3T magnetic resonance spectroscopy of the posterior cingulate following rivastigmine treatment in Alzheimer's disease

3T magnetic resonance spectroscopy of the posterior cingulate following rivastigmine treatment in Alzheimer's disease

P166 Poster Presentations: P1 population of cognitively intact and mildly impaired elderly subjects with increased VRF was similar to that in precli...

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Poster Presentations: P1

population of cognitively intact and mildly impaired elderly subjects with increased VRF was similar to that in preclinical AD with exception with the more severely affected CA3&DG. Elevated SBP and TChol were associated with volume loss in CA3&DG while CA1 and CA1-2transition were influenced by SBP respectively TChol. The selective vulnerability of these subfields for hypertension/hyperlipidemia is consistent with that described in animal models and autopsy studies. Their usefulness for diagnostic purposes has to be further investigated. Figure 1. (Row 1: 1, 4, 8, 12 hours j Row 2: 24, 36, 48 hours, 7 days) P1-164

NEUROOPHTHALMOLOGIC FINDINGS IN TGA

SangYun Kim1, Youngsoon Yang2, 1Seoul National University Hospital, Seongnam-si, Kyungki-do, South Korea; 2Veterans Hospital, Seoul, Korea, Seoul, South Korea. Background: Transient global amnesia (TGA) is characterized by sudden anterograde and retrograde amnesia lasting for up to 24 hours. Diffusion-weighted magnetic resonance imaging (DWI) in cases of TGA and ischemia demonstrates a high frequency of high signal intensities restricted to the hippocampus, and this has been proposed as an etiology of TGA. The aims of this study were to characterize the DWI and single-photon-emission computed tomography (SPECT) findings during the acute and recovered phases of TGA and to correlate the findings with oculomotor abnormalities. Methods: 40 consecutive patients with a clinical diagnosis of TGA underwent DWI and SPECT of the brain within 24 hours after symptom onset and again 3 days later. Eye movements were also recorded using three-dimensional video-oculography. Results: In all patients, DWI disclosed small punctuate (1-3 mm), highsignal lesions in the lateral portion of the hippocampus. The initial SPECT also revealed hypoperfusion in the cerebellar vermis, which had recovered by the follow-up examination. 35 patients showed saccadic hypermetria or impaired smooth pursuit only during the acute phase. Conclusions: Our patients with TGA showed cerebellar vermian hypoperfusion in addition to ischemic insults to the lateral hippocampus. The oculomotor abnormalities observed in our patients support the occurrence of cerebellar dysfunction during the TGA attack.

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TAU IMMUNOTHERAPY IMPROVES AXONAL TRANSPORT AS DETECTED IN VIVO BY MANGANESE-ENHANCED MAGNETIC RESONANCE IMAGING

Benjamin Little1, Umer Khan1, Anne Bertrand1, Hameetha Rajamohamedsait1, Lindsay Hill1, Dung Minh Hoang1, Youssef Zaim Wadghiri2, Einar M. Sigurdsson2, 1New York University School of Medicine, New York, New York, United States; 2New York University, New York, New York, United States. Background: Immunotherapy targeting hyperphosphorylated tau is a promising prospect to mitigate the neurodegenerative effects of tauopathies. Assessing the effectiveness of such immunotherapies often involves sacrifice of the animal. However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Methods: Twenty-five homozygous JNPL3 tangle transgenic mice underwent MEMRI at 6 months of age. Thirteen of the mice received tau immunotherapy with Tau379-408[P-Ser396,404] in alum adjuvant from 3 months of age, and twelve controls received an adjuvant alone. Imaging studies were performed on a 7-T micro-MRI. Mice were imaged pre-injection, then injected in one nostril with a solution of 2.5 M MnCl 2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36 and 48 hours, and finally at 7 days (Fig 1). The datasets were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model using MATLAB. Fitting enabled the estimation of the timing (Pt) and intensity (Pv) of the bolus peak of Mn, and maximal slope of uptake

(Sv). Results: A significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer (35%, P <.005) and glomerular layer (36%, P <0.02) in treated JNPL3 mice compared to identical controls. There was also a significant increase in bolus peak value, Pv, in the mitral layer in the treated group (7%, P ¼ 0.02). Furthermore, in the immunized mice, there was a strong trend for a decrease in the time to peak value, Pt (-9%P ¼ 0.10), in the mitral cell layer, compared to the controls. Conclusions: Utilizing MEMRI’s non-invasive, longitudinal measurements from 1 hour to 7 days, allowed us to detect substantial improvements in neuronal transport following tau immunotherapy. We are analyzing tau pathology in olfactory sections from these mice to assess the correlation of these benefits with clearance of tau lesions, which we have shown previously to occur with this treatment.

