Search

The difference between brain age predicted from MRI and chronological age (the so-called BrainAGE) has been proposed as an ageing biomarker. We analyse its cross-species potential by testing it on rats undergoing an ageing modulation intervention. Our rat brain age prediction model combined Gaussian process regression with a classifier and achieved a mean absolute error (MAE) of 4.87 weeks using cross-validation on a longitudinal dataset of 31 normal ageing rats. It was then tested on two groups of 24 rats (MAE = 9.89 weeks, correlation coefficient = 0.86): controls vs. a group under long-term environmental enrichment and dietary restriction (EEDR). Using a linear mixed-effects model, BrainAGE was found to increase more slowly with chronological age in EEDR rats ( p = 0.015 for the interaction term). Cox regression showed that older BrainAGE at 5 months was associated with higher mortality risk ( p = 0.03 ). Our findings suggest that lifestyle-related prevention approaches may help to slow down brain ageing in rodents and the potential of BrainAGE as a predictor of age-related health outcomes.

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ-/APOE-, Aβ+/APOE-, Aβ-/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ-/APOE-, Aβ+/APOE- and Aβ-/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.

In this study, we investigated associations between neuropsychiatric symptoms (i.e., apathy, anxiety, and depression) and cerebral atrophy, white matter lesions (WML), beta-amyloid (Aβ) deposition, and cognitive decline in a nondemented sample. 104 cognitively unimpaired and 53 subjects with mild cognitive impairment were followed for up to 4 years within the Swedish BioFINDER study. Neuropsychiatric assessments included the Hospital Anxiety and Depression Scale and the Apathy Evaluation Scale. Magnetic resonance imaging and 18F-flutemetamol-positron emission tomography quantified brain atrophy, WML, and Aβ deposition. Mini-Mental State Examination assessed longitudinal global cognition. Regression analyses were used to test for associations. Apathy and anxiety were shown related to Aβ deposition and predicted cognitive decline. Anxiety also interacted with amyloid status to predict faster cognitive deterioration. Apathy was further related to frontotemporal and subcortical atrophy, as well as WML. To conclude, the associations between apathy and anxiety with Aβ deposition and cognitive decline point to these symptoms as early clinical manifestations of Alzheimer's disease.

We investigated whether subtypes of Alzheimer's disease (AD), that is, typical, limbic-predominant, hippocampal-sparing, and minimal atrophy AD, had a specific signature of small vessel disease and neurodegeneration. Four hundred twenty-three clinically diagnosed AD patients were included (161 typical, 121 limbic-predominant, 70 hippocampal-sparing, 71 minimal atrophy). One hundred fifty-six fulfilled a biomarkers-based AD diagnosis. White matter hyperintensities and cerebral microbleeds (CMB) had the highest prevalence in limbic-predominant AD, and the lowest prevalence in minimal atrophy AD. CMB existed evenly in lobar and deep brain areas in limbic-predominant, typical, and hippocampal-sparing AD. In minimal atrophy AD, CMB were mainly located in brain lobar areas. Perivascular spaces in the centrum semiovale were more prevalent in typical AD. Small vessel disease contributed to the prediction of Mini-Mental State Examination. Minimal atrophy AD showed highly pathological levels of cerebrospinal fluid As1-42, total tau, and phosphorylated tau, in the absence of overt brain atrophy. Cerebral amyloid angiopathy seems to have a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy may have a stronger contribution to typical and limbic-predominant AD.

Cognitive aging is highly complex. We applied a data-driven statistical method to investigate aging from a hierarchical, multidimensional, and multivariate approach. Orthogonal partial least squares to latent structures and hierarchical models were applied for the first time in a study of cognitive aging. The association between age and a total of 316 demographic, clinical, cognitive, and neuroimaging measures was simultaneously analyzed in 460 cognitively normal individuals (35–85 years). Age showed a strong association with brain structure, especially with cortical thickness in frontal and parietal association regions. Age also showed a fairly strong association with cognition. Although a strong association of age with executive functions and processing speed was captured as expected, the association of age with visual memory was stronger. Clinical measures were less strongly associated with age. Hierarchical and correlation analyses further showed these associations in a neuroimaging-cognitive-clinical order of importance. We conclude that orthogonal partial least square and hierarchical models are a promising approach to better understand the complexity in cognitive aging.

