Susanna Vestberg

Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42: A Cross-Validation Study Against Amyloid Positron Emission Tomography

IMPORTANCE Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition. OBJECTIVES To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38). EXPOSURES Amyloid positron emission tomography imaging with 18F-flutemetamol. MAIN OUTCOMES AND MEASURES Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples. RESULTS The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE (apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = -0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = -0.32), memory function (r = -0.28), and hippocampal volume (r = -0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort. CONCLUSIONS AND RELEVANCE Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.

Personality characteristics and affective status related to cognitive test performance and gender in patients with memory complaints

The aims are to study personality characteristics of patients with memory complaints and to assess the presence of objective (OMI) versus subjective (SMI) memory impairment, the affective status, as well as potential gender differences. The patients were assessed by means of a neuropsychiatric examination and a neuropsychological test-battery. The Swedish version of the revised NEO Personality Inventory (NEO PI-R) and the Hospital Anxiety and Depression Scale (HADS) were used. The 57 patients (38 women, 19 men, mean age 56.9) differed from the Swedish normative group in three of the five personality factors: neuroticism, extraversion and agreeableness. This was mainly because of the scores of the female patients. Approximately half of the patients had OMI. No differences regarding personality factors or affective status were found between OMI and SMI patients. The female patients scored significantly higher than the male patients on symptoms of anxiety and depression. Neuroticism and symptoms of depression interacted with memory performance and gender. Our findings demonstrate the importance of applying an objective assessment of memory functions and a gender perspective when studying patients with memory complaints.

Stability in the clinical characteristics of patients with memory complaints.

The objectives of this study were to examine potential clinical and neuropsychological changes over time in non-demented patients with subjective memory complaints (<or=70 years) and to compare the patients with objective memory impairment (OMI) with those who suffer from subjective memory impairment (SMI). OMI and SMI patients did not differ regarding duration of memory problems, age or education. At baseline no differences were revealed between the OMI and SMI patients regarding self-reported cognitive deficits, self-reported worry about deficits, and symptoms of anxiety or depression. None of the patients had converted to dementia at follow-up. Eighty percent of the OMI patients and 61% of the SMI patients reported cognitive deficits to the same degree at follow-up as at baseline. Despite a significant reduction of depressive symptoms in the OMI patients, a considerable portion of both OMI and SMI patients scored above the cut off score on both anxiety and depression subscales at baseline as well as at follow-up. Our study reveals close points of similarity between patients with memory complaints, verified by test, and patients with memory complaints, not verified by test, as well as stability over time regarding important clinical aspects.

Striatal Atrophy in the Behavioural Variant of Frontotemporal Dementia: Correlation with Diagnosis, Negative Symptoms and Disease Severity

Introduction Behavioural variant frontotemporal dementia (bvFTD) is associated with changes in dorsal striatal parts of the basal ganglia (caudate nucleus and putamen), related to dysfunction in the cortico-striato-thalamic circuits which help mediate executive and motor functions. We aimed to determine whether the size and shape of striatal structures correlated with diagnosis of bvFTD, and measures of clinical severity, behaviour and cognition. Materials and Methods Magnetic resonance imaging scans from 28 patients with bvFTD and 26 healthy controls were manually traced using image analysis software (ITK-SNAP). The resulting 3-D objects underwent volumetric analysis and shape analysis, through spherical harmonic description with point distribution models (SPHARM-PDM). Correlations with size and shape were sought with clinical measures in the bvTFD group, including Frontal Behavioural Inventory, Clinical Dementia Rating for bvFTD, Color Word Interference, Hayling part B and Brixton tests, and Trail-Making Test. Results Caudate nuclei and putamina were significantly smaller in the bvFTD group compared to controls (left caudate 16% smaller, partial eta squared 0.173, p=0.003; right caudate 11% smaller, partial eta squared 0.103, p=0.023; left putamen 18% smaller, partial eta squared 0.179, p=0.002; right putamen 12% smaller, partial eta squared 0.081, p=0.045), with global shape deflation in the caudate bilaterally but no localised shape change in putamen. In the bvFTD group, shape deflations on the left, corresponding to afferent connections from dorsolateral prefrontal mediofrontal/anterior cingulate and orbitofrontal cortex, correlated with worsening disease severity. Global shape deflation in the putamen correlated with Frontal Behavioural Inventory scores—higher scoring on negative symptoms was associated with the left putamen, while positive symptoms were associated with the right. Other cognitive tests had poor completion rates. Conclusion Behavioural symptoms and severity of bvFTD are correlated with abnormalities in striatal size and shape. This adds to the promise of imaging the striatum as a biomarker in this disease.

