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Neurology News

Follow our Neurology News blog for the latest news on neurologic diseases and research.

Thursday, February 14, 2019

BY LIZETTE BORRELI

Women are more likely to show Alzheimer's disease (AD) pathophysiology, a series of recent studies have shown. Now, an analysis of cross-sectional data, published online on February 4 in JAMA Neurology, provides further support for the theory that women develop more tau pathology than men.

In a study of two cross-sectional cohorts of clinically normal adults, women with a higher amyloid burden showed a higher tau signal in their entorhinal cortices than men.

"These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk," Rachel F. Buckley, PhD, a research fellow in neurology at Massachusetts General Hospital in Boston, and her colleagues, wrote.

A 2018 meta-analysis published in JAMA Neurology reported greater cerebrospinal fluid (CSF) total and phosphorylated tau in female apolipoprotein E (APOE) ε4 carriers than male carriers with the findings influenced by abnormal levels of amyloid-beta.

However, sex differences in amyloid-beta burden alone have not been reported in older adults, and studies have not yet explored these differences in regional tau deposition related to amyloid-beta burden and APOE ε4, according to the researchers.

To observe sex differences in the cross-sectional relationship between amyloid-beta and regional tau deposition as measured with positron emission tomography (PET), the team evaluated the Harvard Aging Brain study (HABS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), both comprising clinically normal individuals, who received both tau and amyloid-beta PET scans from January 2016 to February 2018.

The HABS cohort included 193 individuals (average age, 74 years; 62 percent women) who had carbon 11–labeled Pittsburgh Compound B (PIB) PET to assess amyloid-beta. The ADNI cohort included 103 individuals (average age 76; 51 percent women) who underwent florbetapir PET to assess amyloid beta. Both the HABS and ADNI cohort had tau assessed with flortaucipir F18 PET.

Among both cohorts, the average Mini-Mental State Examination Score (MMSE) in each group was about 29 points out of 30 maximum points on the scale.

The researchers collected a blood sample in each study for direct genotyping of APOE.

The findings revealed the HABS cohort performed significantly better on logical memory (delayed recall) than the ADHI group, but did not differ by age, sex, amyloid positivity, or APOE ε4 status.

In the HABS group, women were younger (average age 73) compared to those in the ADNI group (average age 75).

Among amyloid-positive individuals, women had more tau signal in their entorhinal cortices than men (p=.02). This became more evident as the presence of amyloid increased. Higher amyloid-burden led women to have higher entorhinal cortex tau than men in both the HABS (p=.04) and the ADNI cohorts (p value?)

Sex and the presence of APOE did not appear to influence tau deposition in the HABS group. However, in the ADNI group, the interaction between sex and APOE ε4 was spotted in a meta-region that included the entorhinal cortex, inferior temporal cortex, amygdala, fusiform gyrus, and the parahippocampal cortex, with the association stronger among women than men.

Overall, clinically normal women showed higher regional tau compared to men, especially women with higher amyloid-beta burden, specifically seen in the entorhinal cortices.

Study limitations included using cohort samples—the ADNI group was older, had lower memory performance, and were more likely to have an advanced preclinical AD trajectory—compared with the HABS group. Moreover, both groups experienced different assessments of amyloid-beta.

Dr. Buckley is funded with the National Health and Medical Research Council Dementia Research Fellowship (APP1105576). Other researchers reported relationships with Eli Lilly, Biogen, Cortexyme, the European Union's Horizon 2020 Research and Innovation Programme, Janssen Pharmaceuticals, Lundbeck Pharmaceuticals, Bayer, GE Healthcare, Siemens Medical Solutions, Sanofi Genzyme, Novartis, Roche, Ionis Pharmaceuticals, AZTherapies, Lundberg, AbbVie, Navidea, Bracket, Avid Radiopharmaceuticals, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer's Association.

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Buckley RF, Mormino EC, Rabin JS, et al. "Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults." JAMA Neurol 2019; Epub 2019 Feb 4.

Monday, February 11, 2019

BY LIZETTE BORRELI        

Hypertensive older adults with periventricular white matter hyperintensities (WMH) on MRI had an increased risk for incident mild cognitive impairment (MCI), according to a longitudinal population-based study in Spain published online on January 4 in Hypertension.

Those who showed a marked progression of these lesions had a sixfold risk of incident MCI, compared with patients who showed no progression.

