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Tuesday, May 26, 2015




A growing body of research suggests depression may be a risk factor for Parkinson’s disease (PD), or even an early feature of the disease. Now, a new study published in the May 20 online edition of Neurology offers new evidence that strengthens that association.


Study author Peter Nordström PhD, a professor and chief physician in the Department of Community Medicine and Rehabilitation at Umeå University in Sweden, and his colleagues looked at a sample of 140,688 people from a national register of health records for the Swedish population who were aged 50 or older at the end of 2005 and were diagnosed with depression between 1987 and 2012. They matched each of these patients with three control subjects of the same age and sex who did not have depression, for a total study population of 562,631. They then followed these people for up to 26 years, with a median follow-up of 6.8 years.


During that time, 1,485 people with depression (or 1.1 percent of the depressed group) and 1,775 people without depression (or 0.4 percent of the non-depressed group) developed PD. Compared with those without depression, people who were depressed were 3.2 times more likely to develop PD within the year after they were diagnosed (95% confidence interval [CI], 2.5-4.1), Dr. Nordström and colleagues found. And 15 to 25 years after the depression diagnosis, those with depression were still approximately 50 percent more likely to develop PD than non-depressed people (95% CI, 1.1-2.0).


The researchers also found that patients who had been hospitalized at least once for depression were 3.5 times more likely to be diagnosed with PD than those who received treatment for depression but were never hospitalized (95% CI, 2.9-4.1). Those who had been hospitalized for depression five or more times were 40 percent more likely to be diagnosed with PD than patients who had been hospitalized for depression only once (95% CI, 1.1-1.9).


To determine if genetic or environmental factors contributed to the association between the two conditions, Dr. Nordström and colleagues looked at the incidence of depression and PD in 540,811 pairs of siblings. They found that although Parkinson’s was more common among people who had a sibling with PD (odds ratio [OR] 1.91; 95% CI, 1.3-2.9), depression in one sibling did not increase the risk of the other sibling developing Parkinson’s (OR 1.11; 95% CI, 0.9-1.4).


This finding strengthens the evidence that PD and depression are associated because “if the diseases were independent of each other but caused by the same genetic or early environmental factors, then we would expect to see the two diseases group together in siblings, but that didn’t happen,” Dr. Nordström said in a news release.


“The key finding of this study is a distinct relationship between depression and a subsequently increased risk of PD; this association weakened over time, but remained significant during a follow-up period of more than 2 decades,” Dr. Nordström and colleagues wrote.


The researchers proposed three theories that might explain the persistent link between Parkinson’s and depression. First, they said, depression and/or drugs used to treat depression could increase the risk for PD. Second, depression may be an early symptom of Parkinson’s disease, appearing well before motor symptoms and other manifestations of the disease occur. Lastly, they said, it’s possible that genetic or environmental factors that cause depression may also cause PD—although the results of their study in siblings make this theory less likely.


“The persistence of the association during the entire follow-up period highlights the importance of investigating potential risk markers for PD from a long-term perspective, and may be a finding of significance in clinical practice; the increased risk of PD among patients with a long history of depression should be considered when other symptoms attributable to PD arise,” they concluded.


For more stories about the link between depression and Parkinson’s, browse our archives here.


Image via Lloyd Morgan on Flickr.

Friday, May 22, 2015



Two new studies published in the May 19 issue of JAMA offer valuable data on the prevalence of amyloid plaques among adults with and without dementia across the adult lifespan. The findings could help establish a diagnosis for early-onset Alzheimer’s disease (AD) and identify candidates for studies that test AD drugs in the disease’s preclinical stages, the study investigators said.


The studies also lend support to the notion that amyloid is the earliest pathological sign of the disease in the brain, appearing as much as 20 to 30 years before the onset of dementia, and that the apolipoprotein e4 (APOE4) gene, known to increase the risk of AD, is linked to an accelerated accumulation of amyloid.


PET images from an Alzheimer disease subject (left) and an age-matched control subject (right) with corresponding MRI images. Courtesy of C. A. Mathis and W. E. Klunk, University of Pittsburgh.


Amyloid Burden in Non-Demented Individuals

For the first study, Willemijn J. Jansen, MSc, and Pieter Jelle Visser, MD, PhD, of Masstricht University in the Netherlands, performed a meta-analysis of studies estimating the prevalence of amyloid pathology (as measured by positron emission tomography [PET] or in cerebrospinal fluid [CSF]) in more than 7,500 participants, aged 18 to 100, from 55 studies: 2,914 with normal cognition, 697 with subjective cognitive impairment (SCI; patients with self-reported concerns about cognition), and 3,972 with mild cognitive impairment (MCI).


