Anti-neutrophil cytoplasmic antibody associated vasculitis of the brain and oral cavity: a case report.

We report a patient with a novel presentation of anti-neutrophil cytoplasmic antibody positive (ANCA+) vasculitis of the brain and oral mucosa. ANCA+ vasculitis of the brain is usually associated with pachymeningitis and hypophysitis, and there are no cases reported with simultaneous brain and oral mucosal involvement. A 35-year-old African Zambian man presented with headache and bleeding swollen gingiva. He was myeloperoxidase (MPO) antibody positive with cytoplasmic staining. His MRI showed stable small callosal, periventricular and subcortical white matter non-enhancing lesions, without change over 15 months-compatible with vasculitis. His gingival biopsy was consistent with vasculitis. His headache and oral lesions responded to oral corticosteroids and intravenous immunoglobulin which have induced clinical remission. Our patient expands the clinical syndrome of ANCA+ MPO+ C-type vasculitis of the central nervous system with headaches complicating cerebral vasculitis and oral mucosal involvement.

Anosognosia Is Associated With Greater Caregiver Burden and Poorer Executive Function in Huntington Disease.

BACKGROUND: Anosognosia, or unawareness of one's deficits, is estimated to occur in 25% to 50% of Huntington disease (HD). The relationship between anosognosia and increased caregiver burden found in other dementias has not been determined in HD. METHODS: Patient-caregiver dyads presenting to a statewide HD clinic were assessed using the Anosognosia Scale and grouped into "anosognosia" and "no anosognosia." Caregiver burden, measured by Zarit Burden Interview (ZBI) and Caregiver Burden Inventory (CBI), demographic data, and Unified Huntington's Disease Rating Scale, including Mini-Mental State Examination, Stroop, Trail Making, Verbal Fluency, and Symbol Digit Modalities Tests, were compared between groups. RESULTS: Of the 38 patients recruited, 10 (26.3%) met criteria for anosognosia. Patients with anosognosia elicited higher caregiver burden ratings on both the ZBI (mean difference 16.4 [12.1], P < .001) and CBI (16.7 [15.0], P < .005) while also demonstrating poorer executive function. Except for CAG burden score, between-group characteristics did not differ significantly. Stroop Interference predicted both anosognosia and caregiver burden. CONCLUSIONS: In HD, anosognosia is associated with greater caregiver burden and executive deficits. Its occurrence should prompt further patient assessment and increased caregiver support.

Sleep disorders of Whipple's disease of the brain.

OBJECTIVE: To understand the effects of Whipple's disease (WD) of the brain on sleep function. METHODS: Clinical and polysomnographic studies of two patients with severe disruption of sleep due to WD: a 48-year-old female with primary WD of the brain and a 41-year-old male with secondary WD of the brain. RESULTS: The patient with primary WD had hypersomnolence with severe obstructive sleep apnoea, reduced sleep efficiency, frequent waking and sleep fragmentation. The patient with secondary WD was also hypersomnolent with oculomastictory myorhythmia. He was shown to have severe sleep initiation insomnia with poor sleep efficiency, severe obstructive sleep apnoea/hypopnoea and oculomasticatory myorhythmia at sleep-wake transitions. CONCLUSION: WD of the brain may affect sleep biology in its primary and secondary forms leading to hypersomnolence from obstructive sleep apnoea, sleep fragmentation, reduced sleep efficiency, sleep initiation insomnia and intrusive oculomasticatory myorhythmia.

Early-onset Alzheimer's disease: a global cross-sectional analysis.