Similar to cerebral microbleeds and lacunar infarcts, WMH on MRI are viewed as typical markers of cerebral small vessel disease (cSVD), which is commonly associated with an increased risk for stroke, death and dementia.

A 2006 study published in the Journal of Neurology, Neurosurgery, and Psychiatry, reported that the progression of periventricular WMH was associated with decreases in executive function and information processing speed.

However, no study has addressed cognitive changes in hypertensive patients and "considering that hypertension is one of the principal risk factors for cognitive impairment and the progression of cerebral small vessel disease, this is an important gap in the literature," the researchers, led by Joan Jiménez Balado, MSc, a PhD student at Vall D'Hebron Research Institute in Barcelona, wrote.

To observe how changes in cSVD lesions are correlated with cognitive decline and MCI in hypertensive patients, the team followed 345 hypertensive men and women in the Investigating Silent Strokes in Hypertensives: A Magnetic Resonance Imaging Study (ISSYS), an ongoing longitudinal population-based study on hypertensive patients aged 50 to 70 years who did not have dementia and had not had a stroke at baseline.

In this study, on average, patients were age 65; 94.2 percent were being treated for hypertension, and 55.4 percent were male.

Patients underwent brain MRI and cognitive testing both at baseline and follow-up. The researchers used the Dementia Rating Scale 2nd version (DRS-2) to assess cognitive function. A second evaluation was conducted if participants' DRS-2 scores indicated cognitive impairment.

The average follow-up was 3.95 years and average blood pressure was 144.5/76.5 mmHg.

During the study, 75 percent of patients showed no signs of cognitive dysfunction at baseline or follow-up; 7 percent of those with baseline MCI had a non-affected status at follow-up; 9 percent had stable MCI and another 9 percent developed MCI.

Twenty-two percent of the patients had minor or marked periventricular WMH progression; 48 percent had deep WMH progression.

Patients with marked progression of periventricular WMH showed a significant decrease in global cognition, compared with those without progression (p=.004). Moreover, these patients were more vulnerable to develop incident MCI (p=.011).

The researchers noted only marked progression of periventricular WMH was associated with incident MCI.

Among the study limitations, the research team only selected patients for follow-up based on the severity of baseline cSVD, which limits the findings' generalizability for hypertensive patients; they used qualitative assessments to measure MRI changes in hyperintensities; and did not include neurodegeneration markers, such as tau or amyloid-beta.

The Instituto de Salud Carlos III and AGAUR, with the support of the Secretary of Universities and Research of the Department of Economy and Knowledge, and the European Regional Development Fund helped fund the study.

The researchers reported no conflicts of interest.

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Jimenez-Balado J, Riba-Llena I, Abril O, et al. Cognitive impact of cerebral small vessel disease changes in patients with hypertension. Hypertension 2019. Epub 2019 Jan 4.

Wednesday, February 6, 2019

BY LIZETTE BORRELI

Elevated blood pressure was associated with lower gray matter volume in young adults, according to a German study published online on January 23 in Neurology.

In individuals age 40 years or younger, those with blood pressure levels above 120/80 mmHg, but who are not considered hypertensive, had lower brain volumes in regions associated with gray matter decline in older individuals with hypertension.

The researchers, led by Lina Schaare, PhD candidate, department of neurology, Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany, believe the results "highlight the importance of taking BP levels as a continuous measure into consideration, which could help initiate such early preventive measures."

Previous studies have looked at specific brain structures and found a link between hypertension and reductions in brain volume in the medial temporal lobe and other regions. Elevated blood pressure in midlife also has been linked to lower brain volume on autopsy and increases in the tangles and plaques associated with Alzheimer's disease in the hippocampus. But the effects of elevated blood pressure on the brains of individuals age 40 or younger are unclear.

To find out whether elevated blood pressure levels are associated with lower gray matter volume in brain regions, specifically in the frontal and medial temporal lobes, the researchers assessed four unpublished datasets of studies conducted in Germany between 2010 and 2015.

The team identified 423 participants, average age 27.7 years; 42 percent women, who had not been previously diagnosed with hypertension.

They measured systolic blood pressure (SBP) and diastolic blood pressure (DBP) at varying times of day. The researchers then took the average of these multiple measurements to one average systolic and one average diastolic reading for each participant.

Using the 2013 European guidelines for the management of arterial hypertension, they classified participants based on blood pressure levels: individuals in category 1 had SBP < 120 mmHg and DBP < 80 mmHg; category 2 had SBP 120-129 mmHg or DBP 80-84 mmHg; category 3 had SBP 130-139 mmHg or DBP 85-89 mmHg; and category 4 had SBP ≥ 140 mmHg or DBP ≥ 90 mmHg.

