Posts tagged cognitive impairment

Cognitive neuroscience research has shown that certain brain regions are associated with specific cognitive abilities, such as language, naming, and decision-making.

How and where these specific abilities are integrated in the brain to support complex cognition is still under investigation. However, researchers at the University of Iowa and Washington University in St. Louis, Missouri, believe that several hub regions may be especially important for the brain to function as an integrated network.

In research published online Sept. 15 in the Early Edition of the Proceedings of the National Academy of Sciences, scientists studied neurological patients with focal brain damage, and found that damage to six hub locations—identified in a model developed at Washington University using resting state fMRI, functional connectivity analyses, and graph theory—produced much greater cognitive impairment than damage to other locations.

Doctors have long observed that despite having similar locations or extent of brain injury, patients often present with wide-ranging degrees of impairment and exhibit different recovery trajectories. A better understanding of brain networks and hubs may improve the understanding of outcomes of brain injuries (for example, stroke, resection, or trauma) and help inform prognosis and rehabilitation efforts.

“We were able to identify a set of brain hubs and show that damage to those locations unexpectedly causes widespread cognitive impairments,” says David Warren, cognitive neuroscientist at the University of Iowa and lead study author. “We hope that this framework will help neurologists with diagnosis and prognosis, and neurosurgeons with surgical planning.”

Two contrasting views of brain hubs exist. One view focuses on the sheer number of connections between brain regions, with those regions showing the most connections considered hubs.

Warren and his colleagues contend that the number of connections a given region makes may not reflect the importance of a region to network function because it can be strongly influenced by network size. Instead, their framework defines hubs as brain regions that show correlated activity with multiple brain systems (rather than regions). The authors predicted that because hubs should be critical for brain function and complex cognition, damage to true hubs should produce widespread cognitive impairment.

This study evaluated long-term cognitive and behavioral data in 30 patients in the Iowa Neurological Patient Registry—19 with focal damage to one of the authors’ six target hub locations and 11 with damage to two control locations that fit the alternative hub definition.

On average, patients with lesions to target hubs had significant impairment in nine major cognitive domains—orientation/attention, perception, memory, language skills, motor performance, concept formation/reasoning, executive functions, emotional functions, and adaptive functions. In contrast, the group with lesions to control hubs was significantly impaired in just three of the nine domains (executive functions, emotional functions, and adaptive functions).

Additionally, the target group had significantly greater cognitive deficits than the control group in seven of nine domains (all except perception and emotional functions), again showing the widespread cognitive effects of target hub lesions.

“With a grant from the McDonnell Foundation, we’re planning to follow up by exploring the effects of damage to additional brain hubs, examining how damage to hubs alters brain activation, and studying neurosurgery patients prospectively before and after their surgeries,” says senior study author Daniel Tranel, professor of neurology in the UI Carver College of Medicine and psychology in the College of Liberal Arts and Sciences. “We think that this work could have a tremendous influence on clinical practice.”

(Source: now.uiowa.edu)

Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. This therapeutic strategy not only suppressed seizure activity and premature death, but also improved cognitive and behavioral abnormalities that can accompany this syndrome.

Previous studies from this group have shown that lowering tau levels reduces abnormal brain activity in models of Alzheimer’s disease, but this is the first demonstration that tau reduction may also be beneficial in intractable genetic epilepsy.

"It would really be wonderful if tau reduction turned out to be useful not only in Alzheimer’s disease, but also in other disabling neurological conditions for which there currently are no effective treatments," said senior author Lennart Mucke, MD, the director of the Gladstone Institute of Neurological Disease and a professor of Neurology and Neuroscience at the University of California, San Francisco. "We suspected that this approach might be beneficial in Dravet, but we couldn’t be sure because of the severity of this syndrome and the corresponding model. We are thrilled that our strategy was so effective, but a lot more work is needed to advance it into the clinic."

Dravet syndrome is one of the most challenging forms of childhood epilepsy, resulting from a specific genetic mutation that affects sodium channels in the brain. Frequent, relentless seizures are accompanied by cognitive impairments and behavioral problems similar to autism, and up to 20% of patients succumb to sudden death. Current treatments for Dravet syndrome are largely ineffective, making research into the disorder particularly urgent.

"I am especially excited about the improvements we observed in cognitive and behavioral dysfunctions because these abnormalities are particularly hard on the kids—and their parents," said first author Ania Gheyara, MD, PhD, a staff scientist at Gladstone who is also affiliated with the UCSF Department of Pathology. "Our hope is that this approach will be broadly applicable to many different types of epilepsy."

In the study, which was published online today in the Annals of Neurology, the scientists reduced the level of the protein tau by genetically engineering Dravet mouse models, “knocking out” the gene associated with tau production. The deletion of one copy of the gene resulted in substantial improvements in most symptoms, while deleting both copies eliminated them almost completely. This included a significant reduction in both spontaneous and heat-induced seizures. The latter were used to mimic the fever-related seizures that are often seen in the early stages of Dravet syndrome. Network activity in the brain was also normalized, providing additional support for the remarkable ability of tau reduction to suppress epileptic activity.