BACKGROUND AND PURPOSE: Little is known about factors associated with early-onset Alzheimer's disease (EOAD), which occurs before 65 years of age. The identification of factors of EOAD might provide insights into Alzheimer's disease (AD) pathogenesis. METHODS: Data from over 3000 subjects with AD from C-Path Online Data Repository were used to compare demographics, comorbidities and prescribed medications between EOAD and late-onset Alzheimer's disease (LOAD). The generalized estimating equations binomial model was used to identify factors associated with EOAD, allowing for within-trials correlation (multiple patients from one single trial). RESULTS: Despite the similar proportions in White, Asian and Black between EOAD and LOAD, a significantly higher proportion of EOAD population was from other races: Native American Indian, Alaskan and Hawaiian and other minorities (including Hispanics) (P < 0.0001); and were more likely to have anxiety or depression (P < 0.0001). A high proportion of the LOAD population reported a history of AD from any relative (70% vs. 58%); atrial fibrillation, hypertension, heart disease, stroke, hypercholesterolaemia and hypothyroidism were over-represented in LOAD (P < 0.01). LOAD patients used more risperidone and donepezil (P < 0.01). The multivariable model results showed that, compared with LOAD, EOAD patients were more frequently from other races and were more likely to have anxiety or depression, with less hypertension, stroke and atrial fibrillation. CONCLUSION: Early-onset Alzheimer's disease is found more frequently in Native American Indians, Alaskans, Hawaiians and other minorities, including Hispanics; patients with EOAD have more anxiety or depression. EOAD occurs independently of hypertension, stroke and atrial fibrillation.

Predictive gene testing for Huntington disease and other neurodegenerative disorders.

BACKGROUND: Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. AIMS: This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. METHODS: A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. RESULTS: Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. CONCLUSIONS: People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection.

Neurological disorders in a rural Western Australian population.

BACKGROUND: There is limited information on the causes of neurological disorders in an Australian rural setting. METHODS: This study reports on a prospective cohort of 160 patients (95 women and 65 men) with a mean age of 55.1 years (standard deviation 19.78 years, range 12-92 years) receiving a neurological work-up from one neurologist attending the Geraldton and Midwest region of Western Australia over a 12-month period. RESULTS: Patients were divided into 15 diagnostic classifications. Movement disorders were the most common diagnostic classification (38 of 160 or 23.75%) and Parkinson's disease was the most common movement disorder (30 of 38 or 78.95%) with an estimated period of prevalence of 187.5 persons per 1000. Of the other neurological disorder diagnosis classifications the following number of patients per group was observed: epilepsy (27 or 16.87%); neuromuscular disorders (22 or 13.75%); multiple sclerosis (12 or 7.5%); cerebrovascular disease (10 or 6.25%); headaches (7 or 4.37%); neurodegenerative (7 or 4.37%); dementias (6 or 3.75%); memory dysfunction (6 or 3.75%); gait disorders (4 or 2.5%); vestibular syndrome (3 or 1.87%); pain syndrome (3 or 1.87%); sensory syndrome (2 or 1.25%); brain injury (1 or 0.62%) and miscellaneous (12 or 7.5%). A high number of persons having Parkinson's disease was found. CONCLUSION: Possible risk factors for Parkinson's disease for individuals living in Geraldton and Midwest region need to be investigated. This study raises issues pertaining to the provision of services and allocation of resources in rural areas, especially for patients with Parkinson's disease.

Huntington disease in indigenous Australians.

Huntington disease (HD) in indigenous Australians is a poorly analysed and difficult problem. This study addresses the issue of HD in remote indigenous Australian populations in the north-west of Western Australia. Proband identification, clinical assessment, neurogenetic studies and pedigree analysis led to the discovery of HD in the 63-year-old male proband and his family. HD in remote indigenous Australian communities is a challenging diagnostic and management problem compounded by the complexity of distance.

Correlative studies of structural and functional imaging in primary progressive aphasia.

RATIONALE: To compare and contrast structural and functional imaging in primary progressive aphasia (PPA). METHODS: A cohort of 8 patients diagnosed with PPA presenting with nonfluency were prospectively evaluated. All patients had structural imaging in the form of MRI and in 1 patient CAT scanning on account of a cardiac pacemaker. All patients had single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging. RESULTS: SPECT and PET imaging had 100% correlation. Anatomical imaging was abnormal in only 6 of the 8 patients. Wernicke's area showed greater peak Z score reduction and extent of area affected than Broca's area (McNemar paired test: P = .008 for Z score reduction; P = .0003 for extent). PET scanning revealed significant involvement of the anterior cingulum. CONCLUSION: Functional imaging in PPA: (a) identified more patients correctly than anatomic imaging highlighting the importance of SPECT and PET in the diagnosis; and (b) demonstrated the heterogeneous involvement of disordered linguistic networks in PPA suggesting its syndromic nature.

Primary Whipple's disease of the brain: characterization of the clinical syndrome and molecular diagnosis.