Ten percent of the study participants with normal cognition had amyloid pathology at age 50, increasing to 44 percent at age 90. Amyloid positivity increased from 12 percent at age 50 to 43 percent at age 90 among those with SCI, and from 27 percent to 71 percent among those with MCI.


APOE status was also linked to amyloid prevalence: Patients with the APOE4 risk gene had two to three times greater amyloid prevalence than those without it. At age 90, about 40 percent of APOE4 non-carriers and more than 80 percent of APOE4 carriers had amyloid pathology on PET or in CSF.


“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the study authors wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggest a 20 to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”


The authors added that long-term follow-up studies will be needed “because not all persons with amyloid pathology will become demented during their lifetime, and not all individuals with a clinical diagnosis of AD-type dementia have amyloid pathology.” Therefore, “amyloid positivity in these individuals should not be equated with impending clinical dementia but rather seen as a risk state.”


Amyloid Burden in Dementia Patients

In the second JAMA study, Rik Ossenkoppele, PhD, and his colleagues at VU University Medical Center Amsterdam conducted a meta-analysis of studies on the prevalence of PET amyloid positivity in patients with AD and other dementias, including frontotemporal dementia, vascular dementia, corticobasal syndrome, and dementia with Lewy bodies. They included data on 1,359 people with AD and 538 people with non-AD dementia.


Dr. Ossenkoppele and colleagues found that amyloid was positive on PET for 88 percent of those with AD; that prevalence decreased from 93 percent at age 50 to 79 percent at age 90. However, among those with the APOE4 gene — 593 patients — amyloid prevalence remained at roughly 90 percent regardless of age, declining from 97 percent at age 50 to 90 percent age 90 (p<0.01).


Among the 377 AD patients who were APOE4 non-carriers, the researchers observed a decrease in amyloid prevalence from 86 percent at age 50 to 68 percent at age 90. The researchers did not offer an explanation for this observation, but Roger N. Rosenberg, MD, the Abe (Brunky), Morris and William Zale distinguished chair in neurology at the University of Texas Southwestern Medical Center and editor of JAMA Neurology, commenting on the finding in an accompanying editorial, said that “the value of these observations is that amyloid imaging may be most critical in making the correct diagnosis in early-onset dementia [when amyloid burden will be highest], especially to rule in AD dementia.”


In most other forms of dementia, in contrast, the percentage of those positive for amyloid increased from 60 to 80 years, with greater increases for APOE4 carriers, suggesting “that amyloid is present as secondary pathology and the clinical syndrome is driven by non-AD pathologies,” Dr. Rosenberg said.


The main findings of the analysis, the researchers said, were that “the prevalence of amyloid on PET decreased with age in participants diagnosed with AD (greatest in APOE e4 noncarriers) and increased with age in most non-AD dementias.”


They added, “the convergence of amyloid positivity across dementias with increasing age suggests that amyloid imaging might have the potential to be most helpful for differential diagnosis in early-onset dementia, particularly if the goal is to rule in AD dementia. However, the high concordance between PET and pathology suggests that amyloid imaging might have the potential to be used to rule out AD dementia regardless of age. Furthermore, amyloid in non-AD dementia may be clinically important as amyloid positivity was associated with worse global cognition.”


Implications of the Findings

In his editorial, Dr. Rosenberg commented that “these data show the immense potential clinical use of amyloid imaging to make the correct diagnosis in early-onset dementia and, more specifically, to establish the diagnosis of AD-type dementia and non-carrier APOE4 genotype among persons older than 70 years.”


For clinical trials of anti-amyloid therapies that can be initiated during the long preclinical phase of AD, these studies “provide the basis for clarifying the parameters…and providing impressions as to which patients are most at risk and would potentially benefit most with anti-amyloid-β therapy,” he concluded.


Look for more information about these studies, plus expert commentary, in an upcoming issue of Neurology Today. For more coverage of the latest research on amyloid and Alzheimer’s, browse our archives here.

Thursday, May 21, 2015



By streamlining the process of admitting and evaluating stroke patients, two hospitals — one in Washington, DC, and another in Bethesda, MD — significantly reduced door-to-needle times for ischemic stroke patients who underwent screening with magnetic resonance imaging (MRI) and subsequently received intravenous tissue plasminogen activator (IV tPA).


The results of this study, called SMART (Screening with MRI for Accurate and Rapid Stroke Treatment), which was sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), were published in the May 13 online edition of Neurology.


