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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.

Aetiology of transient global amnesia (TGA) remains uncertain, though many have been proposed, including ischaemic, migrainous or epileptic pathologies. We attempted to determine risk factors for TGA, as well as prognostic factors that may cause recurrence. We evaluated clinical history, family history and magnetic resonance diffusion-weighted imaging (DWI) studies of 93 prospective patients with TGA. Patients were followed up regarding recurrence and prognostic factors. Fifteen of 93 (16%) patients experienced a recurrence of TGA. Among precipitating events, physical activities inducing Valsalva-like manoeuvres were most common, followed by emotional stress. Eighty-four patients had possible comorbidities or risk factor for TGA, though no single risk factor was ubiquitous. Risk factors associated with recurrence were head injury (isolated vs. recurrent, 16,7% vs. 53.5%, p < 0.01), depression (isolated vs. recurrent, 15.4% vs 46.7%, p = 0.01) and family history of dementia (isolated vs. recurrent, 20.5% vs 46.7%, p = 0.03). Of 15 patients with confirmed recurrent TGA, two developed dementia and four subjective memory impairment. DWI lesions were observed in 24 patients and located anywhere within the hippocampus. DWI lesions were not significantly associated with outcomes (recurrence, subjective memory impairment, dementia). Findings suggest TGA is a heterogeneous syndrome. Among those with recurrence, depression, previous head injury and family history of dementia may be predictive factors. Encouraging primary prevention of head injury, managing depression and assisting in development of adequate coping mechanisms may decrease incidence. Education of healthcare works will also increase diagnostic rates, allowing for improved education and comfort for patients and families.

BACKGROUND Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). OBJECTIVE Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. METHODS Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians. RESULTS Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p < 0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians. CONCLUSIONS Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.

The use of sentence repetition tasks to distinguish dementia syndromes, particularly variants of primary progressive aphasia (PPA), is receiving growing attention. Impaired sentence repetition is a core feature of logopenic variant PPA, although the underlying cognitive mechanisms of this impairment and its significance as a diagnostic criterion remain poorly understood. Sentence repetition abilities of 12 people with dementia, using an adapted error classification schema, were analyzed, along with digit span abilities, a measure frequently used to assess working memory capacity, to explore error patterns and correlations. Participants with semantic variant PPA showed the greatest performance on sentence repetition and digit span in comparison to the logopenic variant PPA and Alzheimer's disease participants. Sentence repetition errors were characterized by middle omissions for semantic variant PPA, ending omissions and phonological errors for logopenic variant PPA, and ending omissions and unrelated word substitutions for Alzheimer's disease. Significant correlations were found between sentence repetition and digit span abilities. Findings are discussed in relation to working memory capacity theories, specifically, the dual-component model.

Purpose: Using connected speech to assess progressive language disorders is confounded by uncertainty around whether connected speech is stable over successive sampling, and therefore representative of an individual’s performance, and whether some contexts and/or language behaviours show greater stability than others. Method: A repeated measure, within groups, research design was used to investigate stability of a range of behaviours in the connected speech of six individuals with primary progressive aphasia and three individuals with Alzheimer’s disease. Stability was evaluated, at a group and individual level, across three samples, collected over 3 weeks, involving everyday monologue, narrative and picture description, and analysed for lexical content, fluency and communicative informativeness and efficiency. Result: Excellent and significant stability was found on the majority of measures, at a group and individual level, across all genres, with isolated measures (e.g. nouns use, communicative efficiency) showing good, but greater variability, within one of the three genres. Conclusion: Findings provide evidence of stability on measures of lexical content, fluency and communicative informativeness and efficiency. While preliminary evidence suggests that task selection is influential when considering stability of particular connected speech measures, replication over a larger sample is necessary to reproduce findings.

Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.