BACKGROUND: Whipple's disease (WD) of the brain without evidence of systemic involvement is a rare illness that is difficult to recognize and potentially life-threatening. AIM: To elucidate the clinical features and diagnosis of primary WD of the brain. DESIGN: A single case study, with review of published data. METHODS: We linked the information about our patient with 956 citations to published WD material. We were able to identify 19 other patients with primary WD of the brain. RESULTS: Our patient was a 48-year-old woman who presented 2 years ago with generalized tonic/clonic seizures. WD of the brain was diagnosed after a life-threatening subacute deterioration leading to reduced consciousness and eye movement abnormalities. She had atrophy and gliosis of the right hippocampal formation, and nodular enhanc-ing lesions. She developed the syndrome of inappropriate ADH secretion, blepharospasm with a complete paralysis of vertical gaze, a severe amnesic syndrome, obstructive sleep apnoea, altered sleep physiology and CSF oligoclonal bands. Primary WD of the brain was diagnosed after PCR confirmed Tropheryma whipplei DNA in CSF and blood. She recovered after intravenous methylprednisolone, meropenem and cotrimoxazole. She has now survived for 24 months, lives independently and drives. Comparing our patient with the 19 others, two clinical syndromes were apparent, in both adults and children: (i) multifarious neurological symptoms and signs with a CT or MRI showing multiple nodular enhancing lesions; (ii) focal neurology secondary to solitary mass lesions. DISCUSSION: Primary WD of the brain may be diagnosed by recognition of these two clinical syndromes, and confirmed by the application of molecular biological techniques such as PCR.

Presenilin immunoreactivity in Alzheimer's disease.

The role of presenilin (PS) mutations in familial Alzheimer's disease (AD) may be as a toxic gain of function, but in sporadic disease their contribution is more difficult to understand. In this study, we investigated PS proteins in sporadic AD by comparing the immunocytochemical profiles in sporadic AD with control brains using a quantitative immunocytochemical approach to both the N- and C-terminals of PS1 and PS2. Ten patients with pathologically proven AD (using modified Consortium to Establish a Registry for Alzheimer's Disease [CERAD] criteria) and 10 controls were age- and sex-matched. The immunocytochemical primary antibodies were affinity-purified goat polyclonal antibodies and the secondary antibodies were biotinylated donkey anti-goat to the N- and C-terminal of both PS1 and PS2. The number of PS-containing neurones was quantified manually and without the knowledge of the diagnosis. We found no significant differences in the number of PS1- and PS2-containing neurones in three anatomical regions for both N- and C-terminals between AD and controls. Our findings argue in favour of functional changes in PS molecules contributing to the pathogenesis of AD and are consistent with the hypothesis of dysfunction of the entire gamma-secretase complex, of which PS proteins are a constituent.

The contribution of the study of neurodegenerative disorders to the understanding of human memory.

Memory impairment is one of the most common complaints affecting patients with neurodegenerative disorders, and its investigation has provided insights into the function and properties of human memory. The study of Alzheimer's disease has indicated the importance of mesial temporal structures and the hippocampus in episodic memory. In progressive supranuclear palsy, frontotemporal dementias, Parkinson's disease and Huntington's disease fronto-striatal networks are involved in working memory and higher level cognition. The study of semantic dementia, where there is lobar atrophy of the temporal lobe, has shown that the temporal neocortex has an important function in semantic memory. The investigation of human memory in neurodegenerative disorders suggests that the interaction of networks subserving episodic memory, semantic memory, and working memory contributes to higher level cognition and results in the fundamental homeostatic processes of recall and learning.

Polymorphisms in the tau gene in sporadic frontotemporal dementia and other neurodegenerative disorders.

