Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer's disease.

Defining the progression of blood biomarkers of Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD. In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (CU, N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD). Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.

High-Resolution MRI for Evaluation of Ventriculostomy Tubes: Assessment of Positioning and Proximal Patency.

BACKGROUND AND PURPOSE: Imaging evaluation of ventriculostomy tubes, despite the frequency of malfunction, has remained inadequate due to the absence of a systematic way of assessing the catheter itself. In this retrospective review, we assessed the utility of high-resolution 3D MR imaging techniques, including CISS and volumetric interpolated breath-hold examination sequences, in the evaluation of ventriculostomy catheters. MATERIALS AND METHODS: We performed a retrospective review of 23 clinical MR imaging cases of shunted hydrocephalus spanning a 3-year period, all depicting ventriculostomy catheters. The MR imaging examinations included isotropic CISS and volumetric interpolated breath-hold examination sequences performed with and without contrast. These were independently evaluated by 2 neuroradiologists with respect to the catheter course, side hole position, relationship of the side holes to the ventricles, patency, and the presence or absence of intraluminal debris. RESULTS: The catheter tip was best seen on isotropic CISS sequences reformatted in an oblique plane, and side holes were visualized as CSF signal defects along the catheter wall in 10/23 (43%) cases. The relationship of the catheter side holes to the ventricles was seen in 47% of cases and was best visualized on the coronal CISS sequences. Catheter patency was confirmed in 12/23 (52%) cases, while the other 48% were notable for T2 hypointense filling defects compatible with luminal obstruction. Enhancement of some of these filling defects on imaging is suggestive of choroid plexus ingrowth rather than debris. CONCLUSIONS: High-resolution 3D MR imaging using isotropic CISS sequences allows systematic evaluation of catheter positioning, patency, and potential etiologic differentiation of filling defects when shunt dysfunction is suspected.

The Occipital Emissary Vein: A Possible Marker for Pseudotumor Cerebri.

BACKGROUND AND PURPOSE: Transverse sinus stenosis can lead to pseudotumor cerebri syndrome by elevating the cerebral venous pressure. The occipital emissary vein is an inconstant emissary vein that connects the torcular herophili with the suboccipital veins of the external vertebral plexus. This retrospective study compares the prevalence and size of the occipital emissary vein in patients with pseudotumor cerebri syndrome with those in healthy control subjects to determine whether the occipital emissary vein could represent a marker of pseudotumor cerebri syndrome. MATERIALS AND METHODS: The cranial venous system of 46 adult patients with pseudotumor cerebri syndrome (group 1) was studied on CT venography images and compared with a group of 92 consecutive adult patients without pseudotumor cerebri syndrome who underwent venous assessment with gadolinium-enhanced 3D-T1 MPRAGE sequences (group 2). The presence of an occipital emissary vein was assessed, and its proximal (intraosseous) and distal (extracranial) maximum diameters were measured and compared between the 2 groups. Seventeen patients who underwent transverse sinus stent placement had their occipital emissary vein diameters measured before and after stent placement. RESULTS: Thirty of 46 (65%) patients in group 1 versus 29/92 (31.5%) patients in group 2 had an occipital emissary vein (P < .001). The average proximal and distal occipital emissary vein maximum diameters were significantly larger in group 1 (2.3 versus 1.6 mm, P <.005 and 3.3 versus 2.3 mm, P < .001). The average maximum diameters of the occipital emissary vein for patients who underwent transverse sinus stent placement were larger before stent placement than after stent placement: 2.6 versus 1.8 mm proximally (P < .06) and 3.7 versus 2.6 mm distally (P < .005). CONCLUSIONS: Occipital emissary veins are more frequent and larger in patients with pseudotumor cerebri syndrome than in healthy subjects, a finding consistent with their role as collateral venous pathway in transverse sinus stenosis. A prominent occipital emissary vein is an imaging sign that should raise the suspicion of pseudotumor cerebri syndrome.

Does Phase-Contrast Imaging through the Cerebral Aqueduct Predict the Outcome of Lumbar CSF Drainage or Shunt Surgery in Patients with Suspected Adult Hydrocephalus?

BACKGROUND AND PURPOSE: Radiologic imaging plays a key role in diagnosing chronic adult hydrocephalus, but its role in predicting prognosis is still controversial. We sought to evaluate the effectiveness of cardiac-gated phase-contrast MR imaging through the cerebral aqueduct in predicting the clinical response to diagnostic lumbar puncture/lumbar drainage and shunt surgery in suspected adult hydrocephalus. MATERIALS AND METHODS: In this retrospective study, the phase-contrast MR imaging of 185 patients with suspected chronic adult hydrocephalus was evaluated using the CSF Flow software package. Decision-making for shunt placement was performed in this cohort on the basis of clinical assessment alone without the availability of quantitative phase-contrast MR imaging results. We recorded the response to lumbar puncture or lumbar drainage and shunt surgery using quantitative tests such as the Tinetti Test, the Timed Up and Go, and the Mini-Mental State Examination and qualitative measures of gait, urinary, and cognitive symptom improvement before and after lumbar puncture/lumbar drainage and shunt surgery. Quantitative analysis of phase-contrast MR imaging was compared with clinical outcome measures. RESULTS: Both CSF stroke volume and flow rate overlapped between lumbar puncture/lumbar drainage responders and nonresponders. There was also a significant overlap between shunt responders and nonresponders. Aqueductal stroke volume or flow rate alone was a poor predictor of lumbar puncture/lumbar drainage and shunt surgery response. Quantitative clinical measures after lumbar puncture/lumbar drainage were better predictors of shunt response. CONCLUSIONS: This study suggests that the results of phase-contrast MR imaging through the cerebral aqueduct alone should not be used to select patients for diagnostic or therapeutic CSF diversion.