All participants had at least one blood pressure reading: 41 percent had blood pressure lower than 120/80 mmHg (defined as normal); 29 percent had blood pressure between 120/80 to 129/84; 19 percent between 130/85 and 139/89; and 11 percent above 140/90 (defined as hypertension in the European study).

The researchers used a statistical mapping technique to detect small differences between volumes in brain regions on MRI scans.

The findings revealed increases in SBP (above 120/80 mmHg) was linked to lower gray matter volume in the hippocampus, amygdala, thalamus, frontal, and parietal structures.

Meanwhile, increases in DBP were associated with lower gray matter volume in the bilateral anterior insula, frontal regions, right midcingulate cortex, bilateral inferior parietal areas, and right superior temporal gyrus.

Differences in gray matter volume were seen among people with blood pressure less than 120/80 mmHg and those with the next two levels of elevated blood pressure.

No significant associations were identified between elevated blood pressure and total brain size.

The findings only show an association, not causality between lower brain volumes and hypertension. The exact mechanism behind the association remains unknown. But, the researchers emphasized, "it has been proposed that medial temporal (and frontal regions) might be especially sensitive to effects of pulsation, hypoperfusion, and ischemia, which often result from increasing pressure."

Further research is needed to observe whether gray matter volume changes in young age could increase the risk for stroke, dementia, and other diseases later in life.

The Max Planck Institute for Human Cognitive and Brain Sciences supported the study.

The researchers reported no conflicts of interest.

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Schaare HL, Masouleh SK, Beyer F, et al. Association of peripheral blood pressure with gray matter volume in 19- to 40-year-old adults. Neurology 2018; Epub 2018 Jan 23.

Tuesday, February 5, 2019

BY KURT SAMSON

Using next-generation genomic sequencing, researchers at Memorial Sloan Kettering Cancer Center have successfully tracked the evolution of some gliomas with liquid biopsy of cerebrospinal fluid (CSF) for circulating tumor cell DNA.

The process, though it requires a lumbar puncture, is less invasive than surgery for a biopsy of tissue, the authors of the new study noted. They found circulating tumor DNA (ctDNA) was detected in almost half of the patients they tested, and it was associated with increased disease burden and poorer outcomes. The findings were published in the January 23 online edition of Nature.

A wide range of genetic alterations were detected in CSF and these closely matched those collected using regular tumor biopsies. Patients with tumor DNA had a fourfold higher risk of death than those who did not, but there was no significant association between ctDNA-positive CSF and glioma grade, disease duration, or prior therapy. No oncogenic variants were found in the CSF of seven patients who had non-malignant neurological conditions.

Circulating ctDNA remained a statistically significant prognostic factor, even after adjustment for the extent of the original resection site, tumor burden at the time of CSF collection, and status of IDH mutation, which is implicated in gliomas. Tracking gliomas currently requires surgical or punch biopsies, repeated over the course of the cancer.

The assay could also be used for genotype-specific clinical trials of potential targeted therapies and to detect biomarkers, said co-author Alexandra M. Miller, MD, PhD, a neuro-oncologist at Memorial Sloan Kettering Cancer Center.

"When tumors recur, a lumbar puncture is a simpler and safer procedure than a second craniotomy. However, shedding of tumor DNA into the CSF does not appear to be a universal property of diffuse glioma, even in previously treated patients," Dr. Miller told Neurology Today.

"In patients who have a tumor that cannot be approached surgically, a lumbar puncture offers an opportunity to obtain a molecular signature and potentially a definitive diagnosis. The procedure, while not pleasant, is much better than brain surgery."

Study Design

Forty-two of 85 patients who participated in the study had at least one tumor-derived genetic alteration detectible in their CSF. Almost all had undergone surgery, radiation treatment, and/or chemotherapy. The gene sequencing assay (MSK-IMPACT) is approved by the Food and Drug Administration and can identify 410 known cancer-associated gene mutations.

There was little difference between the results of CSF DNA analysis and genetic data from tissue biopsies, or in the plasma of 19 patients.

To establish a benchmark the researchers compared data from 553 glioma biopsy samples at the institution, and blood and tissue biopsy samples when available.