Recent findings show that structural network topology is disrupted in Alzheimer's disease (AD), with changes occurring already at the prodromal disease stages. Amyloid accumulation, a hallmark of AD, begins several decades before symptom onset, and its effects on brain connectivity at the earliest disease stages are not fully known. We studied global and local network changes in a large cohort of cognitively healthy individuals (N = 299, Swedish BioFINDER study) with and without amyloid-β (Aβ) pathology (based on cerebrospinal fluid Aβ42/Aβ40 levels). Structural correlation matrices were constructed based on magnetic resonance imaging cortical thickness data. Despite the fact that no significant regional cortical atrophy was found in the Aβ-positive group, this group exhibited an altered global network organization, including decreased global efficiency and modularity. At the local level, Aβ-positive individuals displayed fewer and more disorganized modules as well as a loss of hubs. Our findings suggest that changes in network topology occur already at the presymptomatic (preclinical) stage of AD and may precede detectable cortical thinning.

The aggregation and deposition of amyloid-β (Aβ) peptides into plaques is an early event in Alzheimer's disease (AD), which is followed by different aspects of neurodegeneration that can be measured in the cerebrospinal fluid (CSF) or plasma using neurofilament light (NFL), neurogranin (Ng), total Tau (T-Tau), and phosphorylated tau (P-Tau) levels. The relationship between these biomarkers and regional brain atrophy across the different stages of AD remains largely unexplored. In this study, we assessed whether NFL, Ng, T-Tau, and P-Tau levels in CSF and NFL in plasma are associated with cortical thinning and subcortical volume loss in cognitively normal, mild cognitive impairment, and AD subjects with and without Aβ pathology. Our main findings showed that CSF NFL levels were associated with brain atrophy in all groups, but plasma NFL only correlated with atrophy in symptomatic cases. In contrast, Ng was associated with regional brain atrophy only in individuals with Aβ pathology. Altogether, our main findings suggest that Ng is strongly associated with Aβ pathology, whereas NFL is more unspecific.

The present theoretical framework of Alzheimer's disease proposes that pathophysiological changes occur 10-20 years before the diagnosis of dementia. We addressed the question of how age-related changes in gray matter mediate the cognitive performance during middle age. Eighty-two participants (40-50 years, ±2) were assessed with a comprehensive neuropsychological battery covering a broad spectrum of cognitive domains and components. Mediation effects were studied with hierarchical regression and bootstrapping analysis. Results showed that more vulnerable cognitive components were related to executive functioning and in a lesser degree to processing speed. Age-related differences in gray matter mainly involved the frontal lobes. Moreover, age-related differences in visuoconstructive, visuospatial functions, reaction time, and mental flexibility and executive control were mediated by several gray matter regions. It is important to increase the knowledge of the impact of brain changes on cognitive function during middle age. To define the early stages of the aging process may allow early detection of pathologic changes and therapeutic interventions.

To study the ability of neuropsychological tests, manual MRI hippocampal volume measures, regional volume and cortical thickness measures to identify subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. Neuropsychological tests, manual hippocampal volume, automated regional volume and regional cortical thickness measures were performed in 120 AD patients, 120 MCI subjects, and 111 controls. The regional cortical thickness and volumes in MCI subjects were significantly decreased in limbic/paralimbic areas and temporal lobe compared to controls. Atrophy was much more extensive in the AD patients compared to MCI subjects and controls. The combination of neuropsychological tests and volumes revealed the highest accuracy (82% AD vs. MCI; 94% AD vs. control; 83% MCI vs. control). Adding regional cortical thicknesses into the discriminate analysis did not improve accuracy. We conclude that regional cortical thickness and volume measures provide a panoramic view of brain atrophy in AD and MCI subjects. A combination of neuropsychological tests and regional volumes are important when discriminating AD from healthy controls and MCI.

Translational biomarkers in Alzheimer's disease based on non-invasive in vivo methods are highly warranted. (1)H magnetic resonance spectroscopy (MRS) is non-invasive and applicable in vivo in both humans and experimental animals. In vivo(1)H MRS and 3D MRI were performed on brains of double transgenic (tg) mice expressing a double mutant human beta-amyloid precursor protein APP(K670N,M671L) and human mutated presenilin gene PS1M146L, and wild-type (wt) littermates at 2.5, 6.5 and 9 months of age using a 9.4T magnet. For quantification, LCModel was used, and the data were analyzed using multivariate data analysis (MVDA). MVDA evidenced a significant separation, which became more pronounced with age, between tg and wt mice at all time points. While myo-inositol and guanidoacetate were important for group separation in young mice, N-acetylaspartate, glutamate and macrolipids were important for separation of aged tg and wt mice. Volume segmentation revealed that brain and hippocampus were readily smaller in tg as compared to wt mice at the age of 2.5 months. Amyloid plaques were seen in 6.5 and 9 months, but not in 2.5 months old animals. In conclusion, differences in brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with MVDA. First differences in metabolite content were readily seen at 2.5 months, when volume defects in tg mice were present, but no amyloid plaques.

Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.