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Background: Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer’s disease (AD). Objective: To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Methods: Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher’s Exact Test. Results: Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Conclusion: Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele.

Background Young onset dementia (YOD) is a major diagnostic and management problem. Methods We set out to explore if electroencephalography (EEG) might be useful in the diagnosis of young onset Alzheimer’s disease (YOAD) and young onset frontotemporal dementia (YOFTD). The ARTEMIS project is a 25-year prospective study of YOD based in Perth, Western Australia. 231 participants were included: YOAD: n = 103, YOFTD: n = 28, controls: n = 100. EEGs were performed prospectively, with 30-minute recording time for each subject, without knowledge of diagnosis or other diagnostic data. Results 80.9% of patients with YOD had abnormal EEGs (P P P = 0.32), with 38.8% of YOAD and 28.6% of YOFTD patients having epileptiform activity. Slow wave changes were more generalized in YOAD (P = 0.001). Slow wave changes and epileptiform activity were not sensitive to the diagnosis of YOD, but highly specific (97–99%). The absence of slow wave changes and epileptiform activity had a 100% negative predictive value and likelihood radio 0.14 and 0.62 respectively, meaning that those without slow wave changes or epileptiform activity had low probability of having YOD. No relationship was established between EEG findings and the patient’s presenting problem. Eleven patients with YOAD developed seizures during the study, and only one with YOFTD. Conclusions The EEG is highly specific for the diagnosis of YOD with the absence of slow wave changes and epileptiform phenomena making the diagnosis unlikely, with 100% negative predictive value and with low probability for the dementia diagnosis.

Autosomal dominant variants in ELOVL4 cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Maltese-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next-generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C > T p.(Thr233Met). The variant was initially classified as a variant of uncertain significance; however, through segregation studies, we reclassified the variant as likely pathogenic. We next identified an individual from another family (Algerian-Maltese-Australian) with the same ELOVL4 variant with spinocerebellar ataxia but without dermatological manifestations. We subsequently performed the first dedicated literature review of ELOVL4-associated ataxia to gain further insights into genotype–phenotype relationships. We identified a total of 60 reported cases of SCA34 to date. The majority had gait ataxia (88.3%), limb ataxia (76.7%), dysarthria (63.3%), and nystagmus (58.3%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.3%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa, and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple system atrophy type C) was seen in 32.4% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.

Background: Dementia is a major global health problem and the search for improved therapies is ongoing. The study of young onset dementia (YOD)—with onset prior to 65 years—represents a challenge owing to the variety of clinical presentations, pathology, and gene mutations. The advantage of the investigation of YOD is the lack of comorbidities that complicate the clinical picture in older adults. Here we explore the origins of YOD. Objective: To define the clinical diversity of YOD in terms of its demography, range of presentations, neurological examination findings, comorbidities, medical history, cognitive findings, imaging abnormalities both structural and functional, electroencephagraphic (EEG) data, neuropathology, and genetics. Methods: A prospective 20-year study of 240 community-based patients referred to specialty neurology clinics established to elucidate the nature of YOD. Results: Alzheimer’s disease (AD; n = 139) and behavioral variant frontotemporal (bvFTD; n = 58) were the most common causes with a mean age of onset of 56.5 years for AD (±1 SD 5.45) and 57.1 years for bvFTD (±1 SD 5.66). Neuropathology showed a variety of diagnoses from multiple sclerosis, Lewy body disease, FTD-MND, TDP-43 proteinopathy, adult-onset leukoencephalopathy with axonal steroids and pigmented glia, corticobasal degeneration, unexplained small vessel disease, and autoimmune T-cell encephalitis. Non-amnestic forms of AD and alternative forms of FTD were discovered. Mutations were only found in 11 subjects (11/240 = 4.6%). APOE genotyping was not divergent between the two populations. Conclusion: There are multiple kinds of YOD, and most are sporadic. These observations point to their stochastic origins.

