MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

The clinical profile of NMOSD in Australia and New Zealand.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics.

BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival. OBJECTIVE: To identify predictors of mortality in patients with MCI. METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline. RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality. CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

Predictors of Mortality in Dementia: The PRIME Study.

BACKGROUND: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients' symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients' demographic and clinical features are controlled for. OBJECTIVE: To identify predictors of mortality in patients with dementia. METHOD: Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline. RESULTS: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality. CONCLUSIONS: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications.

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts.

BACKGROUND: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed. OBJECTIVE: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment. METHODS: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function. RESULTS: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04). CONCLUSIONS: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.

Prevalence and predictors of burden in caregivers of people with dementia.

OBJECTIVE: To examine prevalence and predictors of burden in caregivers of people with dementia attending memory clinics. METHODS: This Prospective cohort study conducted at nine memory clinics in Australia rated 732 outpatient attendees and their primary caregivers at baseline and at 3, 6, 12, 24, and 36 months. Ratings were based on the following: dementia diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-Cognitive, Functional Autonomy Measurement System, Neuropsychiatric Inventory, use of psychotropic and antidepressant medications, patient and caregiver resource use, and the Zarit Caregiver Burden Interview (ZBI). RESULTS: Half the caregivers had significantly high levels of burden, rising to 57.7% at 12 months; with moderate to severe burden rates, rising from 14.7% at baseline to 22.8% at 12 months; and mean ZBI levels rising from 22.9 at baseline to 25.5 at 6 months and 27.7 at 12 months. Caregiver predictors of 6- and 12-month burden were their neuroticism and baseline ZBI score. Patient predictors were their level of behavioral symptoms, use of antipsychotics and antidepressants, and more rapid functional decline. Other predictors (female caregiver, level of cognition and function, diagnosis of frontotemporal dementia) were not significant in regression analyses. CONCLUSION: Caregivers of people with dementia have high and persistent rates of burden. Identification of caregivers likely to have high levels of burden at 12 months may allow more accurate targeting of interventions.

Increased risk of cognitive impairment in patients with diabetes is associated with metformin.

OBJECTIVE: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS: Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22). RESULTS: Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92]). CONCLUSIONS: Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Patients in Australian Memory Clinics: baseline characteristics and predictors of decline at six months.

BACKGROUND: The Prospective Research In MEmory clinics (PRIME) is a three-year non-prescriptive, observational study identifying and measuring relationships among predictor and outcome variables. METHODS: Patients from nine memory clinics, diagnosed with dementia or mild cognitive impairment (MCI), living in the community with <40 hours/week nursing care were divided into diagnostic groups defined at baseline as Alzheimer's disease (AD) early or late onset, frontotemporal dementia (FTD), vascular dementia (VaD), mixed (AD and VaD) and other dementia. To achieve outcome measures, baseline and change over six months in all measures by diagnostic group, and predictors of change at six months were examined. RESULTS: Of the 970 patients enrolled, 967 were eligible for analysis. The most common disorder was AD (late onset) accounting for 46.5% of this population. Patients had an overall slight worsening on all assessment scales over the six-month period. Patients with FTD had a more marked change (decline) in cognition, function and behavior over six months compared to other diagnostic groups. However, in the regression analysis the difference was not significant between groups. Predictors of decline in Mini-Mental State Examination (MMSE) scores were not robust at six months, and longer follow-up is required. Patients with FTD were more likely to be prescribed psychotropics. CONCLUSION: The PRIME study is continuing and will provide important data on predictors of decline along with differences between diagnosis groups on the rate of change.

Does executive impairment define a frontal variant of Alzheimer's disease?

BACKGROUND: People with Alzheimer's disease (AD) who present with prominent frontal features such as a dysexecutive syndrome may be difficult to differentiate clinically from subjects with frontotemporal lobar degeneration (FTLD). This study was performed to improve the differential diagnosis between AD and FTLD and to better characterize the AD subgroup with greater executive dysfunction. METHODS: Using a well-defined prospectively studied cohort of cognitively impaired subjects, which included those with AD and with FTLD, we nominated a frontal variant of AD (FvAD) group as those AD subjects with the lowest quartile of scores on the Frontal Assessment Battery (FAB), indicating greatest executive dysfunction, and compared them with the rest of the AD cases (whom we called the AD group) and those with FTLD across several baseline variables including cognitive, functional and behavioral scales. We also compared the changes from baseline for these three groups at 6 and 12 months. Additionally, we controlled for dementia severity by matching AD and FTLD cases on a functional scale, the SMAF, and repeated the same comparisons with these severity-matched groups. RESULTS: The 114 FvAD subjects had a mean age of 78.1 years and Mini-mental State Examination (MMSE) scores of 16.6, and the (remaining) AD group had a mean age of 78.4 years and MMSE of 22.4. There were 30 FTLD subjects with a mean age at baseline of 70.9 years and a mean baseline MMSE of 23.4. The FvAD group was significantly more severely impaired than the other two groups on all baseline assessments except the behavioral scale, the Neuropsychiatric Inventory (NPI), where there was insignificantly less impairment than in the FTLD group. In the analysis of subjects matched at baseline for functional impairment, the FvAD and FTLD groups were not significantly different on most assessment scales although on the FAB, clock-drawing and MMSE the FvAD subjects were still significantly more impaired. These two severity-matched groups were also similar in other baseline characteristics except for older age and less psychotropic use in the FvAD group. The severity-matched FvAD group was significantly different from the AD group in almost all assessment scales. All three unmatched and matched groups declined similarly over 12 months. CONCLUSIONS: When groups were not matched for baseline severity, the use of the FAB defined a group of AD subjects with greater executive dysfunction that were distinguished from both the remainder of the AD and FTLD subjects in almost all domains except behavioral disturbance and probably were just more severely affected AD subjects. The FAB is thus more useful as a marker of dementia severity than as a scale to detect a frontal variant of AD or to distinguish AD from FTLD. Controlling for severity, however, did allow the definition of a subgroup of AD subjects that more closely resembled FTLD subjects than the remainder of the AD subjects. It is proposed that subjects with dementia presenting with greater executive impairment but without prominent behavioral symptoms are likely to have AD rather than FTLD, especially if they are quite functionally impaired. With time FTLD subjects develop increasing executive dysfunction and increasingly resemble the more severely affected AD subjects.