Additionally, tau reduction ameliorated the learning and memory deficits and behavioral abnormalities present in the Dravet mice, which may relate to the cognitive impairments and autism-like behaviors seen in the human condition.

"The next steps are to develop tau-lowering therapeutics that could be used in humans and to evaluate their safety and efficacy in preclinical studies," said Dr. Mucke, "objectives we are pursuing actively."

(Source: eurekalert.org)

In a long-term, large-scale population-based study of individuals aged 55 years or older in the general population researchers found that those diagnosed with mild cognitive impairment (MCI) had a four-fold increased risk of developing dementia or Alzheimer’s disease (AD) compared to cognitively healthy individuals. Several risk factors including older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, as well as specific MRI findings were associated with an increased risk of developing MCI. The results are published in a supplement to the Journal of Alzheimer’s Disease.

“Mild cognitive impairment has been identified as the transitional stage between normal aging and dementia,” comments M. Arfan Ikram, MD, PhD, a neuroepidemiologist at Erasmus MC University Medical Center (Rotterdam). “Identifying persons at a higher risk of dementia could postpone or even prevent dementia by timely targeting modifiable risk factors.”

Unlike a clinical trial, the Rotterdam study is an observational cohort study focusing on the general population, instead of persons referred to a memory clinic. The Rotterdam study began in 1990, when almost 8,000 inhabitants of Rotterdam aged 55 years or older agreed to participate in the study. Ten years later, another 3,000 individuals were added. Participants undergo home interviews and examinations every four years.

“This important prospective study adds to the accumulating evidence that strokes, presumably related to so called ‘vascular’ risk factors, also contribute to the appearance of dementia in Alzheimer’s disease. This leads to the conclusion that starting at midlife people should minimize those risk factors. The recent results of the Finish FINGER study corroborate this idea. It should be remembered that delaying the onset of dementia by five years will reduce the prevalence of the disease by half. And of course, since there is no cure for AD, prevention is the best approach at present,” explains Professor Emeritus Amos D Korczyn, Tel Aviv University, Ramat Aviv, Israel, and Guest Editor of the Supplement.

To be diagnosed with MCI in the study, individuals were required to meet three criteria: a self-reported awareness of having problems with memory or everyday functioning; deficits detected on a battery of cognitive tests; and no evidence of dementia. They were categorized into those with memory problems (amnestic MCI) and those with normal memory (non-amnestic MCI).

Of 4,198 persons found to be eligible for the study, almost 10% were diagnosed with MCI. Of these, 163 had amnestic MCI and 254 had non-amnestic MCI.

The risk of dementia was especially high for people with amnestic MCI. Similar results were observed regarding the risk for Alzheimer’s disease. Those with MCI also faced a somewhat higher risk of death. 

The research team investigated possible determinants of MCI, considering factors such as age, APOE-ɛ status, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke. Only older age, being an APOE-ɛ4 carrier, low total cholesterol levels, and stroke at baseline were associated with developing MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI.

When the investigators analysed MRI studies of the brain, they found that participants with MCI, particularly those with non-amnestic MCI, had larger white matter lesion volumes and worse microstructural integrity of normal-appearing white matter compared to controls. They were also three-times more likely than controls to have lacunes (3 to 15 mm cerebrospinal fluid (CSF)-filled cavities in the basal ganglia or white matter, frequently observed when imaging older people). MCI was not associated with total brain volume, hippocampal volume, or cerebral microbleeds.

“Our results suggest that accumulating vascular damage plays a role in both amnestic and non-amnestic MCI,” says Dr. Ikram. “We propose that timely targeting of modifiable vascular risk factors might contribute to the prevention of MCI and dementia.”

Reference:

Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study. Renée F.A.G. de Bruijn, Saloua Akoudad, Lotte G.M. Cremers, Albert Hofman, Wiro J. Niessen, Aad van der Lugt, Peter J. Koudstaal, Meike W. Vernooij, M. Arfan Ikram. Journal of Alzheimer’s Disease, Volume 42/Supplement 3 (August 2014): 2013 International Congress on Vascular Dementia (Guest Editor: Amos D. Korczyn)

(Source: iospress.nl)

A study published in the American Journal of Geriatric Psychiatry indicates that middle-aged adults with a history of problem drinking are more than twice as likely to suffer from severe memory impairment in later life.

The study highlights the hitherto largely unknown link between harmful patterns of alcohol consumption and problems with memory later in life – problems which may place people at a high risk of developing dementia.

The study was carried out by researchers from the University of Exeter Medical School with support from the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR PenCLAHRC).

The research team studied the association between a history of alcohol use disorders (AUDs) and the onset of severe cognitive and memory impairment in 6542 middle-aged adults born between 1931 and 1941. These individuals participated in the Health and Retirement Study in the US.

Participants were first assessed in 1992 and follow-up assessments took place every other year from 1996 to 2010.

A history of AUDs was identified using the CAGE* questionnaire (short for Cut down, Annoyed, Guilty, Eye-opener). Where participants registered a history of AUDs their chances of developing severe memory impairment more than doubled.