Neurodegenerative disorders and cancer are two of the most common groups of conditions in our world. Some studies have proposed that neurodegenerative disorders may be protective of the development of cancer. We tested this hypothesis using two neurodegenerative disorders with different molecular pathophysiology – Alzheimer’s disease (AD) and Huntington’s disease (HD) – to see if the inverse relationship between cancer and neurodegeneration was generalizable. Five-year cancer incidence was determined in two large datasets: AD using the C-Path Online Date Repository (CODR) database (n = 6383) and HD using the ENROLL-HD database (n = 2608). Cancer incidence was determined in the populations and compared to normal population data for Australia, United Kingdom and the United States of America. Age-sex standardized rates of cancer were determined and expressed as 95% confidence intervals. We describe an age-sex standardized cancer rate of 1179.6/per 100,000 population to 1253.7/per 100,000 population in normal populations. The rate in AD was 815.2/per 100,000 population (95% CI 813.32–817.5/per 100,000 population) and for HD 1296.6/per 100,000 population (95% CI 1288–1308.2/per 100,000 population). We conclude that patients with AD have a reduced age-sex standardized rate of developing cancer not shared with HD, a finding that hints at different molecular mechanisms.

Purpose Positive intervention effects following lexical retrieval interventions are increasingly reported with people with progressive language impairments; however, generalization of therapy gains are less frequently evident and less well understood. This study sought to explore the impact of specific therapy ingredients on generalization outcomes. Method Twelve participants with progressive lexical retrieval deficits (four each with semantic variant primary progressive aphasia, logopenic variant primary progressive aphasia, and Alzheimer's disease, amnestic presentation) and their family members participated in a 6-week intervention that aimed to increase access to different word classes (nouns, verbs, and adjectives) through a strategic self-cueing approach. Generalization was actively facilitated through strategy practice in connected speech. Repeated baselines of picture naming and connected speech were conducted prior to intervention and repeated immediately post and at 6 weeks following intervention. Results All three diagnostic groups showed significant improvements in naming performance post-intervention for all word classes and for both treated and untreated items, demonstrating consistent treatment effectiveness and generalization at the word level. No changes in the informativeness or efficiency of connected speech were found. Conclusions Despite heterogeneity across participants, widespread evidence of both treatment effects and generalization to untreated items was found for all diagnostic groups and word classes. The consistent within-level generalization across all groups is explored here in relation to optimization of strategy use through incorporation of cognitive scaffolds, strategic practice at the connected speech level, and the inclusion of family members. The absence of across-level generalization to connected speech is also explored. Supplemental Material https://doi.org/10.23641/asha.14219771

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD’s interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Author(s): Fischer, Corinne E; Ismail, Zahinoor; Youakim, James M; Creese, Byron; Kumar, Sanjeev; Nunez, Nicolas; Ryan Darby, R; Di Vita, Antonella; D'Antonio, Fabrizia; de Lena, Carlo; McGeown, William J; Ramit, Ravona; Rasmussen, Jill; Bell, Joanne; Wang, Huali; Bruneau, Marie-Andree; Panegyres, Peter K; Lanctot, Krista L; Aguera-Ortiz, Luis; Lyketsos, Constantine; Cummings, Jeffrey; Jeste, Dilip V; Sano, Mary; Devanand, DP; Sweet, Robert A; Ballard, Clive | Abstract: BackgroundPsychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice.ObjectiveTo establish research criteria for the diagnosis of psychosis in AD.MethodsThe International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria.ResultsConsensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers.ConclusionWe propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Guillain-Barré Syndrome (GBS)—an immune-mediated condition—is the most common cause of acute flaccid paralysis, since the elimination of poliomyelitis. We present a case of GBS as a rare complication of meningococcal meningitis based on clinical features, nerve conduction studies and magnetic resonance imaging (MRI) findings. GBS has rarely been described after meningitis. This case is unique in that our findings show that GBS may be observed after meningococcal meningitis.

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.