Among patients who also underwent surgical biopsy, tumor cells exactly matched those in their CSF, the researchers found. Patients with larger tumors were more likely to have tumor cells in their CSF. It was unclear why 43 patients lacked any evidence of tumor cell shedding in their CSF.

Among tumor types, 54 percent were grade IV glioblastomas; 31 percent were grade III gliomas; and 15 percent were grade II gliomas. Most patients positive for ctDNA did not have detectible malignant cells using standard CSF cytopathologic analysis.

All of the patients underwent glioma treatment before CSF was collected, and all underwent brain MRIs before and directly after the initial resection. The results were later reviewed by a blinded neuroradiologist.

"Our study shows that tumor-derived DNA in CSF provides a comprehensive and genetically faithful representation of the tumor genome at the time of collection, and the frequency and type of alterations in the CSF closely resembled the genomic landscape of diffuse glioma," said Dr. Miller.

For more on the study, look for the February 21 issue of Neurology Today.

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Miller AM, Shah RH, Pentsoval EI, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 2019; Epub 2019 Jan 23.

Changcun P, Diplas BH, Chen X, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF‑derived circulating tumor DNA. Acta Neuropathol 2018; Epub 2018 Nov 20.

Thursday, January 31, 2019

BY LIZETTE BORRELI

Intensively lowering blood pressure was associated with a reduced risk of developing mild cognitive impairment (MCI) in older adults with hypertension, according to a multi-center randomized clinical trial published online on January 28 in The Journal of the American Medical Association (JAMA).

The Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT MIND) trial found a blood pressure target of 120 mmHg, compared to the standard blood pressure goal of 140 mmHg, lowered the risk for MCI by 19 percent and probable dementia by 17 percent; the reduced risk for probable dementia was not statistically significant, however. The results were first presented at the Alzheimer's Association International Conference in 2018 and were reported by Neurology Today.

SPRINT-MIND, a sub study of the Systolic Blood Pressure Intervention Trial (SPRINT)—designed to test the effect of intensively lowering blood pressure on the heart, kidney, and brain over five years—failed to meet its primary endpoint: reducing dementia incidence. The researchers suggest the success of SPRINT, which led to the trial's early termination at 3.3 years in 2015, cut the study duration too short to accurately assess whether consistently lowering blood pressure would reduce dementia risk.

"Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point," the researchers, led by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, North Carolina, wrote.

To find out whether intensive treatment is associated with reduced dementia risk, the Alzheimer's Association announced it would fund two more years of the study in SPRINT-MIND 2.0.

In the SPRINT-MIND trial, the team followed 9,361 healthy participants with systolic blood pressure (SBP) between 130 and 180 mmHg, both treated and untreated, who were at increased risk for cardiovascular disease for seven years. The average age was 68 years; about 30 percent were black, and 10 percent were Hispanic. About a third had a SBP of 132 mmHg or less; a third had SBP 132–145 mmHg; and the rest had a SBP greater than 145 mmHg.

Researchers randomly assigned participants to either undergo intensive lowering of SBP (goal, <120 mmHg) or standard treatment (goal, <140 mmHg).

Participants received antihypertensive medications from physicians to achieve their assigned blood pressure target. The study did not mandate the use of any specific drug. Most drugs used were generic.

The findings revealed trial interventions did help to successfully control blood pressure with a significant difference between the two treatment groups. The intensive blood pressure group had a mean SBP of 121.6 mm Hg, compared to 134.8 mmHg in the standard group.

During follow-up, participants in the intensive treatment group experienced more significant reductions in MCI risk p (14.6 vs 18.3 per 1000 person-years; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69 - 0.95) and the risk for combined cognitive impairment outcome (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74 - 0.97).

It remains unknown whether a reduction in MCI risk will lead to a reduction in the risk of progression of dementia.

The National Institutes of Health funded the SPRINT trial with the support of the Department of Veterans Affairs, the Kulynych Family Foundation, and the Oristano Family Foundation. Takeda Pharmaceuticals International provided medications for the study.

Dr. Williamson and his colleagues disclosed relevant relationships with Biogen, Lilly, Sanofi Pharmaceuticals, Novartis Pharmaceuticals, Takeda Pharmaceuticals, Actelion Clinical Research Inc, Boehringer Ingelheim/Lilly, Lundbeck, Novo Nordisk, 98point6, George Clinical Pty, Idorsia Pharmaceuticals, Pfizer, and ROX Medica.

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Williamson JD, Pajewski NM, Auchus AP et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA 2019. Epub 2019 Jan 28.