Multimodal MRI, compared with non-contrast computed tomography (CT), can provide more comprehensive information about a patient’s stroke, including “the location and size of the stroke if present, when it occurred, the extent of blood vessel blockage and amount of brain tissue at risk, new or old bleeding, and potentially the cause of the stroke,” said senior author Amie Hsia, MD, medical director of the Comprehensive Stroke Center at MedStar Washington Hospital Center (MWHC), in a news release. However, CT is often used as the first-line screening tool because of concern over delays in accessing MRI, which could, in turn, delay life-saving treatment.


For the SMART study, the researchers sought to prove that they could use MRI as the first-line brain imaging and meet the national benchmark of initiating tPA treatment within 60 minutes from a patient’s arrival in the emergency room — the “golden hour” in which treatment is most likely to result in favorable outcomes.


The researchers implemented principles gleaned from “lean” manufacturing processes to address specific hurdles that lengthened door-to-needle times at MWHC and Suburban Hospital in Bethesda. In the first quarter of 2013, the researchers created “process maps” to highlight all of the steps involved in delivering IV tPA to acute stroke patients arriving in the emergency room, then identified steps that did not add value or contributed significantly to time delays. During the second quarter of 2013, they implemented specific interventions to reduce these delays.


For example, at Suburban Hospital, key interventions included “bypassing the ED [emergency department] bay and bringing the patient directly to MRI on the emergency medical services stretcher,” and “creating a treatment bay within the MRI suite so that IV tPA could be administered in the MRI suite rather than transferring the patient back to the ED before treatment,” the authors explained.


They reported that 157 patients with acute ischemic stroke received treatment with IV tPA at these two centers between 2012 and 2013; 135 of them (or 86 percent) were screened with MRI. The study protocol reduced door-to-needle times from a median of 93 minutes in the first half of 2012 to 55 minutes in the last half of 2013, a 40 percent reduction at both hospitals (p<0.0001). Also, the proportion of patients treated within the golden hour rose from 13 percent in the first half of 2012 to 61.5 percent in the last half of 2013, a statistically significant fourfold increase. The improvement in door-to-needle time was largely attributable to the improvement in door-to-MRI time (p<0.0001).


“This study demonstrates that consistently achieving DTN [door-to-needle] time of ≤60 minutes is feasible using multimodal MRI as the first-line imaging modality to screen patients,” the researchers said.


Furthermore, the processes used to reduce door-to-needle time at these hospitals, including “creating process maps to identify roadblocks causing delays, reorganizing the work flow to reduce hand-offs, and assigning specific roles to each member of the team,” have the potential to be widely applicable to other hospitals, Dr. Hsia and colleagues wrote.


“With the help of the strategies described here,” they concluded, “it should be possible to create the infrastructure necessary to use MRI for rapid and accurate decision-making in acute stroke thrombolysis.”  


For more coverage of the efforts to expedite and improve stroke treatment, browse our archives here.

Tuesday, May 19, 2015




Obese teenagers have higher serum levels of the proteins amyloid-beta 42 (Aβ42) and presenilin 1 (PSEN1) compared with healthy-weight and overweight teens, according to an Italian study published in the May 11 online edition of Pediatrics. Both proteins are believed to be predictive of Alzheimer’s disease (AD).


The researchers, from Bambino Gesu Children’s Hospital in Rome, looked at the link between obesity, insulin resistance, and potential biomarkers of AD in more than 400 preschool and teenage boys who were enrolled in two studies at the hospital. Because insulin resistance and type 2 diabetes, which are common in obese patients, have been linked to an increased risk of AD and dementia, the researchers theorized that the changes associated with dysfunctional insulin signaling in the brain may already be visible in childhood and adolescence.


For the study, the investigators measured fasting glucose, insulin, lipid profile, liver function, white blood cell count, and C-reactive protein in 440 normal weight, overweight, and obese preschoolers (aged 2 to 6 years old) and teens (aged 12 to 18), and analyzed levels of Aβ42 and PSEN1 in blood samples. Among the teenagers, 129 were obese, 135 were overweight, and 176 had a normal weight.


The researchers chose to look for elevated levels of Aβ42 based on its role in the formation of amyloid plaques. Past studies have found elevated levels of Aβ42 in patients who later developed AD, they noted, although it is unclear whether Aβ42 can reliably be used to predict Alzheimer’s. They chose to analyze PSEN1 because of its involvement in the production of toxic Aβ42.


They also looked at whether Aβ42 and PSEN1 levels were correlated with body mass index (BMI), the homeostasis model of insulin resistance (HOMA-IR; a method of quantifying insulin resistance and beta-cell function), and the Quantitative Insulin Sensitivity Check Index (QUICKI; a method of measuring insulin sensitivity that combines fasting insulin and fasting glucose).


