen. Daarna wordt het paard in beweging bekeken waarbij vooral de overgangen en het stappen in kleine cirkels en zigzaglijnen, gebreken in de coördinatie kunnen aantonen. Het onderscheid met orthopedische problemen is echter niet altijd eenvoudig te maken. Vooral paarden in laterale decubitus vormen een extra uitdaging voor de onderzoeker aangezien het neerliggen op zich reeds een afwijking in responsen kan veroorzaken. Bijkomend onderzoek is daarom vaak gewenst om een neurologisch probleem te bevestigen of om een letsel in beeld te brengen. Bloedonderzoek (algemeen, serologie, virusisolatie), lever- of spierbiopten, onderzoek van cerebrospinaal vocht en radiografieën kunnen in de praktijk uitgevoerd worden. In gespecialiseerde centra zijn elektrodiagnostische testen beschikbaar en uitgebreide beeldvormingsmogelijkheden (CT, MRI, scintigrafie). Door deze technieken te combineren met het klinisch neurologisch onderzoek kan een (differentiaal)diagnose (op)gesteld worden.

Characterization of a Novel Murine Model to Study Zika Virus.

The mosquito-borne Zika virus (ZIKV) is responsible for an explosive ongoing outbreak of febrile illness across the Americas. ZIKV was previously thought to cause only a mild, flu-like illness, but during the current outbreak, an association with Guillain–Barré syndrome and microcephaly in neonates has been detected. A previous study showed that ZIKV requires murine adaptation to generate reproducible murine disease. In our study, a low-passage Cambodian isolate caused disease and mortality in mice lacking the interferon (IFN) alpha receptor (A129 mice) in an age-dependent manner, but not in similarly aged immunocompetent mice. In A129 mice, viremia peaked at ∼107 plaque-forming units/mL by day 2 postinfection (PI) and reached high titers in the spleen by day 1. ZIKV was detected in the brain on day 3 PI and caused signs of neurologic disease, including tremors, by day 6. Robust replication was also noted in the testis. In this model, all mice infected at the youngest age (3 weeks) succumbed to illness by day 7 PI. Older mice (11 weeks) showed signs of illness, viremia, and weight loss but recovered starting on day 8. In addition, AG129 mice, which lack both type I and II IFN responses, supported similar infection kinetics to A129 mice, but with exaggerated disease signs. This characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines.

Communicating With the Motor Cortex? Cortisol and Yawning As Possible Biomarkers for the Detection of Neurological Disease

Cortisol and yawning have been proposed as new potential biomarkers for the early detection of signs of neurological disease. Recent evidence from neuroscience has shown that there is communication between the motor cortex and more remote but vital centres such as the brain-stem and hypothalamus. Hormonal as well as neuronal links form the prosed network that influences and monitors the regulation of cortisol and the regulation of brain temperature governed by the hypothalamus. This evidence tends to support the prosed linkage between brain-stem, hypothalamus and motor cortex and lends support for the Thompson Cortisol Hypothesis which proposes threshold levels of cortisol elicit yawning for brain cooling, and parakinesia brachialis oscitans, the observed arm movement seen in brain-stem ischaemic stroke patients during involuntary yawning.

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15-25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood-brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8(+) effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood-brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8(+) T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.

Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction?

Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95% CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95% CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ (2) test, p<0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (χ (2) test, left eye and right eye: p<0.0001), associated with horizontal gaze-evoked nystagmus (χ (2) test, p<0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease.

Neurological Examination and Diagnostic Testing in Birds and Reptiles

Neurological dysfunction is a frequently presenting sign in avian and reptile patients. Clinical neurological signs are rarely pathognomonic, often requiring the attending veterinary surgeon to perform more involved diagnostic tests to achieve a diagnosis. Variations in patient anatomy, physiology and demeanour present unique challenges to the veterinarian evaluating the bird or reptile that has neurological disease signs. Despite these challenges, a well-structured physical and neurological examination can often be accomplished with minimal equipment. A structured neurological examination is essential to formulate an appropriate investigative plan and therapeutic regime for these difficult cases and to provide the owner with an accurate prognosis.

Suspect West Nile encephalitis in a horse imported into the UK from Europe

The authors have detected West Nile virus-specific antibodies in a horse in the UK with signs of neurological disease. The horse had recently been imported from Europe and does not...

Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease.

The neuropathological substrate of dementia in patients with Parkinson's disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinson's disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinson's disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippocampus of six demented and five non-demented patients with Parkinson's disease and five age-matched control individuals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippocampus and frontal cortex of eight demented and eight non-demented patients with Parkinson's disease, as well as in the same areas of eight age-matched controls. All patients with Parkinson's disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinson's disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippocampal cholinergic activity was consistently reduced in all patients with Parkinson's disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinson's disease dementia were differentiated by a significant reduction in hippocampal cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippocampus. Overall, these results point to increasing α-synuclein deposition and hippocampal dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinson's disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinson's disease.

Fatal Disseminated Toxoplasmosis in a Black Bear Cub

ABSTRACT A black bear (Ursus americanus) cub with signs of neurological disease was captured in West Milford, NJ. The animal died in captivity and was examined because of suspected rabies. At necropsy, the lungs were reddened and noncollapsed and had multiple pale round foci. Foci of necrosis were associated with Toxoplasma gondii cysts and tachyzoites in several organs. Rabies antigen was not detected.