Does the Presence or Absence of DESH Predict Outcomes in Adult Hydrocephalus?

BACKGROUND AND PURPOSE: The DESH (disproportionately enlarged subarachnoid-space hydrocephalus) pattern of "tight high-convexity and medial subarachnoid spaces, and enlarged Sylvian fissures with ventriculomegaly" is used to determine which patients undergo an operation for adult hydrocephalus at many centers. Our aim was to review adult hydrocephalus cases when DESH has not been a criterion for an operation to determine the prevalence of DESH among the cohort and compare the surgical outcomes in the presence or absence of DESH. MATERIALS AND METHODS: A retrospective cohort study was conducted at a single institution (Johns Hopkins Hospital) to include patients surgically treated for adult hydrocephalus between 2003 and 2014 drawn from a data base of patients who had undergone standardized hydrocephalus protocol MR imaging. Preoperative imaging was reviewed by 2 blinded neuroradiologists to characterize the presence of DESH. Preoperative and postoperative clinical symptomatology was recorded. Frequencies were compared using the Fisher exact test, and nonparametric means were compared using the Mann-Whitney U Test. RESULTS: One hundred thirty-three subjects were identified and included (96 DESH absent, 37 DESH present). Shunting led to significant improvement in gait and urinary and cognitive symptoms for the overall cohort and for patients with and without DESH (P < .05). The Fisher exact test did not demonstrate any significant differences in either gait or urinary or cognitive symptom improvement between patients with or without DESH (P > .05). CONCLUSIONS: The current study demonstrated symptom improvement in patients with adult hydrocephalus following shunting, with no significant differences between subjects with and without DESH. Thus, shunt insertion for patients with adult hydrocephalus should not rely solely on the presence of preoperative DESH findings.

Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.

Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

Action versus animal naming fluency in subcortical dementia, frontal dementias, and Alzheimer's disease.

Accumulating evidence indicates action naming may rely more on frontal-subcortical circuits, and noun naming may rely more on temporal cortex. Therefore, noun versus action fluency might distinguish frontal and subcortical dementias from cortical dementias primarily affecting temporal and/or parietal cortex such as Alzheimer's disease (AD). We hypothesized patients with subcortical dementia, e.g., normal pressure hydrocephalus (NPH) and patients with dementias predominantly affecting frontal cortex, e.g., behavioral variant frontotemporal dementia (bv-FTD) and progressive nonfluent aphasia (PNFA) have more difficulty on action fluency versus noun fluency (e.g., animal naming). Patients with AD, who have temporo parietal cortical dysfunction, should have more difficulty on noun versus verb fluency. A total of 234 participants, including healthy controls (n = 20) and patients diagnosed with NPH (n =144), AD (n = 33), bv-FTD (n = 22) or PNFA (n =15) were administered animal fluency, action fluency, and letter fluency tasks, and the Mini-Mental State Examination (MMSE, to control for dementia severity). NPH and bv-FTD/PNFA patients had significantly higher MMSE scores and animal fluency than AD patients (after adjusting for age), but their action fluency tended to be lower than in AD. Only NPH and bvFTD/PNFA patients showed significantly lower action verb than animal fluency. Results provide novel evidence that action naming relies more on frontal-subcortical circuits while noun naming relies more on temporoparietal cortex, indicating action verb fluency may be more sensitive than noun fluency, particularly for detecting frontal-subcortical dysfunction.

Effect of a clinical stroke on the risk of dementia in a prospective cohort.

OBJECTIVE: To examine the risk and determinants of dementia following a clinically overt stroke in a prospectively followed cohort of elderly subjects. METHODS: We examined the effect of a clinically detectable stroke on the risk of dementia using prospective data from 335 subjects in the Baltimore Longitudinal Study of Aging, all of whom were cognitively and neurologically normal at entry into the study (mean age at entry 75.1 +/- 4.2 years). RESULTS: Clinically overt strokes are common in our cohort (cumulative risk by age 90, 15.4%; 95% CI: 10 to 22%) and confer an increased risk of dementia compared to subjects without stroke (odds ratio [OR] 5.55; 95% CI: 2.76 to 11.4). The majority of patients who became demented after a stroke had evidence of mild cognitive impairment preceding the stroke (14 of 19). Moreover, a clinically symptomatic stroke was a major risk factor for the conversion of mild cognitive impairment to dementia (OR 12.4; 95% CI: 1.5 to 99). When cognitive impairment did not precede the stroke, there was no increase in the risk of subsequent dementia. Pathologic data indicate that both vascular and Alzheimer pathology leads to the prestroke impairment. CONCLUSION: Dementia after stroke may be determined by cognitive impairments that exist prior to the stroke.