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3T MAGNETIC RESONANCE SPECTROSCOPY OF THE POSTERIOR CINGULATE FOLLOWING RIVASTIGMINE TREATMENT IN ALZHEIMER’S DISEASE

Jacob Penner1, Matthew Smith2, Jennie Wells2, Marybelle Campbell2, Michael Borrie2, Robert Bartha1, 1Robarts Research Institute, Western University, London, Ontario, Canada; 2Lawson Health Research Institute, London, Ontario, Canada. Background: Rivastigmine is a cholinesterase inhibitor used for the treatment of Alzheimer disease (AD) that provides positive effects on cognition, behaviour, and function. Proton Magnetic Resonance Spectroscopy (1 H MRS) has been previously used to monitor metabolic changes in brain tissue following cholinesterase inhibitor treatment in subjects with AD. The purpose of this study was to compare metabolic changes in the posterior cingulate to changes in cognition in subjects with AD following rivastigmine treatment. Methods: Five subjects with AD (3 males, age 70 6 11 years) were recruited. Cognition was measured with the MMSE and the ADAScog performed before beginning rivastigmine treatment via the Exelon Patch (4.6 mg/24 hours for the first month, 9.5 mg/24 hours thereafter), and again after four months of treatment. All MR imaging and spectroscopic data were acquired on a 3T Siemens whole-body MRI. T 2 -weighted images (0.7x0.7x4 mm 3 resolution, TR ¼ 6s, TE ¼ 84 ms) were acquired for MRS voxel placement. MRS data were acquired from an 8 cm 3 volume of interest (TR ¼ 2s, TE ¼ 135 ms) in the posterior cingulate at baseline and after four months of treatment. N -acetylaspartate (NAA), choline (Cho), myo-inositol (Myo), glutamate (Glu), and glutamine (Gln) were measured and normalized to creatine (Cr) for evaluation of changes over time. Results: The ratio of Glu/Cr decreased by 27% (P ¼ 0.062) following treatment, trending towards statistical significance. No other changes in metabolite ratios were observed. The average MMSE and ADAS-cog scores at baseline were 24.8 6 2.9 and 11.2 6 5.5, respectively, and were unchanged after 4 months of rivastigmine treatment. Changes in cognitive scores did not correlate with changes in Glu/Cr. Conclusions: Previous studies have found an increase in Glu/Cr in the hippocampus following galantamine treatment and no change in Glu in the hippocampus following donepezil treatment. Along with increasing choline levels there is evidence that rivastigmine modulates the glutamatergic system by increasing the expression of the Glu reuptake carrier resulting in reduced extracellular Glu. This preliminary observation of a trend toward a decrease in Glu/Cr in the posterior cingulate following

Poster Presentations: P1 rivastigmine treatment may be related to the effect of rivastigmine on glutamate uptake.

Figure. Changes in average metabolite ratios (A) and cognitive scores (B) from baseline to four months (Error bars represent 6 1 standard deviation, # represents P<0.1).

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NEURAL BASIS FOR COGNITIVE CONTROL ENHANCEMENT IN ELDERLY PEOPLE

Jeanyung Chey, Hoyoung Kim, Seoul National University, Seoul, South Korea. Background: Cognitive function is an important aspect of the individual’s functional independence and quality of life especially in the aging population. Cognitive control is a core function for daily adaptation but also an area most vulnerable to aging. This study was intended to develop a training program for older adults to enhance the cognitive control function, and to examine its effects comprehensively. Methods: Twenty seven community-dwelling adults aged 60 and older without diagnosis of significant cognitive impairment participated in this study (training group n ¼ 14; the control group n ¼ 13). A training program targeting cognitive control was developed, which was offered only to the training group. Duration of training was 1 hour per day, 3 days per week, for 8 weeks. We examined the training-related changes in cognitive function and cortical activity with Multisource Interference Task which required cognitive control yet was different from the main training program. More specifically, we compared the regional brain activation utilizing the functional MRI, before and after training. A comprehensive neuropsychological assessment was also completed pre- and post-training. Results: Trained older adults showed overall enhancement in cognitive functions compared with those who were not trained, particularly in the cognitive control measures. In addition, the training effect was also significant in the recognition tasks of working memory and episodic memory tasks, where interference resolution capabilities were required. In addition, general intellectual functioning, as measured with the Korean version of the DRS2, also improved after cognitive control training. The cognitive control trained group showed increased cortical activation in areas of the right fronto-parietal control network, whereas no significant activation change was found between the pre scan and post scan in the control group. Furthermore, cognitive enhancement was significantly correlated to brain activity change in these over-recruited areas in the trained group. Conclusions: We demonstrated the effect of cognitive control training and its neural correlates with functional MRI. The results of this study suggest a compensatory neural process that involves the fronto-parietal control network.