Neuromyelitis optica is a rare, severe inflammatory demyelinating disease of the central nervous system, previously described as affecting only the optic nerve and spinal cord. Since the discovery of a highly specific autoantibody, anti-aquaporin-4, lesions are now recognized outside these regions. We report a man with severe, debilitating symptoms resulting from a symptomatic lesion within the diencephalon, manifesting with abnormal circadian rhythms, autonomic dysfunction, behavioral disturbance, and complex visual hallucinations. The patient reported seeing nonexistent small people and animals, streaks of color across people's faces, movement of objects and facial features, water cascading down walls, bright spots, and writing appearing as hieroglyphics. His centrally driven sick sinus syndrome required insertion of a permanent cardiac pacemaker. We have been able to suppress his disease activity with methotrexate for 30 months. We review the literature on patients with positive anti-aquaporin-4 serology and dysregulation of hypothalamic function, to provide evidence that the clinical manifestations can include complex visual phenomena.

A prospective longitudinal evaluation of 12 patients over a 16-year interval using clinical neurological and imaging data to determine whether posterior cortical atrophy syndrome (PCA) related to early-onset Alzheimer disease (AD) and to examine its natural history. Our 12 patients had a median age of onset of 56 years (range, 48 to 63 y) and were followed for a median of 6 years (range, 3 to 9 y). Patients either presented with complex visual phenomena or developed them with time. Six patients underwent flurodeoxyglucose and Pittsburgh investigational compound B imaging which showed a mismatch between metabolic activity and amyloid deposition with reduced metabolism in parieto-occipital regions on flurodeoxyglucose positron emission tomography and diffuse neocortical uptake of amyloid without occipital predominance. All patients progressively deteriorated using a quality of life and total functional capacity assessments and this change is similar to the natural history of other early-onset AD variants (typical amnestic presentation, logopenic, and frontal). Two patients had neuropathologic assessments and were shown to have AD using standard pathologic criteria. Of interest, 5 of our 12 patients had occupations strongly dependent on visuospatial functioning. PCA is a syndrome that is most likely a variant of early-onset AD and our correlative clinical, structural, functional, and amyloid imaging data, along with neuropathologic studies in 2 patients, support this concept. The natural history of PCA shows progression with time and this trajectory seems to reflect that of other variants of early-onset AD.

Aim: To investigate the patterns of inheritance and gene mutation status in early-onset dementia (EOD). Methods: Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer’s disease (EOAD, n = 120) and early-onset frontotemporal dementia (EOFTD, n = 82) were studied. Results: The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. Conclusion: Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden.

Genetic mutations as a cause of prion diseases are rare. We describe a large family with multiple affected members with the codon E200K prion mutation. To improve understanding of the genotype–phenotype correlations of prion gene mutations, clinical, genetic and neuropathological data were obtained from family members over 15 years. Six patients with the codon E200K mutation and 2 patients without the codon 200 mutation from this family were followed. The 6 patients with the codon 200 mutation had a mean age onset of 58.83 years (SD 7.2; lower 95 % CI 51.0; upper 95 % CI 66.4). The most common symptoms at onset were memory loss, walking difficulties and hallucinations. The most frequent neurological phenomena were a rapidly progressive dementia, eye movement abnormalities and ataxia. The mean duration of onset of symptoms to death was 3.9 months (SD 1.1; lower 95 % CI 2.8; upper 95 % CI 5.1). Two male patients developed neurodegenerative disorders unrelated to the prion codon 200 mutation: progressive supranuclear palsy and olivopontocerebellar degeneration. Their mean survival was 96 months (SD 33.9; p < 0.0001). Individuals from families with the prion codon 200 mutation may have a rapidly progressive dementia. Members of families with inherited prion mutations may be at risk of other neurodegenerative disorders unrelated to the prion mutation.

Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes.A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.We identified a nonpolymorphic mutation (c.672*51GT) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51GT mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold.SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Whipple's disease of the brain is one of the most challenging neurological diagnoses. "Is it Whipple's disease?" is a frequent question, but rarely is the answer yes. The neurological manifestations do not help to distinguish primary from secondary Whipple's disease of the brain, and although MR brain scanning with gadolinium is mandatory, it can be normal and any abnormalities are non-specific. There must be a comprehensive search for multisystem involvement such as raised inflammatory markers, lymphadenopathy or malabsorption; biopsy of lymph node or duodenum may be necessary. PCR and DNA sequencing for Tropheryma whipplei on lymphocytes from blood and cerebrospinal fluid is essential. Treatment is as difficult as the diagnosis-there are no randomised controlled trials.

