The Patient-Determined Disease Steps scale is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis.

BACKGROUND AND PURPOSE: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. METHODS: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). RESULTS: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. CONCLUSION: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.

Cognitive assessment during the phases of a spontaneous migraine: a prospective cohort study.

INTRODUCTION: Cognitive symptoms are reported commonly throughout all phases of a migraine; however, there is a paucity of objective cognitive profiling. Previous studies have been limited by practice effect, and variable populations. METHODS: Participants completed 1 month of daily testing with a computerised cognitive battery involving a simple reaction (SRT), choice reaction (CRT) and a working memory test (WM). Results were correlated with their diary to identify interictal scores, and scores during each phase of a migraine, and non-migraine headache days. RESULTS: A total of 16 patients with episodic migraine participated. During the headache phase of a migraine, responses to SRT, CRT and WM tasks were significantly slower and less accurate than interictally. During the postdrome, WM task performance was slower and less accurate. Non-migraine headache days were not associated with significant change. CONCLUSION: The headache and postdromal phase of a migraine day was associated with objective evidence of cognitive dysfunction in patients with episodic migraine.

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Aggregation of Abnormal Memory Scores and Risk of Incident Alzheimer's Disease Dementia: A Measure of Objective Memory Impairment in Amnestic Mild Cognitive Impairment.

OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.

Baseline Amnestic Severity Predicts Progression From Amnestic Mild Cognitive Impairment to Alzheimer Disease Dementia at 3 Years.

BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.

A pilot study investigating the feasibility of symptom assessment manager (SAM), a Web-based real-time tool for monitoring challenging behaviors.

OBJECTIVE: Improving and minimizing challenging behaviors seen in psychiatric conditions, including behavioral and psychological symptoms of dementia are important in the care of people with these conditions. Yet there is a lack of systematic evaluation of these as a part of routine clinical care. The Neuropsychiatric Inventory is a validated and reliable tool for rating the severity and disruptiveness of challenging behaviors. We report on the evaluation of a Web-based symptom assessment manager (SAM), designed to address the limitation of previous tools using some of the Neuropsychiatric Inventory functions, to monitor behaviors by staff caring for people with dementia and other psychiatric conditions in inpatient and residential care settings. METHODS: The SAM was piloted in an 8-bed inpatient neuropsychiatry unit over 5 months. Eleven nurses and 4 clinicians were trained in usage of SAM. Primary outcomes were usage of SAM and perceived usability, utility, and acceptance of SAM. Secondary outcomes were the frequencies of documented behavior. Usage data were analyzed using chi-square and logistic regression analyses. RESULTS: The SAM was used for all admitted patients regardless of diagnosis, with a usage rate of 64% for nurses regularly employed in the unit. Staff provided positive feedback regarding the utility of SAM. CONCLUSIONS: The SAM appeared to offer individualized behavior assessment by providing a quick, structured, and standardized platform for assessing behavior in a real-world setting. Further research would involve trialing SAM with more staff in alternative settings such as in home or residential care settings.

Does left ventricular hypertrophy affect cognition and brain structural integrity in type 2 diabetes? Study design and rationale of the Diabetes and Dementia (D2) study.

BACKGROUND: Cognitive impairment is common in type 2 diabetes mellitus, and there is a strong association between type 2 diabetes and Alzheimer's disease. However, we do not know which type 2 diabetes patients will dement or which biomarkers predict cognitive decline. Left ventricular hypertrophy (LVH) is potentially such a marker. LVH is highly prevalent in type 2 diabetes and is a strong, independent predictor of cardiovascular events. To date, no studies have investigated the association between LVH and cognitive decline in type 2 diabetes. The Diabetes and Dementia (D2) study is designed to establish whether patients with type 2 diabetes and LVH have increased rates of brain atrophy and cognitive decline. METHODS: The D2 study is a single centre, observational, longitudinal case control study that will follow 168 adult patients aged >50 years with type 2 diabetes: 50% with LVH (case) and 50% without LVH (control). It will assess change in cardiovascular risk, brain imaging and neuropsychological testing between two time-points, baseline (0 months) and 24 months. The primary outcome is brain volume change at 24 months. The co-primary outcome is the presence of cognitive decline at 24 months. The secondary outcome is change in left ventricular mass associated with brain atrophy and cognitive decline at 24 months. DISCUSSION: The D2 study will test the hypothesis that patients with type 2 diabetes and LVH will exhibit greater brain atrophy than those without LVH. An understanding of whether LVH contributes to cognitive decline, and in which patients, will allow us to identify patients at particular risk. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12616000546459 ), date registered, 28/04/2016.