BACKGROUND: Indigenous Australians are of increased risk of developing dementia - Alzheimer's disease and mixed dementia diagnoses are the most common. Whilst prion diseases have been reported in Indigenous peoples of Papua New Guinea and the United States of America, the occurrence and phenotype of prion disease in Indigenous Australians is hitherto unreported. AIM: Report the incidence rate and clinical phenotype of Creutzfeldt-Jakob disease (CJD) in Indigenous Australians. METHOD: Calculation of crude sporadic CJD (sCJD) incidence rates and indirect age-standardisation of all CJD to calculate the standardised mortality ratio (SMR) for the Indigenous Australian population in comparison to the all-resident Australian population, along with analysis of clinical phenotype. RESULTS: Illustrative case report of an Indigenous Australian from regionally remote Western Australia dying from typical "probable "sCJD two months after disease onset, with Australian National CJD Registry (ANCJDR) surveillance overall ascertaining eight Indigenous Australians dying from sCJD (5 post-mortem confirmed, 3 classified as "probable") with the clinical phenotype similar to non-Indigenous people, including median age at death of 61 years (interquartile range IQR = 16 years) and median duration of illness 3 months (IQR = 1.6 months). Indigenous Australians with sCJD were geographically dispersed throughout Australia. The calculated overall crude annual rate of sCJD in Indigenous Australians compared to the remainder of the Australian population was not significantly different (0-3.87/million for Indigenous Australians; 0.94-1.83/million for non-Indigenous). The indirect age-standardised all CJD mortality ratio for the Indigenous population for the years 2006 to 2018 was 1.49 (95% CI, 0.75-2.98), also not significantly different to the all-resident Australian population. CONCLUSION: CJD occurs in Indigenous Australians with the clinical phenotype and occurrence rates similar to non-Indigenous Australians. These findings contrast with a previous report wherein the incidence rate of CJD in a non-Australian Indigenous populations was reported as decreased. This article is protected by copyright. All rights reserved.

Background: Despite a growing literature characterising connected speech and discourse impairments associated with primary progressive aphasia (PPA), intervention in PPA has focused predominantly on lexical retrieval and picture-naming treatments, with limited generalisation of therapy gains reported. Recent developments in the post-stroke aphasia literature with discourse-level approaches have provided highly promising findings for the generalisation of language gains to everyday communication, and an opportunity to investigate whether the same benefits may be found in the PPA population.Aims: This study evaluated the effectiveness of a discourse intervention in two individuals with PPA to determine whether significant improvements were seen in word retrieval and discourse organisation in everyday discourse.Methods & Procedures: KW, a 54-year-old man, who presented with semantic variant PPA, and AS, a 59-year-old woman, presenting with logopenic variant PPA, completed the NARNIA intervention prog...

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 from 2004-2016. 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 factors 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 were located anywhere within the hippocampus. DWI lesions were not significantly associated with outcomes (recurrence, subjective memory impairment, dementia). We have found that depression, previous head injury and family history of dementia may predict TGA recurrence.

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.

Background Statins are a first-line drug treatment for hypercholesterolaemia. Recently there has been general public and media interest surrounding uses and side effects of statins, including memory loss. Aims We analysed an Australian experience in statin usage in an attempt to improve understanding of the relationship between statins and memory-related adverse events. Methods Total adverse events (TAE) and adverse events with single suspected medicines (SSM) for memory loss and other memory-related adverse events were searched for statin compounds from January 1992 to May 2013, using the Medicare Australia and Pharmaceutical Benefits Scheme (PBS) websites and Therapeutic Goods Administration (TGA) adverse events data. TAE and SSM were compared to the number of prescriptions by item number searched using the PBS. The process was repeated for non-statin cholesterol-lowering drugs. Results The most common adverse event was amnesia (167 events for statins and six for non-statins). There were 239 TAE (incidence rate=0.88) listed for statins and 10 for non-statins (incidence rate=0.53). There were 217 SSM events listed for the statins (incidence rate = 0.08) and eight for the alternatives (incident rate=0.04). The differences between TAE and SSM incidence rates between statins and non-statins drugs were not significant (both p values >0.05). Conclusion We found that there were no differences in memory-related adverse events between statins and other cholesterol-lowering medications using Australian PBS and TGA adverse events data.

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.

It is generally regarded that patients with hereditary neuropathy to pressure palsies, due to a deletion in the PMP22 gene, show recurrent pressure palsy and generalised peripheral neuropathy (pes cavus and hammer toes sometimes develop). Brachial plexopathy is rarely identified as a first presentation of hereditary neuropathy to pressure palsies. We describe a young man who developed a painless flail upper limb with a clinical diagnosis of a brachial plexopathy after his partner slept on his arm - a PMP22 deletion was found. His father, who had a symmetrical polyneuropathy without recurrent mononeuropathies, shared the PMP22 deletion.

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.

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.

Neurodegenerative diseases represent a daunting challenge in clinical diagnosis and management. Biomarkers that might aid in the diagnosis of these devastating and globally important diseases are urgently sought and required. Here we describe the application and state of development of a range of cerebrospinal fluid biomarkers in common neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia and prion diseases.

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 per cent 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.