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.

Purpose: Within the current literature, positive intervention effects demonstrate the significant potential for people with Primary Progressive Aphasia (PPA) to learn/relearn words. Generalisation of intervention effects to other words and/or other contexts, however, remains unclear. Method: This multiple baseline, case-series design investigated the effects of a self-cueing lexical retrieval intervention across word classes (nouns, verbs and adjectives) on four individuals with PPA, three suggestive of the semantic variant and one of the logopenic variant. The intervention integrated semantic, phonological and orthographic levels of language production and drew on autobiographical memory. Changes in accuracy in retrieving treated and untreated items (pre-intervention, post-intervention and 4-weeks maintenance) were determined using the Cochran’s Q test, with follow-up McNemar pairwise comparisons. Result: All participants showed significant improvements in naming treated items, across all word classes. Different patterns of generalised improvement to untreated words were found for each participant. In discourse, the semantic variant participants demonstrated a significant increase in correct information units, in contrast to the participant with the logopenic variant who remained stable. Conclusion: This study provides evidence that people with PPA can show improved lexical retrieval following intervention. The findings suggest possible differences in generalisation across word classes and according to underlying deficit.

Dementia in young adults is not very well studied in terms of clinical effects on the patient, and not much is known about the effects on spouses and caregivers. This study assessed the psychological impact of the diagnosis of young onset dementia on spouses. A questionnaire that used the Zarit Burden Interview and the Beck Depression Index was sent to 120 spouses of a cohort of patients with established diagnoses of young onset dementia (age of onset before 65 years), including frontotemporal lobar degeneration, Alzheimer’s disease, and primary progressive aphasia. A total of 100 usable responses were received. The mean age of respondents was 62.3 years (54% women, 46% men). A cross-sectional analysis showed that the diagnosis of young onset dementia has a significant impact on spouses, characterized by concerns of dependency, fear, and increased depression, especially in the spouses of patients with frontotemporal lobar degeneration.

The authors performed a prospective, unbiased analysis of a cohort of young patients assessed consecutively with the question of dementia. The onset of patients’ cognitive symptoms was prior to the age of 65 years. A study group of 226 patients was followed for a mean duration of 4.59 ∓ 2.23 years (1 SD; range, 0.04-7.86 years). The diagnoses were established using published diagnostic criteria. A diagnosis of dementia was made in 112 patients (49.56%). Psychiatric disease was the most common diagnosis in those who did not have dementia (24.3%) followed by frontotemporal lobar degeneration (19.0%), Alzheimer’s disease (11.9%), patients with cognitive symptoms who obtained normal neuropsychometric profiles (10.6%), nonneurological disorders (eg, obstructive sleep apnea [8.4%]), neurological disorders (eg, Parkinson’s disease [4.9%]), and mild cognitive impairment (4.9%). The frequencies of frontotemporal lobar degeneration and psychiatric disease were higher than Alzheimer’s disease, unlike in older populations.

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited.

Our aim is to elucidate the clinical variables associated with the development of manifest HD in patients with intermediate CAG repeat lengths. 2,167 participants were seen throughout 44 research sites in the United States, Canada or Australia over a five-year natural history observational study (2006–2011) (Trial # NCT00313495). The Chi-square test and a generalised linear model were used to examine the differences in demographics and cognitive tests among three groups of CAG repeat length. The mixed model was then used to examine the time effect on cognitive assessments by CAG groups. No patient with CAG repeat length 27–35 developed manifest HD, whereas three patients with 36–39 did. Total motor score, maximal chorea score and maximal dystonia score were significantly different at baseline (p

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.