Age-related incidence and family history in frontotemporal dementia: data from the Swedish Dementia Registry.

Objectives Frontotemporal dementia (FTD) is considered to be a mainly early-onset neurodegenerative disorder with a strong hereditary component. The aim of the study was to investigate age-related incidence and family history in FTD compared to other dementia disorders, especially Alzheimers disease (AD). Methods The Swedish Dementia Registry (SveDem) registers all new cases of dementia diagnosed by the participating centres, including data on demographics, diagnosis, and investigations used. Data for the period 2008–2011 were extracted and compared with age-related population data on a regional and national level. Results There were 20 305 patients registered in SveDem during 2008–2011, whereof 352 received a diagnosis of FTD. Mean age at diagnosis for FTD was 69.6 years and almost 70% of FTD cases were 65 years or older at the time of diagnosis. Both FTD and AD showed an increased incidence with age, which reached a maximum in the age group 80–84 years at 6.04 and 202 cases per 100 000 person-years, respectively. The proportion of cases with a positive family history was significantly lower in FTD than in AD. Conclusions Contrary to general opinion within the field, data from SveDem show that the incidence of FTD increases with age, and that the majority of cases are diagnosed after the age of 65 years. In addition, data from SveDem might suggest that the importance of hereditary factors in general is similar in FTD and AD. The recognition of these findings has important consequences for the diagnosis, treatment and care of patients with FTD.

Subjective experience of memory deficits related to clinical and neuroimaging findings.

The aim of this study was to evaluate cognitive impairment, psychiatric symptoms and cerebral blood flow (CBF) patterns in middle-aged (35–64 years) and younger old patients (65–74 years) with subjective experience of memory deficits. The study group was heterogeneous with patients fulfilling criteria for dementia, as well as patients with mild cognitive impairment (MCI) and with non-verified cognitive impairment (non-MCI). Seventy per cent of the non-MCI patients reported long-lasting experiences of psychosocial stress tentatively causing the memory problems. The MCI patients were subdivided into two groups: MCI type 1 included patients with isolated memory impairment, while MCI type 2 included patients with memory impairment together with slight verbal and/or visuospatial impairments. CBF measurements comparing the two MCI groups with the non-MCI group were performed. The MCI type 2 showed reduced CBF in the left anterior medial temporal lobe as well as in parts of the posterior cingulate gyrus. The CBF pattern in MCI type 2 concurs with the pathophysiological process of Alzheimer’s disease. The results indicate that it is important to make a subdivision of MCI patients regarding the presence of isolated memory impairments or memory impairments together with other slight cognitive deficits.

Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease

Disinhibition is an important symptom in neurodegenerative diseases. However, the clinico-anatomical underpinnings remain controversial. We explored the anatomical correlates of disinhibition in neurodegenerative disease using the perspective of grey and white matter imaging. Disinhibition was assessed with a neuropsychological test and a caregiver information-based clinical rating scale in 21 patients with prefrontal syndromes due to behavioural variant frontotemporal dementia (n = 12) or progressive supranuclear palsy (n = 9), and healthy controls (n = 25). Cortical thickness was assessed using the Freesurfer software on 3T MRI data. The integrity of selected white matter tracts was determined by the fractional anisotropy (FA) from Diffusion Tensor Imaging. Disinhibition correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula and the FA of the right uncinate fasciculus and right anterior cingulum. Notably, no relationship was seen with the thickness of ventromedial prefrontal cortex. Our results support an associative model of inhibitory control, distributed in a medial temporal lobe-insular-orbitofrontal network, connected by the intercommunicating white matter tracts. This reconciles some of the divergences among previous studies, but also questions the current conceptualisation of the “prefrontal” syndrome and the central role attributed to the ventromedial prefrontal cortex in inhibitory control.