The tau gene on chromosome 17 is fundamental in the pathogenesis of a number of neurodegenerative disorders. Mutations in tau are found in familial frontotemporal dementia (FTD) and the A0/A0 genotype associated with progressive supranuclear palsy (PSP). This study investigates the hypothesis that polymorphisms in the tau gene are associated with sporadic FTD. Western Australian populations of patients with sporadic frontotemporal dementia, PSP, Alzheimer's disease (AD), Huntington's disease (HD) and normal controls were studied. A new method was developed using fluorescently labelled probes to determine polymorphisms in the GT repeat region of intron 9. The A0/A0 genotype was found in 95% of PSP patients (n=20), 58.3% of FTD patients (n=48), 60.8% of AD patients (n=52), 75% of HD patients (n=40), and 75% of normal controls (n=40). None of these differences in genotype frequency were found to be significant by the Fisher exact test (P > 0.05). There were no significant differences in the frequencies of A0/A3 and A0/A1 haplotypes. We have not observed a significant increase in the A0/A0 genotype frequency in sporadic frontotemporal dementia suggesting that this polymorphism is unlikely to be related to the development of this condition. Furthermore, we have observed an increase in the A0/A0 genotype in PSP which did not reach statistical significance, suggesting that there may be population differences in the role of genetic factors in conferring risks to neurodegenerative disorders. Our work does not exclude that tau may interact with other genetic factors.

The mRNA of the NR1 subtype of glutamate receptor in Alzheimer's disease.

Glutamate has been implicated in the pathogenesis of Alzheimer's disease (AD). Controversial data exists regarding changes in the N-methyl-D-aspartate (NMDA) receptor complex in AD. We wished to elucidate the hypothesis that the NMDA receptor system is involved in the pathogenesis of AD using a gene expression approach targeting the mRNA of the universal subtype of the NMDA receptor NR1. This was performed using in situ hybridization and antisense 35S-labelled oligonucleotides on brain tissue collected at post-mortem. Relative mRNA expression was measured in standardised optical density units (OD units) using videodensitometry without knowledge of the diagnosis. The study population consisted of AD (n = 6) and neurodegenerative non-Alzheimer controls (non-AD, n = 14). Gene expression was measured in the frontal lobe, superior temporal gyrus and three areas within the hippocampus. We have observed no significant differences in the relative mRNA expression of the NR1 subtype of glutamate receptor in the following regions: frontal lobe AD = 60.7 +/- 14.1 OD units mRNA (x +/- 1SE) vs 52.6 +/- 1 in non-AD (Mann-Whitney test, p = 0.477); the superior temporal gyrus: AD = 53.3 +/- 13.9 vs 38.2 +/- 7 (p = 0.37); the CA1 region: AD = 37.8 +/- 7.75 vs 81.5 +/- 25.7 (p = 0.66); subiculum AD = 46.7 +/- 11.0 vs 105 +/- 43.3 (p = 0.82); parahippocampal gyrus AD = 36.6 +/- 9.3 vs 81.7 +/- 40.6 (p = 0.90). There were trends to a reduction in NR1 mRNA in the hippocampus and increased NR1 within the frontal and superficial temporal gyrus which were not significant. There was variation within and between all patients with and without AD in the magnitude of NR1 expression in all anatomical regions studied. The findings suggest heterogeneity in the involvement of the post-synaptic glutamatergic system in AD.

A new PRNP mutation (G131V) associated with Gerstmann-Sträussler-Scheinker disease.

BACKGROUND: Gerstmann-Sträussler-Scheinker disease is a rare form of prion disease. OBJECTIVE: To determine the prion mutation in a 51-year-old man without a family history of neurologic disease who died from Gerstmann-Sträussler-Scheinker disease. PATIENT AND METHODS: The patient was a 51-year-old man who died after a 9-year illness characterized by dementia and eventually ataxia. Neuropathologic studies were performed, the results of which revealed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration. RESULTS: Genetic analysis of the prion protein gene showed a novel mutation at codon 131 that caused a valine-for-glycine substitution (G131V) and homozygosity at codon 129 (129M). Proteinase K-resistant prion protein was detected by Western blot analysis. CONCLUSIONS: This is the first mutation described in the short, antiparallel beta-sheet domain of the prion protein. This report highlights the importance of genetic analysis of patients with atypical dementia even in the absence of a family history.

The functions of the amyloid precursor protein gene.

The amyloid precursor protein (APP) gene and its protein products have multiple functions in the central nervous system and fulfil criteria as neuractive peptides: presence, release and identity of action. There is increased understanding of the role of secretases (proteases) in the metabolism of APP and the production of its peptide fragments. The APP gene and its products have physiological roles in synaptic action, development of the brain, and in the response to stress and injury. These functions reveal the strategic importance of APP in the workings of the brain and point to its evolutionary significance.

Genetic testing for Alzheimer's disease.

Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD. If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia. The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient. APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements. APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support. APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD. Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol.

Amyloid precursor protein gene isoforms in Alzheimer's disease and other neurodegenerative disorders.

Differential expression of the amyloid precursor protein gene (APP) may be important in the development of amyloidosis in Alzheimer's disease (AD) and experimentally in the brain's response to injury. Controversial data suggests that APP isoforms containing the Kunitz protease inhibitor isoform (APP KPI+) are over expressed in the brains of patients with AD when compared to the non-Kunitz protease inhibitor containing isoforms (APP KPI-). We have investigated this hypothesis using a quantitative analysis of gene expression on brain tissue collected at post-mortem. In situ hybridization has been used with synthetic oligonucleotide probes labelled with 35S to detect the two principal splice variants of APP: APP 695 (KPI-) and APP 751 (KPI+). A prospective brain bank of frozen brain specimens has been established and includes pathologically proven AD (n=15) and other neurodegenerative disorders as controls (n=18). The controls consist of frontal lobe atrophy (n=4), Huntington's disease (n=5), Parkinson's disease (n=4), motor neuron disease (n=2), multi-infarct dementia (n=1), multisystem atrophy (n=1), and subacute sclerosing panencephalitis (n=1). We have observed no significant differences in the expression of APP 695 KPI- mRNA in frontal lobe: 17.49+/-3.26 optical density (OD) units of mRNA expression in AD vs. 16.13+/-1.76 OD units mRNA in controls (P=0.80, linear regression); or temporal lobe: 14.73+/-2.96 in AD vs. 16.49+/-2.15 in controls (P=0.55). No significant differences have been found in APP 751 KPI+ in frontal lobe: 12.86+/-2.98 in AD vs. 13.70+/-2.88 in controls (P=0.97); and temporal lobe: 13.31+/-4.93 in AD vs. 11.07+/-1.99 in controls (P=0. 65). Analysis of the ratios of APP 751 KPI+ OD units of mRNA to APP 695 KPI- mRNA revealed a trend to an increased ratio which did not reach statistical significance: frontal lobe APP 751 KPI+/APP 695 KPI- 1.92+/-1.04 in AD vs. 0.86+/-0.17 in controls (P=0.54); temporal lobe 2.54+/-1.59 in AD vs. 0.96+/-0.11 controls (P=0.34). Our data has not revealed differential expression of APP mRNA isoforms in AD and supports the hypothesis that post-translational events in APP metabolism are important in amyloidogenesis and the pathogenesis of AD.

Butyrycholinesterase K variant and Alzheimer's disease.

This study attempted to corroborate findings on the association between butyrylcholinesterase K variant and Alzheimer's disease. This was performed on an autopsy-confirmed series of patients with Alzheimer's disease and controls. The butyrylcholinesterase K variant was found to be of increased allele frequency in patients with sporadic Alzheimer's disease. When related to APOE epsilon4 typing the association was specific but not sensitive for the diagnosis of Alzheimer's disease.

The effects of excitotoxicity on the expression of the amyloid precursor protein gene in the brain and its modulation by neuroprotective agents.

This work has explored the relationship between excitotoxicity and the amyloid precursor protein gene (APP) which may be relevant to future therapeutic developments in Alzheimer's disease. The excitotoxic effects of kainic acid (KA) and pentylenetetrazole (PTZ) have been compared and contrasted on the two major mRNA isoforms of APP using in situ hybridization and quantitative analysis of gene expression in rat brain. The Kunitz Protease Inhibitor containing isoform APP 770 KPI+, the major glial cell isoform, has been shown to be stimulated after KA and was related to neuronal loss and astrocyte activation as gauged by GFAP mRNA. This was associated with reduced expression of APP695 KPI- isoform, the major neuronal isoform. These changes were not observed after PTZ where there was no neuronal loss and no glial reaction. The KA induced changes in APP were prevented by pretreatment with the non-competitive NMDA receptor antagonist dizocilpine and the barbiturate pentobarbitone, but not with the kappa-opioid receptor agonist enadoline. These findings were related to the suppression of seizures and the survival of neurons. In conclusion, excitotoxic stimulation leading to neuronal death was associated with increased expression of APP KPI+ mRNA and decreased APP KPI- mRNA, a finding which may relate to the plasticity of the central nervous system.