Using in situ hybridization, we have shown that the kappa-opioid receptor agonist enadoline (CI-977) and the non-competitive NMDA receptor antagonist dizocilpine (MK-901) induced the immediate early gene c-fos in dorsal medial thalamic nuclei. Dizocilpine, and not enadoline, also induced c-fos in the posterior cingulate cortex and retrosplenial cortex. Enadoline's stimulation of c-fos mRNA was dose and time dependent and completely inhibited by pretreatment with naltrexone. Morphine did not stimulate c-fos in the thalamus. It is suggested that the stimulation of c-fos with enadoline represents a specific kappa-opioid receptor effect.

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with

Aim: The burden of early-onset dementia (EOD) is often overshadowed by an ageing population. Methods: A questionnaire comprising 12 items was completed by 18 patients with EOD (15 with Alzheimer’s disease [AD] and 3 with frontotemporal dementia) and 39 caregivers (20 spouses, 8 children, 7 siblings, 2 carers, and 2 health professionals). The onset of patients’ symptoms was prior to the age of 65 years. Caregivers had to be supporting someone who matched these criteria. Results: Early recognition and referral was perceived as the principle area of improvement by both patients (94.4%) and carers (69.2%; P < .0002). Patients evaluated “diagnosis” as the area of most need (88.9%) compared with caregivers who rated “treatment” (69.2%) as their principle concern. Conclusion: The perceived concerns of patients with EOD differ from that of the caregivers. Continued consumer involvement is essential in ensuring a tailored approach to young people with dementia.

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1078-9) contains supplementary material, which is available to authorized users.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Aim: Cognitive reserve (CR) is important in protecting the brain from injury and has not been investigated in people with early-onset dementia (EOD). Methods: A retrospective case control study of 44 patients with dementia onset prior to 65 years of age: Alzheimer’s disease (AD) = 23; frontotemporal dementia (FTD) = 21. Groups were matched for age, education, Mini-Mental State Examination (MMSE), premorbid IQ, sex and APOE ε4 genotype. Years of formal education were used as a marker of CR. Relationships between education and neuropsychological data was examined using linear regression analyses. Results: There were no demographic differences between the AD and FTD groups. Significant associations were found between education and attention, working memory and visuospatial abilities. There was an effect of CR for the EOD group and selective effects in FTD and AD. Conclusion: Our findings suggest CR is operational in patients with FTD and AD.

Objective This study aims to understand the neurological manifestations of patients with an indeterminate CAG repeat length (36–39) of the Huntingtin gene, HTT . Methods A longitudinal evaluation of 10 patients was performed. Duration of follow-up was mean=4.23years (standard deviation 1.068; 95% CI 3.466–4.994; range 3–6.4years). Three patients had a CAG repeat length of 37, three 38 and four 39. Mean CAG repeat length=38 (standard deviation 0.88; 95% CI 37.47–38.73; range 37–39). Data from clinical histories, neurological examinations, the United Huntington's Disease Rating Scale (UHDRS) and MRI imaging were collected. Results Four patients developed facial chorea, ataxia, impaired tongue protrusion, abnormal saccades and intermittent eye pursuits, dysarthria and impaired Luria 3 hand test. Early in its natural history the neurological syndrome is dominated by perioral chorea, subtle cognitive deficits and mild ataxia. Three patients developed a formal diagnosis of HD within 5years. The illness progression was variable and associated with different co-morbidities. MRI scans showed ventricular dilatation as a common finding. Scores from UHDRS, Total Functional Capacity (TFC) and mini-mental state examination (MMSE) suggested significant behavioural and functional impairment with compromised cognitive abilities. Two patients had subtle manifestations and four remained asymptomatic (3 patients CAG=37; 1 patient CAG=39). Conclusions This study documents the disease manifestations and natural history of people with CAG repeat lengths within the indeterminate range. The findings reveal heterogeneity in disease progression and have implications on the advice that should be given to patients and families on risk assessment and prognosis. Long-term follow up of such patients is essential as the neurological presentation of indeterminate CAG repeat length mutation might be accelerated by associated medical disorders and treatments, environmental and modifying genetic factors.

