51 research outputs found
Causes and Correlates of Brain Atrophy: A population-based MRI study
__Abstract__
In 1906, Alois Alzheimer described for the first time a form of dementia that later became
known as Alzheimerâs disease. At necropsy, he had observed that the brain of a 51-year-old
woman with progressive cognitive decline was filled with âat that time still anonymousâ amyloid
plaques and neurofibrillary tangles. Since then, numerous investigators saw in patients
with dementia the same pathological findings that Alzheimer had seen. Clinically, Alzheimerâs
disease is recognized by a long period of progressive cognitive decline. Braak and Braak
showed in the late eighties that the accumulation of plaques and tangles in the brain follows
a predictable pattern over time that parallels this cognitive decline. In their now widely accepted
staging system, they identify a long phase where the medial temporal lobe is the first
area to be afflicted whereas only in the later disease stages the pathology involves the isocortices.
However, recent pathological studies show that brains of elderly patients, unlike the
middleâaged patient that Alzheimer had observed, who in life receive a diagnosis of Alzheimerâs
disease have a rather mixed bag of brain pathology. Not only the traditionally recognized
amyloid plaques and neurofibrillary tangles are observed but also cerebrovascular disease is
found which could have contributed to the cognitive decline.
The search for causes of Alzheimerâs disease is hampered by its long preclinical period and
the pathological diversity that contribute to clinical symptoms of Alzheimerâs disease
Silent brain infarcts and the risk of dementia and cognitive decline
BACKGROUND: Silent brain infarcts are frequently seen on magnetic
resonance imaging (MRI) in healthy elderly people and may be associated
with dementia and cognitive decline. METHODS: We studied the association
between silent brain infarcts and the risk of dementia and cognitive
decline in 1015 participants of the prospective, population-based
Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia
and stroke at base line. Participants underwent neuropsychological testing
and cerebral MRI at base line in 1995 to 1996 and again in 1999 to 2000
and were monitored for dementia throughout the study period. We performed
Cox proportional-hazards and multiple linear-regression analyses, adjusted
for age, sex, and level of education and for the presence or absence of
subcortical atrophy and white-matter lesions. RESULTS: During 3697
person-years of follow-up (mean per person, 3.6 years), dementia developed
in 30 of the 1015 participants. The presence of silent brain infarcts at
base line more than doubled the risk of dementia (hazard ratio, 2.26; 95
percent confidence interval, 1.09 to 4.70). The presence of silent brain
infarcts on the base-line MRI was associated with worse performance on
neuropsychological tests and a steeper decline in global cognitive
function. Silent thalamic infarcts were associated with a decline in
memory performance, and nonthalamic infarcts with a decline in psychomotor
speed. When participants with silent brain infarcts at base line were
subdivided into those with and those without additional infarcts at
follow-up, the decline in cognitive function was restricted to those with
additional silent infarcts. CONCLUSIONS: Elderly people with silent brain
infarcts have an increased risk of dementia and a steeper decline in
cognitive function than those without such lesions
Homocysteine and brain atrophy on MRI of non-demented elderly
Patients with Alzheimer's disease have higher plasma homocysteine levels
than controls, but it is uncertain whether higher plasma homocysteine
levels are involved in the early pathogenesis of the disease. Hippocampal,
amygdalar and global brain atrophy on brain MRI have been proposed as
early markers of Alzheimer's disease. In the Rotterdam Scan Study, a
population-based study of age-related brain changes in 1077 non-demented
people aged 60-90 years, we investigated the association between plasma
homocysteine levels and severity of hippocampal, amygdalar and global
brain atrophy on MRI. We used axial T(1)-weighted MRIs to visualize global
cortical brain atrophy (measured semi-quantitatively; range 0-15) and a 3D
HASTE (half-Fourier acquisition single-shot turbo spin echo) sequence in
511 participants to measure hippocampal and amygdalar volumes. We had
non-fasting plasma homocysteine levels in 1031 of the participants and in
505 of the participants with hippocampal and amygdalar volumes.
Individuals with higher plasma homocysteine levels had, on average, more
cortical atrophy [0.23 units (95% CI 0.07-0.38 units) per standard
deviation increase in plasma homocysteine levels] and more hippocampal
atrophy [difference in left hippocampal volume -0.05 ml (95% CI -0.09 to
-0.01) and in right hippocampal volume -0.03 ml (95% CI -0.07 to 0.01) per
standard deviation increase in plasma homocysteine levels]. No association
was observed between plasma homocysteine levels and amygdalar atrophy.
These results support the hypothesis that higher plasma homocysteine
levels are associated with more atrophy of the hippocampus and cortical
regions in elderly at risk of Alzheimer's disease
Higher estrogen levels are not associated with larger hippocampi and better memory performance
BACKGROUND: Estrogens may prevent cognitive decline and Alzheimer disease.
