Evaluation of the ATN model in a longitudinal memory clinic sample with different underlying disorders.

INTRODUCTION: To evaluate the usefulness of the 2018 NIA-AA (National Institute on Aging and Alzheimer's Association) research framework in a longitudinal memory clinic study with different clinical outcomes and underlying disorders. METHODS: We included 420 patients with mild cognitive impairment or subjective cognitive impairment. During the follow up, 27% of the patients converted to dementia, with the majority converting to Alzheimer's disease (AD) or mixed dementia. Based on the baseline values of the cerebrospinal fluid biomarkers, the patients were classified into one of the eight possible ATN groups (amyloid beta [Aß] aggregation [A], tau aggregation reflecting neurofibrillary tangles [T], and neurodegeneration [N]). RESULTS: The majority of the patients converting to AD and mixed dementia were in ATN groups positive for A (71%). The A+T+N+ group was highly overrepresented among converters to AD and mixed dementia. Patients converting to dementias other than AD or mixed dementia were evenly distributed across the ATN groups. DISCUSSION: Our findings provide support for the usefulness of the ATN system to detect incipient AD or mixed dementia.

Cognitive reserve lessens the burden of white matter lesions on executive functions in bipolar disorder.

BACKGROUND: The concept of cognitive reserve (CR) hypothesizes that intellectually stimulating activities provide resilience against brain pathology/disease. Whereas brain abnormalities and cognitive impairment are frequently reported in bipolar disorder (BD), it is unknown whether the impact of brain alterations can be lessened by higher CR in BD. METHOD: We tested if higher CR would reduce the influence of total volumes of deep white matter hypointensities (WMH), ventricular cerebrospinal fluid (CSF), and prefrontal cortex on memory, executive, and attention/speed functions in patients with BD (n = 75). Linear regression models with interaction terms for CR and brain volumes were applied to directly test if CR reduces the influence of brain pathology on cognitive domains. RESULTS: CR reduced the influence of total volumes of deep WMH (ß = -0.38, Q = 0.003) and ventricular CSF (ß = -41, Q = 006) on executive functions. CONCLUSIONS: The interactions between CR and total volumes of deep WMH/ventricular CSF appear to account for executive functioning in BD. The results suggest that the concept of CR is applicable in BD. Higher reserve capacity in BD alters the relationship between brain pathology and clinical presentation.

Progression from mild to pronounced MCI is not associated with cerebrospinal fluid biomarker deviations.

BACKGROUND/AIM: Detection of cerebrospinal fluid (CSF) biomarker deviations improve prediction of progression from mild cognitive impairment (MCI) to dementia. However, it is not settled whether the same pattern exists in patients progressing from very mild to more pronounced MCI. Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. METHODS: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), ß-amyloid 1-42 (Aß42) and the light subunit of neurofilament protein (NFL) were determined. RESULTS: Patients with converting MCI and stable dementia had lower CSF Aß42 concentrations and higher T-tau concentrations and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. CONCLUSION: As expected, biomarker deviations predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the underlying cause in this patient group.

A population-based study on the influence of brain atrophy on 20-year survival after age 85.

BACKGROUND: Individuals aged 80 years and older is the fastest growing segment of the population worldwide. To understand the biology behind increasing longevity, it is important to examine factors related to survival in this age group. The relationship between brain atrophy and survival after age 85 remains unclear. METHODS: A population-based sample (n = 239) had head CT scans at age 85 and was then followed until death. Cortical atrophy and ventricular size were assessed. Statistical analyses included Cox proportional hazards models with time to death as the outcome and considering a large number of possible confounders, including baseline cognitive function, incident dementia, and somatic disorders. RESULTS: Mean survival time (±SD) was 5.0 ± 3.6 years (range 0.10-19.8 years). Decreased survival was associated with temporal, and frontal atrophy, sylvian fissure width and a number of ventricular measures after adjustment for potential confounders. In participants without dementia at baseline (n = 135), decreased survival was associated with temporal lobe atrophy and bifrontal ratio. In those with dementia (n = 104), decreased survival was associated with third ventricle width, cella media ratio, and ventricle-to-brain and ventricle-to-cranial ratio. CONCLUSIONS: Several indices of brain atrophy were related to decreased survival after age 85, regardless of dementia status. Brain atrophy is rarely mentioned as a significant indicator of survival in the elderly, independent of traditional predictors such as cardiovascular disease or cancer. The biology behind the influence of brain atrophy on survival needs to be further scrutinized.