Objective To compare the effects of single doses of oral levodopa, subcutaneous apomorphine and sublingual apomorphine. Design Single-blind placebo-controlled comparative study. Setting Subjects were admitted as day patients to the neurology ward. Patients Five patients with idiopathic Parkinson's disease and "end of dose deterioration" entered and completed the study. Interventions Patients were given domperidone (20 mg by mouth three times a day) to prevent nausea and apomorphine (1-3 mg by subcutaneous injection), apomorphine in glycerol (10-30 mg sublingually) or their usual levodopa regimen. Main outcome measures Efficacy, time to onset of effect and duration of effect of oral levodopa, subcutaneous apomorphine and sublingual apomorphine. Tremor amplitude and timed pegboard and gait tasks were used as objective indices of clinical state. Results Maximal efficacy of the three treatments was comparable (P = 0.28-0.99). Mean latency to onset of effect of both formulations of apomorphine was less than that of levodopa (P = 0.022-0.048) but so was the duration of effect (P = 0.044-0.049). Conclusions Sublingual apomorphine may be a convenient means of rapidly terminating "off" periods associated with long term levodopa therapy.

A 58-year-old man with progressive supranuclear palsy (PSP) developed two episodes of respiratory failure associated with laryngeal spasm. It was revealed he had adductor laryngeal breathing dystonia, a relatively unrecognized complication of PSP.

A family from the south of Western Australia is described with Dutch cerebral amyloid angiopathy (HCHWA-D). The proband died at age 60 from recurrent lobar haemorrhages in the brain, as did his sister and five other family members. The APP 693 mutation at position 22 of the Abetapeptide resulting in a glutamine for glutamic acid was identified in the proband and the affected sister. Pathologically lobar haemorrhages were found with cerebrovascular angiopathy; neuritic plaques were found but no neurofibrilary tangles. There was a leukoencephalopathy on MRI scanning. Dementia and cognitive decline has not been observed in this family. This is the first family reported outside of Europe and the Northern Hemisphere. The discovery highlights the importance of detecting this rare cause of fatal cerebral haemorrhage as it has implications for gene testing and general medical management.

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.

Introduction We report the first known case of human T-lymphotropic virus type I associated myelopathy/tropical spastic paraparesis in an Australian Caucasian, a disease reported in Aboriginal and immigrant populations where the virus is often endemic. Case presentation A 41-year-old Caucasian Australian man had a 3-year background of progressive functional decline from a myelopathy with spastic paraparesis and sphincteric dysfunction. Conclusions Although studies have shown a very low prevalence of human T-lymphotropic virus type I in the greater Australian population, increased focus on Aboriginal health, and the expanding diversity and integration of the Australian population means that presentation of human T-lymphotropic virus type I-associated disease is likely to increase.

Background Gerstmann-Straussler-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-Straussler-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 β-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.

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.

The thoracic outlet syndromes encompass the diverse clinical entities affecting the branchial plexus or subclavian artery including cervical ribs or bands. Thoracic outlet syndrome are often difficult to diagnose on existing clinical and electrophysiological criteria and new diagnostic methods are necessary. This study reports our experience with magnetic resonance imaging (MRI) of the brachial plexus in 20 patients with suspected thoracic outlet syndrome. The distribution of pain and sensory disturbance varied widely, weakness and wasting usually affected C8/T1 innervated muscles, and electrophysiology showed combinations of reduced sensory nerve action potentials from the fourth and fifth digits, and prolonged F-responses or tendon reflex latencies. The MRI study was interpreted blind. Deviation of the brachial plexus was recorded in 19 out of the 24 symptomatic sides (sensitivity 79%). Absence of distortion was correctly identified in 14 out of 16 asymptomatic sides (specificity 87.5%). The false positive rate was 9.5%. Magnetic resonance imaging demonstrated all seven cervical ribs visible on plain cervical spine radiographs. Magnetic resonance imaging also showed a band-like structure extending from the C7 transverse process in 25 out of 33 sides; similar structures were detected in three out of 18 sides in control subjects. These MRI bands often underlay the brachial plexus distortion observed in our patients. We also observed instances of plexus distortion by post-traumatic callus of the first rib, and by a hypertrophied serratus anterior muscle. If they did not demonstrate a cervical rib, plain cervical spine radiographs had no value in predicting brachial plexus distortion. We believe MRI to be of potential value in the diagnosis of thoracic outlet syndrome by: (i) demonstrating deviation or distortion of nerves or blood vessels; (ii) suggesting the presence of radiographically invisible bands; (iii) disclosing other causes of thoracic outlet syndrome apart from ribs or bands.