The study was led by Dr Iain Lang. He commented: “We already know there is an association between dementia risk and levels of current alcohol consumption – that understanding is based on asking older people how much they drink and then observing whether they develop problems. But this is only one part of the puzzle and we know little about the consequences of alcohol consumption earlier in life. What we did here is investigate the relatively unknown association between having a drinking problem at any point in life and experiencing problems with memory later in life.”

He added: “This finding – that middle-aged people with a history of problem drinking more than double their chances of memory impairment when they are older – suggests three things: that this is a public health issue that needs to be addressed; that more research is required to investigate the potential harms associated with alcohol consumption throughout life; and that the CAGE questionnaire may offer doctors a practical way to identify those at risk of memory/cognitive impairment and who may benefit from help to tackle their relationship with alcohol.”

Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “When we talk about drinking too much, the media often focuses on young people ending up in A&E after a night out. However, there’s also a hidden cost of alcohol abuse given the mounting evidence that alcohol abuse can also impact on cognition later in life. This small study shows that people who admitted to alcohol abuse at some point in their lives were twice as likely to have severe memory problems, and as the research relied on self-reporting that number may be even higher.

"This isn’t to say that people need to abstain from alcohol altogether. As well as eating a healthy diet, not smoking and maintaining a healthy weight, the odd glass of red wine could even help reduce your risk of developing dementia."

* The CAGE asks four questions (and the acronym comes from words in each question: Cut down, Annoyed, Guilty, Eye-opener):

1. Have you ever felt you should cut down on your drinking?
2. Have people annoyed you by criticising your drinking?
3. Have you ever felt bad or guilty about your drinking?
4. Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)?

(Source: exeter.ac.uk)

Early life experiences, such as childhood socioeconomic status and literacy, may have greater influence on the risk of cognitive impairment late in life than such demographic characteristics as race and ethnicity, a large study by researchers with the UC Davis Alzheimer’s Disease Center and the University of Victoria, Canada, has found.

“Declining cognitive function in older adults is a major personal and public health concern,” said Bruce Reed professor of neurology and associate director of the UC Davis Alzheimer’s Disease Center.

“But not all people lose cognitive function, and understanding the remarkable variability in cognitive trajectories as people age is of critical importance for prevention, treatment and planning to promote successful cognitive aging and minimize problems associated with cognitive decline.”

The study, “Life Experiences and Demographic Influences on Cognitive Function in Older Adults,” is published online in Neuropsychology, a journal of the American Psychological Association. It is one of the first comprehensive examinations of the multiple influences of varied demographic factors early in life and their relationship to cognitive aging.

The research was conducted in a group of over 300 diverse men and women who spoke either English or Spanish. They were recruited from senior citizen social, recreational and residential centers, as well as churches and health-care settings. At the time of recruitment, all study participants were 60 or older, and had no major psychiatric illnesses or life threatening medical illnesses. Participants were Caucasian, African-American or Hispanic.

The extensive testing included multidisciplinary diagnostic evaluations through the UC Davis Alzheimer’s Disease Center in either English or Spanish, which permitted comparisons across a diverse cohort of participants.

Consistent with previous research, the study found that non-Latino Caucasians scored 20 to 25 percent higher on tests of semantic memory (general knowledge) and 13 to 15 percent higher on tests of executive functioning compared to the other ethnic groups. However, ethnic differences in executive functioning disappeared and differences in semantic memory were reduced by 20 to 30 percent when group differences in childhood socioeconomic status, adult literacy and extent of physical activity during adulthood were considered. 

“This study is unusual in that it examines how many different life experiences affect cognitive decline in late life,” said Dan Mungas, professor of neurology and associate director of the UC Davis Alzheimer’s Disease Research Center. 

“It shows that variables like ethnicity and years of education that influence cognitive test scores in a single evaluation are not associated with rate of cognitive decline, but that specific life experiences like level of reading attainment and intellectually stimulating activities are predictive of the rate of late-life cognitive decline. This suggests that intellectual stimulation throughout the life span can reduce cognitive decline in old age.”

Regardless of ethnicity, advanced age and apolipoprotein-E (APOE genotype) were associated with increased cognitive decline over an average of four years that participants were followed. APOE is the largest known genetic risk factor for late-onset Alzheimer’s. Less decline was experienced by persons who reported more engagement in recreational activities in late life and who maintained their levels of activity engagement from middle age to old age. Single-word reading — the ability to decode a word on sight, which often is considered an indication of quality of educational experience — was also associated with less cognitive decline, a finding that was true for both English and Spanish readers, irrespective of their race or ethnicity. These findings suggest that early life experiences affect late-life cognition indirectly, through literacy and late-life recreational pursuits, the authors said.

“These findings are important,” explained Paul Brewster, lead author of the study, a doctoral student at the University of Victoria, Canada, and a pre-doctoral psychology intern at the UC San Diego Department of Psychiatry, “because it challenges earlier research that suggests associations between race and ethnicity, particularly among Latinos, and an increased risk of late-life cognitive impairment and dementia.

”Our findings suggest that the influences of demographic factors on late-life cognition may be reflective of broader socioeconomic factors, such as educational opportunity and related differences in physical and mental activity across the life span.”

(Source: ucdmc.ucdavis.edu)