A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer’s disease

Purpose@#Increasing attention has been paid to low-intensity transcranial focused ultrasound (tFUS) for its potential therapeutic effects in Alzheimer's disease (AD). While preclinical studies have shown promising therapeutic effects of low-intensity tFUS in AD models, its efficacy and safety remain unclear in humans. In this pilot study, we investigated the effects of low-intensity tFUS on blood-brain barrier opening, the regional cerebral metabolic rate of glucose (rCMRglu), and cognition in patients with AD. @*Methods@#After receiving institutional review board approval, four patients with AD received tFUS to the hippocampus immediately after an intravenous injection of a microbubble ultrasound contrast agent. Sonication was delivered at low-intensity, at a pressure level below the threshold for blood-brain barrier opening. Patients underwent brain magnetic resonance imaging, 18F-fluoro-2-deoxyglucose positron emission tomography, and neuropsychological assessments before and after the tFUS procedure. A whole-brain voxel-wise paired t test was conducted to compare rCMRglu before and after tFUS. @*Results@#The sonication, as anticipated, did not show evidence of active blood-brain barrier opening on T1 dynamic contrast-enhanced magnetic resonance imaging. rCMRglu in the superior frontal gyrus (P<0.001), middle cingulate gyrus (P<0.001), and fusiform gyrus increased after tFUS (P=0.001). Patients demonstrated mild improvement in measures of memory, executive, and global cognitive function following tFUS. No adverse events were reported. @*Conclusion@#These results suggest that hippocampal sonication with low-intensity tFUS may have beneficial effects on cerebral glucose metabolism and cognitive function in patients with AD. Further larger studies are needed to confirm the therapeutic efficacy of tFUS in AD.

Brain Perfusion Correlates of Apathy in Alzheimer's Disease

BACKGROUND AND PURPOSE: Apathy is one of the most common neuropsychiatric symptoms in patients with Alzheimer's disease (AD). It may have adverse impacts on the progression of AD. However, its neurobiological underpinnings remain unclear. The objective of this study was to investigate differences in regional cerebral blood flow (rCBF) between AD patients with apathy and those without apathy. METHODS: Sixty-six apathetic AD patients and 66 AD patients without apathy completed Neuropsychiatric Inventory (NPI) and underwent technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT) scans. Voxel-wise differences in rCBF between the 2 groups were examined. Association between rCBF and levels of apathy in the apathetic group was also assessed. RESULTS: AD patients with apathy showed lower rCBF in the bilateral orbitofrontal cortex, left putamen, left nucleus accumbens, left thalamus, and bilateral insula than those without (all p < 0.005). Mean perfusion across all significant clusters showed a negative linear correlation with NPI apathy score in AD patients with apathy (β = −0.25; p = 0.04). CONCLUSIONS: Hypoperfusion in the prefrontal, striatal, and insular areas may be neural correlates of apathy in AD patients.

Associations between Brain Perfusion and Sleep Disturbance in Patients with Alzheimer's Disease

BACKGROUND AND PURPOSE: Although sleep disturbances are common and considered a major burden for patients with Alzheimer's disease (AD), the fundamental mechanisms underlying the development and maintenance of sleep disturbance in AD patients have yet to be elucidated. The aim of this study was to examine the correlation between regional cerebral blood flow (rCBF) and sleep disturbance in AD patients using technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT). METHODS: A total of 140 AD patients were included in this cross-sectional study. Seventy patients were assigned to the AD with sleep loss (SL) group and the rest were assigned to the AD without SL group. SL was measured using the sleep subscale of the Neuropsychiatric Inventory. A whole-brain voxel-wise analysis of brain SPECT data was conducted to compare the rCBF between the two groups. RESULTS: The two groups did not differ in demographic characteristics, severity of dementia, general cognitive function, and neuropsychiatric symptoms, with the exception of sleep disturbances. The SPECT imaging analysis displayed decreased perfusion in the bilateral inferior frontal gyrus, bilateral temporal pole, and right precentral gyrus in the AD patients with SL group compared with the AD patients without SL group. It also revealed increased perfusion in the right precuneus, right occipital pole, and left middle occipital gyrus in the AD with SL group compared with the AD without SL group. CONCLUSIONS: The AD patients who experienced sleep disturbance had notably decreased perfusion in the frontal and temporal lobes and increased rCBF in the parietal and occipital regions. The findings of this study suggest that functional alterations in these brain areas may be the underlying neural correlates of sleep disturbance in AD patients.