High white matter lesion load is associated with hippocampal atrophy in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition suggested as a prodromal state of Alzheimer's disease (AD) and subcortical vascular dementia (SVD). Recent findings suggest that white matter lesions (WML) may be associated with hippocampal atrophy. The objective of the study was to examine hippocampal and WML volumes in MCI patients and to examine if WML were linked to hippocampal atrophy. METHODS: The Gothenburg MCI study is a clinically based longitudinal study with biennial clinical assessments. The participants (n = 166) consist of 92 patients with stable MCI, 30 patients with converting MCI, and 44 healthy controls. WML volumes was measured manually using MRIcron. Automated segmentation of hippocampal and total white matter volumes was performed using FreeSurfer. RESULTS: The patients converting from MCI to dementia had reduced hippocampal volume. Stable MCI patients had fewer WML and converting MCI patients had more WML compared to controls. Hippocampal volume was only correlated to WML volume (ρ = 0.57; p < 0.01) in the quartile (n = 42) with the most WML. CONCLUSIONS: Hippocampal atrophy is present in both AD and SVD. Hippocampal volume was associated with WML volume only in the high WML quartile, suggesting that the WML volume must reach a threshold before hippocampal atrophy is seen.

Combination of hippocampal volume and cerebrospinal fluid biomarkers improves predictive value in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition, and the prognosis differs within the group. Recent findings suggest that hippocampal volumetry and CSF biomarkers can be used to predict which MCI patients have an underlying neurodegenerative disorder. OBJECTIVE: To examine the combined predictive value of hippocampal volume and CSF levels of total tau (T-tau) and beta-amyloid(42) (Abeta(42)) in stable and converting MCI patients. The participants (n = 68) included patients with MCI at baseline and who converted to dementia by the time of the 2-year follow-up (n = 21), stable MCI patients (n = 21) and healthy controls (n = 26). METHODS: The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually, based on data from the 0.5-tesla MRI investigations at baseline. Baseline CSF levels of T-tau and Abeta(42) were measured using commercially available, enzyme-linked immunosorbent assays. RESULTS: The converting MCI group had significantly smaller left hippocampi, lower CSF Abeta(42) and higher T-tau compared to both the stable MCI group and the healthy controls. Multivariate analysis revealed that a combination of the variables outperformed the prognostic ability of the separate variables. CONCLUSIONS: Hippocampal volumes supplement the prognostic accuracy of CSF Abeta(42) and T-tau in MCI.

Cognitive reserve in relation to abeta42 in patients converting from MCI to dementia - a follow-up report.

UNLABELLED: The concept of the cognitive reserve (CR) hypothesizes that premorbid factors such as education enable compensation for the manifestation of brain pathology. Accordingly, pathology should be more prominent in individuals with higher CR before becoming clinically apparent. Previously, we found that patients subsequently converting to dementia with higher CR had lower concentrations of amyloid beta 42 (abeta42) as compared to patients with lower CR. However, the interaction between time, biomarkers, neuropsychological performance and CR is yet to be established. OBJECTIVE: To study the relation between biomarkers, neuropsychological performance and CR longitudinally. METHOD: A mixed between-within subject analysis of variance was performed for longitudinal analysis. Paired t tests were used for within group comparisons. RESULTS: Patients with higher CR (n = 15) had significantly lower concentrations of abeta42 at both time points compared to those with medium (n = 23) and lower CR (n = 28). Also, abeta42 concentrations decreased significantly from baseline to follow-up in patients with higher and medium CR. Groups performed comparably on neuropsychological tests. CONCLUSION: This study provides further support for the applicability of abeta42 as a substitute for pathology in relation to CR. Also, abeta42 reflects the disease progression in patients with higher and medium CR.

Biomarkers in relation to cognitive reserve in patients with mild cognitive impairment--proof of concept.

BACKGROUND: The concept of the cognitive reserve (CR) posits that factors such as education enable compensation for the effect of brain pathology. Consequently, pathology should be more pronounced in individuals with higher CR before becoming clinically apparent. Biomarkers such as total tau (t-tau) and beta-amyloid 42 (Abeta42) may be surrogates for pathology in relation to CR in patients with neurodegenerative disease. OBJECTIVE: To examine the applicability of biomarkers as surrogates for pathology in relation to the CR in patients with mild cognitive impairment (MCI) either converting to dementia or remaining stable at follow-up. METHOD: Comparisons of baseline t-tau, Abeta42, educational years and global cognition for MCI patients either converting to dementia (n = 57) or remaining stable (n = 91) were made. Patients converting to dementia were grouped on the basis of educational level and compared considering biomarkers and neuropsychological tests. RESULTS: Stable MCI patients were better educated, performed better cognitively, had higher Abeta42 levels and lower levels of t-tau. Converting MCI patients with higher education had lower levels of Abeta42 and performed equally in neuropsychological tests compared to those with lower education. CONCLUSION: Our results suggest that highly educated MCI patients subsequently converting to dementia display more amyloid pathology.

Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: the Göteborg MCI study.

BACKGROUND: Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. OBJECTIVE: To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. PATIENTS: The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. METHODS: The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. RESULTS: Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. CONCLUSIONS: In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.