Family members' experience of the pre-diagnostic phase of dementia: a synthesis of qualitative evidence.

BACKGROUND: Most research on family members' experience of dementia has focused on the time after diagnosis. Yet, once people reach clinical attention, families have already been living with the changes for some time. These pre-diagnosis experiences can influence later caregiving. We aimed to synthesize qualitative research exploring family members' experiences of the pre-diagnostic phase of dementia to inform clinical practice. METHODS: We conducted a thematic synthesis of 11 studies that met our inclusion criteria following a comprehensive literature search. RESULTS: An overarching theme, sense-making, captured the primary process that family members engage in throughout the pre-diagnostic period. Within this, four major analytic themes were extracted as central concepts in understanding family members' experiences of the pre-diagnostic phase of dementia: the nature of change; appraisals of change; reactions to change; and the influence of others. CONCLUSIONS: Relevant features of the family experience of dementia onset can be characterized within several major themes. These findings highlight the complex process of recognizing early symptoms of dementia for people living with this condition and their families. Our findings also provide the foundation for developing theoretical frameworks that will ultimately assist with improving recognition of dementia onset, clinical communication with family members, and interventions to reduce family burden.

Rapidly progressive Fronto-temporal dementia (FTD) associated with Frontotemporal lobar degeneration (FTLD) in the presence of Fused in Sarcoma (FUS) protein: a rare, sporadic, and aggressive form of FTD.

Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.

Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL).

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not. METHODS: Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. RESULTS: The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. CONCLUSION: There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.

Aß and cognitive change: examining the preclinical and prodromal stages of Alzheimer's disease.

BACKGROUND: High ß-amyloid (Aß) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aß-related memory decline continues and whether it is associated with increased rate of disease progression. METHODS: Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aß and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later. RESULTS: Compared with low-Aß HCs, high-Aß HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aß did not show any cognitive decline. Rates of disease progression were increased in the high-Aß HC and MCI groups. CONCLUSIONS: In healthy individuals, high Aß likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD.

The association of Aß amyloid and composite cognitive measures in healthy older adults and MCI.

BACKGROUND: To date evidence of the relationship between cognition and Aß amyloid during the early stages of Alzheimer's Disease (AD) has been inconsistent. This study aimed to describe the nature and magnitude of the relationship between Aß amyloid and cognitive performance of individuals without dementia. METHODS: Composite cognitive measures were developed from the Australian Imaging Biomarkers and Lifestyle study neuropsychological test battery using data from 768 healthy older adults and 133 adults with mild cognitive impairment (MCI). A subgroup of this sample (174 healthy, 53 MCI) underwent neuroimaging for Aß amyloid. RESULTS: Within the MCI group individuals with high Aß amyloid showed selective impairment for memory compared with those with low Aß amyloid; however, this difference was not evident in the healthy group. CONCLUSIONS: The current findings provide further evidence of the relationship between Aß amyloid and cognition, with memory impairment being the primary symptom of the underlying disease during the prodromal phases of AD.

Aß amyloid, cognition, and APOE genotype in healthy older adults.

BACKGROUND: Only one study has investigated the relationship between cerebral ß-amyloid (Aß), apolipoprotein E (APOE) ε4 genotype, and cognition. Although significant relationships between cerebral Aß and cognition were observed in ε4 carriers but not noncarriers, the magnitude of this relationship was not reported. Further, when demographic variables were controlled, the influence of APOE ε4 on the relationship between cerebral Aß and cognition dissipated. METHODS: In 144 healthy older adults who had undergone amyloid scanning and APOE ε4 genotyping in the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing, correlations were conducted to determine the magnitude of relationship between cerebral Aß and cognition in ε4 carriers and noncarriers. Fisher's Z was used to compare these correlations and Cohen's q determined the magnitude of difference between correlations. RESULTS: Cerebral Aß was significantly associated with tasks of visual and verbal episodic memory in APOE ε4 carriers. This association was not observed in ε4 noncarriers. The relationship between cerebral Aß and episodic memory in ε4 carriers was significantly different from that in ε4 noncarriers, and the magnitude of this difference was small to moderate. CONCLUSIONS: In APOE ε 4 carriers, there is a moderate negative relationship between cerebral Aß and episodic memory. This suggests that increased cerebral Aß may signify the onset of preclinical AD, especially in healthy older adults who are genetically at risk for AD.

Acute cortical blindness caused by neuropsychiatric systemic lupus erythematosus.