Validity of the IQCODE-CA: An informant questionnaire on cognitive decline modified for a cardiac arrest population ☆

AIM To examine the psychometric properties of a modified version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), for a cardiac arrest population (IQCODE-CA). METHODS The IQCODE-CA, a 26-item observer-reported questionnaire, was completed by informants, defined as relatives or close friends, of 268 out-of-hospital cardiac arrest (OHCA) survivors who participated in the Target Temperature Management trial in a scheduled follow-up 180±14days after OHCA. Survivors completed the Mini Mental State Examination (MMSE), the Rivermead Behavioural Memory Test (RBMT) and the Hospital Anxiety and Depression Scale (HADS). An exploratory factor analysis was performed. Associations between IQCODE-CA results and demographic variables along with other instruments were calculated. Area under the curve (AUC) ratios were evaluated to examine discrimination. RESULTS The IQCODE-CA measured one factor, global cognitive decline, with high internal consistency (ordinal α=0.95). Age, gender or education did not influence the IQCODE-CA score. Associations with performance-based measures of global cognitive function as well as anxiety and depression ranged from small to moderate (rs=-0.29 to 0.38). AUC ratios ranged from fair to good (0.72-0.81). According to the MMSE and RBMT, the optimal cut-off score to identify cognitive decline on the IQCODE-CA was 3.04. Using this value, 53% of the survivors were under the cut-off. CONCLUSIONS The IQCODE-CA identified a large amount of survivors with possible cognitive problems, making it useful when screening for cognitive decline post-CA. Due to lower AUC ratios than desired, additional performance-based measures should be used to improve the overall screening methodology.

Decline in executive functions and speed in suspected low-grade gliomas: A 3-year follow-up of a clinical cohort

ABSTRACT Changes over time in information processing speed and executive functions (EFs) were studied in patients with suspected low-grade gliomas (LGG) 3 years after diagnosis. Using a person-oriented approach, the study aimed at focusing solely on two cognitive domains known to be significant in the understanding of the impact of white matter diseases. The Barkley’s hybrid model of EFs was used as a theoretical framework for the evaluation of EFs. The majority of the patients showed a decline in at least one of these two cognitive domains indicating that the progress of diffuse brain injury cannot be neglected in understanding neuropsychological changes over time in patients with LGG. In our sample, higher age and radiological signs of radiotherapy-induced brain atrophy were seen in patients with a decline in both domains.

Exercise-induced Release of Cytokines/Myokines in a Single Exercise Test before and after a Training Intervention in Patients with Mild Cognitive Impairment

Background: Inflammation may play an important role in development of mild cognitive impairment and also predict progression of cognitive diseases. Studies have shown that aerobic and strength training increases the ability to generate and secrete cytokines from the skeletal muscles (then named myokines) that might be protective. Objectives: This pilot study was intended to explore if it is possible to detect changes in cytokine/myokine levels in response to a single exercise test in patients with mild cognitive impairment before and after a training intervention. Participants and Methods: Participants with mild cognitive impairment (N=33) performed12 weeks aerobic and strength endurance training at moderate (n=13), at high intensity (n=12) or served as control group with no training (n=8). At baseline and after 12 weeks a single maximal exercise test was performed where 2 venous blood samples were collected respectively, one at rest and one at maximal workload. TNF-α, IL-6, IL-1β, and IL -8 were assayed using commercial ELISA kits. Results: Resting values of TNF-α, IL-6, IL-1β, or IL -8 at base line and post training were normal compared to reference values for all patients. At baseline, a single exercise test elevated levels of the myokines, IL-6 (p= 0.002), TNF-α (p