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A LONGITUDINAL FMRI STUDY OF CHOLINERGIC MODULATION IN NONDEMENTED PATIENTS WITH MILD MEMORY IMPAIRMENT

Judy Pa, Anne Berry, Mariana Compagnone, Jacqueline Boccanfuso, Ian Greenhouse, Michael Rubens, Adam Gazzaley, Julene Johnson, University of California, San Francisco, San Francisco, California, United States.

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Background: Cholinesterase inhibitors have been shown to improve or stabilize cognitive functioning in mild-to-moderate Alzheimer’s disease (AD). The increase in acetylcholine (ACh) may aid in synaptic plasticity that facilitates attention and memory. However, the cognitive and neural benefits of enhanced ACh levels in preclinical AD patients have not been well documented. We hypothesized that at-risk, preclinical AD patients would exhibit behavioral and neural benefits with an acetylcholinesterase inhibitor treatment. Methods: We conducted a 3-month, double-blind, placebo-controlled treatment study on the effects of donepezil (brand: Aricept) in twenty-seven non-demented patients with mild objective memory deficits (66.3 6 8 years; range 54-76 years; 12 females). The BOLD signal was measured using functional MRI (fMRI) as a surrogate of neural activity. A face/scene encoding and delayed recognition task was employed. The treatment and placebo groups completed an fMRI scan at baseline prior to treatment and a subsequent 3-month follow-up scan while on a 10mg of donepezil (or placebo) daily regimen. Results: The response time for faces and scenes was significantly faster in the treatment group after 3 months when compared to the placebo group (faces: 175ms gain, scenes: 179ms gain) (P <.05). To control for bottom-up effects due to treatment (e.g., elevated arousal), we used the passive view condition as an internal control. Accuracy for scenes significantly improved in the treatment group when compared to the placebo group (scenes: 6.7% gain; P <.05). The magnitude of change in the univariate BOLD activity was significantly greater in a face-selective region of the fusiform gyrus (FFA) in the treatment group during encoding (P <.05). Using the FFA and parahippocampal place area (PPA) as seeds, we revealed enhanced functional connectivity in prefrontal cognitive control regions and the hippocampus in the treatment group after 3 months (P <.05). Conclusions: These findings suggest that increased cholinergic transmission may improve cognitive and neural processing in patients with mild memory impairment. This mechanism may serve to facilitate the communication of functionally-connected brain networks critical to attention and memory. Longitudinal fMRI may be a useful method for elucidating the neural changes associated with neurochemical modulation and is a potential tool for monitoring treatment efficacy in clinical trials.

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CHANGES OF CAROTID DUPLEX SONOGRAPHIC FINDINGS BEFORE AND AFTER CAROTID ARTERY STENTING IN A POST-STROKE DEMENTIA

Jun Hong Lee1, Soo Jeong Shin2, 1National Health Insurance Corporation Ilsan Hospital, Department of Neurology, Goyang-si, South Korea; 2Yonsei University Medical Center, Seoul, South Korea. Background: Carotid arterial stenosis becomes more common and important risk factor for stroke patients in Asian area. We reviewed stroke database to investigate changes of carotid duplex sonographic findings, which reflects hemodynamic changes before and after carotid stenting in post-stroke dementia patients. Methods: Post-stroke dementia patients of which carotid stenting have been done when admitted at the National Health Insurance Corporation Ilsan Hospital from January 2005 to December 2010 with available carotid ultrasound study that was done before and after carotid stenting formed the analysis cohorts. Retrospective review was performed. Results: A total of 26 patients were included during that period. By duplex ultrasound, common, internal and external carotid arteries were examined and the degree of stenosis was graded by five groups;<50%, >50% and<75%, >75% and<95% stenosis, subtotal occlusion and occlusion. Average follow-up period between before and after stenting was 18 months. 16 patients among 26 patients showed no change of adjacent carotid stenosis degrees between before and after stenting. 5 patients among 26 patients showed changes in the stenosis degree of ipsilateral adjacent carotid and another 5 patients showed changes in the stenosis degree of contralateral adjacent carotid arteries. Conclusions: Between before and after carotid stenting, the flow of adjacent carotid arteries were changed in patients of about one third and another two thirds showed no change. The hemodynamic changes of carotid flow can be