A man in his 30s, who presented with fevers and a diffuse purpuric rash, developed sudden-onset visual loss on day 2. He was unable to perceive light in either eye. Examination by a neurologist confirmed cortical blindness, and the MRI showed subtle juxtacortical infarcts and leptomeningeal enhancement in the occipital region. Further history taken in the patient's native language revealed a history of untreated systemic lupus erythematosus. A diagnosis of central nervous system lupus was made and he was treated promptly with pulse methylprednisolone and cyclophosphamide. His vision gradually improved to 80% on day 10 and eventually returned to baseline. He continued with high-dose prednisolone and monthly cyclophosphamide for 6 months and remained on hydroxychloroquine and mycophenolate mofetil with no relapses. This case shows the importance of approaching the uncommon but potentially dangerous issue of acute visual loss with a broad differential.

Managing cognitive impairment and its impact in multiple sclerosis: An Australian multidisciplinary perspective.

Cognitive impairment in multiple sclerosis (MS) affects approximately 40-70% of patients and can have varying degrees of severity. Even mild cognitive impairment can impact on quality of life and productivity. Despite this, patients are not routinely screened or monitored for cognitive impairment in Australia due to a range of issues, with time and space being the main limiting factors. This Australian multidisciplinary perspective provides recommendations on cognition management in Australia. It gives a broad overview of cognition in MS, advice on the screening and monitoring tools available to clinicians, and strategies that can be implemented in clinics to help monitor for cognitive impairment in patients with MS. We suggest a routine baseline assessment and multidomain cognitive battery in regular intervals; a change should trigger a thorough investigation of the cause.

Deep phenotyping of socio-emotional skills in children with typical development, neurodevelopmental disorders, and mental health conditions: Evidence from the PEERS.

OBJECTIVE: Socio-emotional skills, including social competence and social cognition, form the basis for robust relationships and wellbeing. Despite their importance, these skills are poorly defined and measured, particularly in children with developmental vulnerabilities. As a consequence, targets for effective management and treatment remain unclear. We aimed to i) phenotype social competence and social cognition in typically developing children (TDC) and in children with neurodevelopmental or mental health disorders (clinical groups) and ii) establish the relationships between these child-direct measures and parent ratings of social competence and behavior. METHOD: Using a multi-site, cross-sectional study design, we recruited 513 TDC and 136 children with neurodevelopmental (autism spectrum disorder [ASD], attention deficit hyperactivity disorder [ADHD]) or mental health (Anxiety Disorder [ANX]) diagnoses (age range 5-15 years). We administered the Paediatric Evaluation of Emotions, Relationships and Socialisation (PEERS) to children, and parents completed standardised questionnaires rating children's socio-emotional function. RESULTS: Standardised parent questionnaires revealed a global pattern of everyday socio-emotional impairment that was common to all clinical groups, while PEERS identified disorder-specific socio-cognitive profiles for children with ASD, ADHD and ANX. Compared to TDCs, children with ASD demonstrated global socio-cognitive impairment. Children with ADHD were impulsive, demonstrating difficulties managing speed accuracy trade-offs. Children with ANX exhibited slowed social decision-making, but otherwise intact skills. CONCLUSIONS: Standardized parent questionnaires of child socio-emotional function reveal differences between children with typical and atypical development, but do not yield disorder-specific, socio-emotional profiles. In contrast, findings from the PEERS objective assessment suggest that that ASD, ADHD and ANX are associated with distinct socio-cognitive phenotypes, to more accurately guide and target management and treatment of impaired social competence.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Mild worry symptoms predict decline in learning and memory in healthy older adults: a 2-year prospective cohort study.

OBJECTIVE: : Theoretical models of cognitive aging are increasingly recognizing the importance of anxiety and depressive symptoms in predicting age-related cognitive changes and early dementia. This study examined the association between mild worry and depressive symptoms, and cognitive function in healthy, community-dwelling older adults. METHOD: : A total of 263 healthy older adults participated in an observational prospective cohort study that assessed worry and depression symptoms, and a broad range of cognitive functions over a 2-year period. RESULTS: : Older adults with mildly elevated worry symptoms at baseline performed worse than older adults with minimal worry symptoms on measures of visual and paired associate learning. They were also more likely to show clinically significant (> 1.5 standard deviation) decline in visual learning and memory at a 2-year follow-up assessment (9.4% versus 2.5%; odds ratio = 3.8). CONCLUSION: : Assessment of worry symptoms, even mild levels, may have utility in predicting early cognitive decline in healthy, community-dwelling older adults.