A 29-year-old Caucasian male died from massive cerebral infarction due to unilateral occlusion of the terminal internal carotid artery. The carotid occlusion was secondary to subendothelial fibrous tissue proliferation which was associated with a considerable mononuclear cell infiltration of the carotid wall, characterised as T cells by immunoperoxidase methods. Angiography showed vascular network at the base of the brain compatible with Moyamoya disease. We suggest that the pathogenesis of Moyamoya-like disease in our patient involved a T-cell-mediated attack to a vascular antigen.

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.

Six patients with AIDS and AIDS related complex (ARC) who developed neuromuscular symptoms associated with vesicular changes in muscle fibres are reported. Two patients in the advanced stages of AIDS, who did not receive zidovudine, developed proximal limb weakness and wasting: both had a necrotising myopathy with an unusual segmental vesicular change of myofibres. There were numerous vesicles 0.1 to 2 microns in diameter produced by dilatations of the sarcoplasmic reticulum in fibres depleted of myofibrils. Four patients developed a myopathy while receiving zidovudine for AIDS. One of these had an inflammatory myopathy which showed the development of vesicular change due to enlargement and electron lucency of mitochondria. The three other patients with ARC developed muscle pains or weakness and elevated serum CK while on zidovudine. These patients also showed vesicular changes due to enlargement and electron lucency of mitochondria associated with disruption of sarcomeres and the presence of cytoplasmic bodies. The muscular symptoms resolved when ziduvodine was stopped and repeat biopsy in one case revealed no abnormalities.

A 62 year old male presented with polymyalgia rheumatica and an abdominal aortic aneurysm. The aneurysm was resected and histological examination disclosed necrotizing giant-cell arteritis. This association seems to be unique.

Background The aim of this study was to evaluate the diagnostic accuracy of positron emission tomography (PET) using F18 fluorodeoxyglucose (FDG) in the differential diagnosis of early-onset Alzheimer's disease (AD) and other dementias in a community-dwelling population. Methods A prospective sample of 102 individuals presenting consecutively to a primary care centre for examination of suspected early-onset dementing diseases. The mean age of symptom onset of dementia in our patients was 60.06 ± 4.28 years (mean ± 1SD, 95% lower confidence intervals (CI) 54.75, upper 63.37). Patients were evaluated using standard clinical criteria for the diagnosis of dementia. Functional neuroimaging data was obtained and nuclear medicine physicians blind to the clinical diagnosis generated FDG-PET diagnoses. Final clinical diagnoses based on all available data were then established and compared against PET diagnoses. Results Forty-nine patients received a final clinical diagnosis of early-stage AD (MMSE score 20.97 ± 5.10). There were 29 non-AD demented patients, 11 depressed patients and a miscellaneous group of 13 patients. Among patients with AD, the sensitivity and specificity of FDG-PET was 78% (95% CI: 66–90%) and 81% (95% CI: 68–86%), respectively. The positive likelihood ratio (PLR) for a FDG-PET scan positive for the diagnosis of AD was 4.11 (95% CI: 2.29–7.32) and negative likelihood ratio (NLR) for a negative FDG-PET scan in the absence of AD was 0.27 (95% CI: 0.16–0.46). The pre-test probability was 48% and post-test probability was 79.02%. The specificity of FDG-PET in the differential diagnosis of other dementias, including frontotemporal dementia, was greater than 95%. Recruitment methods in this study provide a sample that may be more representative of patients in the general population and indicate that FDG-PET imaging can contribute to the diagnosis of AD in younger adults with major increases in the positive likelihood rates and post-test probability. Conclusion The high specificity of FDG-PET suggests this technique might help in the diagnosis of frontotemporal dementia and other forms of early-onset dementia.