Animal study findings have shown beneficial effects of estrogen on the
brain, particularly on the hippocampus, a structure related to memory
performance and early Alzheimer disease. OBJECTIVE: To investigate whether
higher levels of endogenous estradiol in older women and men are
associated with larger hippocampal volumes on magnetic resonance imaging
and better memory performance. DESIGN AND SETTING: Cross-sectional
analysis within the Rotterdam Scan Study, a population-based study in the
Netherlands of elderly subjects who do not have dementia. PARTICIPANTS:
Two hundred ten women and 202 men, aged 60 to 90 years, with plasma levels
of total estradiol and, in part, 162 women and 149 men also with levels of
bioavailable and free estradiol. MAIN OUTCOME MEASURE: Hippocampal volumes
on magnetic resonance imaging and memory performance (delayed recall).
RESULTS: Women with higher total estradiol levels had smaller hippocampal
volumes and poorer memory performance -0.29 mL (95% confidence interval,
-0.57 to -0.00) and -0.4 (95% confidence interval, -1.3 to 0.5) fewe
Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia
BACKGROUND: Consumers of light-to-moderate amounts of alcohol have a lower risk of dementia and, possibly, Alzheimer disease than do abstainers. Because vascular disease may contribute to symptoms of Alzheimer disease, reduction of cerebrovascular disease in consumers of light amounts of alcohol could account for that observation. However, a low concentration of alcohol may also have direct effects on the hippocampus, a brain structure highly affected by Alzheimer disease. OBJECTIVE: We investigated alcohol intake in relation to brain magnetic resonance imaging (MRI) findings of presumed vascular
Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study
Objective Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF). Methods Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31). Results GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up. Interpretation We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials
Observational Dutch Young Symptomatic StrokE studY (ODYSSEY): Study rationale and protocol of a multicentre prospective cohort study
Background: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce.Methods/design: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/TIA. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment.Discussion: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size
The influence of cerebral small vessel disease on default mode network deactivation in mild cognitive impairment
Introduction Cerebral small vessel disease (CSVD) is thought to contribute to cognitive dysfunction in patients with mild cognitive impairment (MCI). The underlying mechanisms, and more specifically, the effects of CSVD on brain functioning in MCI are incompletely understood. The objective of the present study was to examine the effects of CSVD on brain functioning, activation and deactivation, in patients with MCI using task-related functional MRI (fMRI). Methods We included 16 MCI patients with CSVD, 26 MCI patients without CSVD and 25 controls. All participants underwent a physical and neurological examination, neuropsychological testing, structural MRI, and fMRI during a graded working memory paradigm. Results MCI patients with and without CSVD had a similar neuropsychological profile and task performance during fMRI, but differed with respect to underlying (de)activation patterns. MCI patients with CSVD showed impaired deactivation in the precuneus/posterior cingulate cortex, a region known to be involved in the default mode network. In MCI patients without CSVD, brain activation depended on working memory load, as they showed relative 'hyperactivation' during vigilance, and 'hypoactivation' at a high working memory load condition in working memory related brain regions. Conclusions We present evidence that the potential underlying mechanism of CSVD affecting cognition in MCI is through network interference. The observed differences in brain activation and deactivation between MCI patients with and without CSVD, who had a similar 'clinical phenotype', support the view that, in patients with MCI, different types of pathology can contribute to cognitive impairment through different pathways
Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease
__Background:__ Neuropsychiatric symptoms (NPS) are very common in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and are associated with various disadvantageous clinical outcomes including a negative impact on quality of life, caregiver burden, and accelerated disease progression. Despite growing evidence of the efficacy of (non)pharmacological interventions to reduce these symptoms, NPS remain underrecognized and undertreated in memory clinics. The BEhavioural symptoms in Alzheimer's disease Towards early Identification and Treatment (BEAT-IT) study is developed to (1) investigate the neurobiological etiology of NPS in AD and (2) study the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) approach to structure and standardize the current care of NPS in AD. By means of the DICE method, we aim to improve the quality of life of AD patients with NPS and their caregivers who visit the memory clinic. This paper describes the protocol for the intervention study that incorporates the latter aim.
__Methods:__ We aim to enroll a total of 150 community-dwelling patients with MCI or AD and their caregivers in two waves. First, we will recruit a control group who will receive care as usual. Next, the second wave of participants will undergo the DICE method. This approach consists of the following steps:
(1) describe the context in which NPS occur,
(2) investigate the possible causes,
(3) create and implement a treatment pl
Hundreds of variants clustered in genomic loci and biological pathways affect human height
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (Pâ<â0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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