Among the findings, levels of Aβ42 and PSEN1 were higher in the obese teenagers than in overweight or normal weight teens (for Aβ42, 190.2 ± 9.16 vs. 125.9 ± 7.38 ± 129.5 ± 7.65 pg/mL; for PSEN1, 2.34 ± 0.20 vs. 1.95 ± 0.20 vs. 1.65 ± 0.26 ng/mL; both p<0.0001). Concentrations of Aβ42 and PSEN1 were significantly correlated with BMI, HOMA-IR, and QUICKI (all p<0.0001). Preschoolers had lower levels of these proteins than teens, and the researchers found no association between the children’s weight and their serum concentrations of Aβ42 or PSEN1.


“For the first time, we observed that overweight and obese adolescents exhibit higher levels of circulating Aβ42 and PSEN1 than normal-weight peers, and their concentrations are significantly correlated with both adiposity and IR [insulin resistance],” the researchers wrote.


It is unclear whether these levels can predict later development of mild cognitive impairment, dementia, or AD, but the findings suggest that obesity may “accelerate release of serum Aβ42,” they said.


“The clinical meaning of this observation is unclear,” they noted, adding that longitudinal studies may be helpful to tease out the implications.


For more coverage of the link between obesity and Alzheimer’s, browse our archives here.


Image via Tony Alter on Flickr.

Thursday, May 14, 2015



Alzheimer’s disease (AD) patients who exhibit at least one clinically significant neuropsychiatric symptom — including hallucinations, delusions, agitation or aggression, anxiety, or depression — may progress faster to severe disease and die earlier, according to a study published in the May 2015 issue of the American Journal of Psychiatry.


During preclinical Alzheimer’s disease, subtle degenerative changes begin to occur, and the person develops mild cognitive impairment. In mild to moderate stages of Alzheimer’s disease, pathologic changes affect the areas of the brain that control memory, language, and reasoning. In the severe stage of Alzheimer’s disease, pathologic changes cause significant atrophy in many areas. (Courtesy of the National Institute on Aging/National Institutes of Health.)


For the study, Matthew E. Peters, MD, a psychiatrist with Johns Hopkins Medicine in Baltimore, MD, and colleagues analyzed the neuropsychiatric symptom prevalence and dementia progression among patients in the Cache County Dementia Progression Study, a cohort of more than 5,092 adults aged 65 and older who were screened for dementia every three to five years between 1995 and 2009.


In this population, Dr. Peters and colleagues identified 335 cases of incident AD with a mean age at onset of 84.3 years, including 68 people (20 percent) classified as having “severe” dementia. At follow-up, in October 2010, 273 participants were deceased. The median time to severe Alzheimer’s dementia was 8.5 years (95% confidence interval [CI], 7.6-9.2) and the median time to death was 5.7 years (95% CI 5.423-6.061).


Among these patients, half (50.9 percent) had neuropsychiatric symptoms at baseline, including 25.9 percent with at least one mild neuropsychiatric symptom and 25 percent with at least one clinically significant neuropsychiatric symptom; 18.1 percent had hallucinations and delusions and 38.8 percent had depression, anxiety, irritability, and agitation. A reported 16.9 percent showed symptoms of apathy or indifference; 10 percent showed agitation or aggression.  


Patients had an increased risk of progressing to dementia if they exhibited hallucinations and delusions (hazard ratio [HR] 2.007; p=0.03), agitation or aggression (HR 2.946; p=0.004), and at least one clinically significant neuropsychiatric symptom (HR 2.682; p=0.001). Patients who experienced several types of severe neuropsychiatric symptoms and at least one clinically significant neuropsychiatric symptom (HR 1.951; p≤0.001), tended to die earlier. The results were not affected by age at onset of dementia, the patient’s health status, or the use of antidepressants, benzodiazepines, or antipsychotic drugs.


Apathy or indifference was not predictive of speedier progression to severe dementia or death in this study, the authors noted.


What explains these findings? “First, it is possible that a confounder that was not being measured in this study exists,” Dr. Peters and colleagues wrote. “Or perhaps localized pathology of brain regions associated with agitation/aggression or psychosis occurs in more aggressive forms of Alzheimer’s dementia.”


Lastly, they suggested, “the presence of these neuropsychiatric symptoms may influence the care environment in some way that in turn affects progression. For example, one may speculate that the presence of psychosis or agitation/aggression may lead to behaviors, situations, and relationships that are more conducive to worsening of disease. Affective symptoms could lead to similar modification.”


Based on these findings, “the treatment of specific neuropsychiatric symptoms in mild Alzheimer’s dementia should be examined for its potential to delay time to severe dementia or death,” Dr. Peters and colleagues concluded.


For more coverage of neuropsychiatric symptoms in Alzheimer’s disease, browse our archives here.