The long-term efficacy and tolerability of donepezil in patients with vascular dementia.

OBJECTIVE: To determine the long-term tolerability and efficacy of donepezil in patients with vascular dementia (VaD). METHODS: International, multicentre, open-label, 30-week extension study of two 24-week, randomised, double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age, 74.7 +/- 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease, who were medically stable and had completed one of two double-blind studies. All patients received donepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments were performed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverse events (AEs) and physical and laboratory evaluations. RESULTS: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study; 127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6-1.15 points) from double-blind study baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patients who received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group that initiated donepezil treatment during the extension study. Most common donepezil-related AEs were nausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred. CONCLUSION: These data suggest that donepezil improves cognition for up to 54 weeks in patients with VaD. Patients initiating donepezil in this extension study did not perform as well on the primary outcome measure as those initiating donepezil in the double-blind study.

Mild autonomic dysfunction in primary Sjögren's syndrome: a controlled study.

INTRODUCTION: The aim of this study was to compare cardiovascular autonomic nervous system function in patients with primary Sjögren's syndrome (pSS) with that in control individuals, and to correlate the findings with autonomic symptoms and the presence of exocrine secretory dysfunction. METHODS: Twenty-seven female patients with pSS and 25 control individuals completed the COMPASS (Composite Autonomic Symptom Scale) self-reported autonomic symptom questionnaire. Beat-to-beat heart rate and blood pressure data in response to five standard cardiovascular reflex tests were digitally recorded using a noninvasive finger pressure cuff and heart rate variability was analyzed by Fourier spectral analysis. Analysis was performed by analysis of variance (ANOVA), multivariate ANOVA and repeated measures ANOVA, as indicated. Factor analysis was utilized to detect relationships between positive autonomic symptoms in pSS patients. RESULTS: Multiple, mild autonomic disturbances were observed in pSS patients relating to decreased heart rate variability, decreased blood pressure variability and increased heart rate, which were most evident in response to postural change. There was a strong trend toward an association between decreased heart rate variability and increased severity of the secretomotor, orthostatic, bladder, gastroparesis and constipation self-reported autonomic symptom cluster identified in pSS patients. This symptom cluster was also associated with fatigue and reduced unstimulated salivary flow, and therefore may be an important component of the clinical spectrum of this disease. CONCLUSION: There was evidence of mild autonomic dysfunction in pSS as measured with both cardiovascular reflex testing and self-reported symptoms. Pathogenic autoantibodies targeting M3 muscarinic receptors remain a strong candidate for the underlying pathophysiology, but practical assays for the detection of this autoantibody remain elusive.

A naturalistic study of galantamine for Alzheimer's disease.

OBJECTIVE: To collect descriptive data on the treatment of Alzheimer's disease with galantamine under naturalistic conditions. STUDY DESIGN: This was a prospective, open-label, observational study. PATIENTS: Subjects (n = 345) with mild to moderately severe dementia of the Alzheimer's type were recruited from 48 hospitals in Australia. METHODS: Subjects were enrolled and received treatment with galantamine for 6 months in a clinical practice setting. Subjects were assessed at baseline and 3 and 6 months after starting treatment using the Mini-Mental State Examination (MMSE), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [the latter only if the baseline MMSE score was at least 25]. Subjects were also assessed using an abridged Instrumental Activities of Daily Living (IADL) questionnaire that included questions on using the telephone, ability to travel more than 1km outside the home, taking medications and managing money, and an 11-item behaviour assessment scale that measured aggression, sleep disturbance, disinhibition, personality changes, irritability, depression, agitation, apathy, inertia, hallucinations and aberrant motor behaviour. RESULTS: Of the 345 subjects who were enrolled in the study (intent-to-treat [ITT] population), 229 completed the baseline, 3- and 6-month visits (per-protocol [PP] population). The mean age of the PP population was 78.0 +/- 6.8 years. At 6 months, most PP subjects (70%) showed an increase in MMSE score compared with baseline, with a mean increase in score of 2.0 +/- 3.1 points from a baseline of 20.8 +/- 4.2 points. In the ITT population, 44% of subjects (151/345) showed an increase in MMSE after 6 months. If data were unavailable the patient was classified as a nonresponder. Of the 21 PP patients who were assessed using ADAS-cog, 18 (86%) demonstrated a decrease in the ADAS-cog score, reflecting an improvement in cognition. Of the ITT population, 33% (19/57) had a decreased ADAS-cog score after 6 months. Most PP subjects (86%) were considered responders according to the CIBIC-plus score, with 65% showing some improvement over 6 months of treatment. Of the ITT population, 54% (187/345) showed no deterioration in CIBIC-plus score after 6 months.No deterioration in IADL or behaviour assessments occurred in the majority of PP subjects over 6 months. CONCLUSIONS: In a clinical practice setting, the majority of subjects receiving galantamine who completed the study maintained their ratings of cognition, function, behaviour or global assessment over the 6-month period.