The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. To date, these scientific advances have not provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so earlier detection of disease can be more readily translated into improved health-related quality of life for families at risk for, or suffering with, neurodegenerative diseases. In this review, we discuss health-related quality of life (HRQOL) measurement in neurodegenerative diseases and the importance of these “patient reported outcomes” for all clinical research. Next, we address HRQOL following early identification or predictive genetic testing in some neurodegenerative diseases: Huntington disease, Alzheimer's disease, Parkinson's disease, Dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy and Wilson's disease. After a brief report of available direct-to-consumer genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance toward predictive genetic testing. Forty-one studies examining health-related outcomes following predictive genetic testing for neurodegenerative disease suggested that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (d) many persons report extensive benefits to receiving genetic information; and (e) stigmatization and discrimination for genetic diseases are poorly understood and policy and laws are needed. Caution is appropriate for earlier identification of neurodegenerative diseases but findings suggest further progress is safe, feasible and likely to advance clinical care.

Background Anti-N-methyl-D-aspartate receptor encephalitis is a recently discovered disease entity of paraneoplastic limbic encephalitis. It largely affects young women and is often associated with an ovarian teratoma. It is a serious yet treatable condition if diagnosed early. Its remedy involves immunotherapy and surgical removal of the teratoma of the ovaries. This case of anti-N-methyl-D-aspartate receptor encephalitis involves an early surgical intervention with bilateral oophorectomy, despite negative imaging evidence of a teratoma. Case presentation A 25-year-old white woman with anti-N-methyl-D-aspartate receptor encephalitis presented with behavioral changes and seizures that were confirmed to be secondary to anti-N-methyl-D-aspartate receptor encephalitis. She required an admission to our intensive care unit for ventilator support and received a number of immunological therapies. Multiple imaging investigations showed no evidence of an ovarian teratoma; she had a bilateral oophorectomy 29 days after admission. Ovarian histology confirmed the presence of a teratoma with neuronal cells. A few days after the operation she began to show signs of improvement and, apart from mild short-term memory loss, she returned to normal function. Conclusions Our patient is an example of teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis, in which the teratoma was identified only microscopically. Her case highlights that even with negative imaging evidence of a teratoma, ovarian pathology should still be considered and explored.

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

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.

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.

In vitro studies suggest Amyloid Precursor Protein Gene (APP) is involved in interaction with the extracellular matrix, neurite growth, adhesion, development, synaptic function, platelet function, and interaction with GTP binding proteins. In vivo experiments show a role in embryonic development, response to cerebral excitotoxicity and gliosis, response to brain injury including ischaemia, hypothalamic function, locomotor function, learning and memory. In vitro observations indicate Aβ has a role in amyloid formation, excitotoxic neuronal injury, tachykinin interaction, endothelial vasoconstrictor response, calcium and oxidative stress, free radical interaction, cell membrane fluidity, apoptosis, astrocyte stimulation, and microglial interaction. Other studies suggest important roles for Aβ oligomers in synaptic function and as an antimicrobial peptide. In vivo investigations show involvement in memory function, the blood brain barrier, and tachykinin response to cerebral injury.

Pharmacological studies reveal APP and Aβ have interactions with glutamate and calcium, cytokines, copper/zinc chelators, secretases and presenilins, nicotinic receptors, acetycholinesterase, neurotrophins, non-steroidal anti-inflame-matory drugs, monoclonal antibodies to Aβ, protease inhibitors, oestrogen, homocysteine, immediate early genes such as c-fos or c-jun and cholesterol. These functional and pharmacological observations highlight the need for greater understanding of APP and Aβ in brain function and have implications for clinical trials.

The amyloid precursor protein gene (APP) and its derivative peptides have important functions in the central nervous system. APP and Aβ fulfil criteria as neuractive peptides: presence, release and identity of action. Aβ is a peptide of 1 - 43 amino acids in length, derived from APP and the major component of the core of neuritic plaques found in Alzheimer’s disease. Analysis of the cDNA of Aβ revealed its origins from the larger precursor protein. There are at least four types of mRNA generated by alternative splicing of exons 7 and 8. Exon 7 encodes a 57 amino acid sequence found in the extracellular domain with major homology to the Kunitz-type of serine protease inhibitors. APP is cleaved by three secretases known as α, β, and γ secretase which act on APP at different sites producing various fragments of differing amino acid length. The γ secretase is a macromolecular enzyme complex composed of presenilin 1, 2 and other molecular constitutents essential for its function.

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.