Cerebral Perfusion Changes after Acetyl-L-Carnitine Treatment in Early Alzheimer's Disease Using Single Photon Emission Computed Tomography

BACKGROUND AND PURPOSE: Although acetyl-L-carnitine (ALC) treatment may have beneficial effects on Alzheimer's disease (AD), its underlying neural correlates remain unclear. The purpose of this study was to investigate cerebral perfusion changes after ALC treatment in AD patients using technetium-99m hexamethylpropylene amine oxime single photon emission computed tomography (SPECT). METHODS: A total of 18 patients with early AD were prospectively recruited and treated with ALC at 1.5 g/day for 1.4±0.3 years. At baseline and follow-up, brain SPECT, Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), and Neuropsychiatric Inventory (NPI) were used to assess participants. After ALC administration, changes in brain perfusion, severity of dementia, cognitive performance, and neuropsychiatric disturbances were examined. RESULTS: After ALC administration, changes in scores of MMSE, CDR, GDS, and NPI were not statistically significant (p>0.05). Voxel-wise whole-brain image analysis revealed that perfusion was significantly (p<0.001) increased in the right precuneus whereas perfusion was reduced in the left inferior temporal gyrus (p<0.001), the right middle frontal gyrus (p<0.001), and the right insular cortex (p=0.001) at follow-up. CONCLUSIONS: Although previous studies have suggested that AD patients generally demonstrate progressive deterioration in brain perfusion and clinical symptoms, this study reveals that the perfusion of the precuneus is increased in AD patients after ALC administration and their cognitive and neuropsychiatric symptoms are not aggravated. Further studies are warranted to determine the potential association between perfusion increase in the precuneus and clinical symptoms after ALC treatment in AD patients.

Changes in Regional Cerebral Perfusion after Nicergoline Treatment in Early Alzheimer's Disease: A Pilot Study

BACKGROUND AND PURPOSE: Nicergoline is an ergoline derivative that is used to treat cognitive deficits in cerebrovascular disease and various forms of dementia. Although therapeutic effects of nicergoline have been established, little is known about its effects on cerebral perfusion in Alzheimer's disease (AD). The aim of this study was to examine the role of nicergoline in regional cerebral blood flow (rCBF) of AD patients using technetium-99m hexa-methyl-propylene-amine-oxime single photon emission computed tomography (SPECT). METHODS: Sixteen patients with early AD underwent a comprehensive clinical assessment including cognitive testing and SPECT scans before and after nicergoline treatment. Nicergoline (30 mg twice daily) was administered for an average duration of 1.5 years. Clinical and cognitive functioning was assessed using the Mini-Mental State Examination, Clinical Dementia Rating (CDR), CDR-Sum of Boxes, Global Deterioration Scale, Barthel Activities of Daily Living Index, Instrumental Activities of Daily Living, and Geriatric Depression Scale. RESULTS: Nicergoline treatment induced changes in the severity of dementia, cognitive function, activities of daily living, and depressive symptoms, which were not statistically significant. During the follow-up, the patients showed significant increases in their relative rCBF in the superior frontal gyrus, precentral gyrus, and postcentral gyrus. CONCLUSIONS: Nicergoline treatment improves perfusion of the frontal and parietal regions in early AD patients. It is possible that the increased perfusion in the superior frontal gyrus may be related to the mechanisms that delay or prevent progressive deterioration of cognitive functions in AD.

Longitudinal Cerebral Perfusion Changes in Parkinson's Disease with Subjective Cognitive Impairment

BACKGROUND AND PURPOSE: Although subjective cognitive impairment (SCI) is often accompanied by Parkinson's disease (PD) and may predict the development of mild cognitive impairment or dementia, longitudinal brain perfusion changes in PD patients with SCI remain to be elucidated. The current prospective study examined cerebral perfusion changes in PD patients with SCI using technetium-99m hexamethylpropylene amine oxime single photon emission computed tomography (SPECT). METHODS: Among 53 PD patients at baseline, 30 patients were classified into the PD with SCI group and 23 patients were assigned to the PD without SCI group. The mean follow-up interval was 2.3±0.9 years. The Mini-Mental State Examination, Clinical Dementia Rating, and Global Deterioration Scale were used to assess impairments in cognitive function. Brain SPECT images were acquired at baseline and follow-up. RESULTS: Significant differences between the two groups were not found for demographic variables, PD severity, or cognitive function at either baseline or follow-up. At baseline, the PD with SCI group showed decreased perfusion in the left angular gyrus compared to the PD without SCI group. Longitudinal analysis revealed widespread perfusion reductions primarily in the bilateral temporo-parieto-occipital areas and cerebellum in the PD with SCI group. Relative to the PD without SCI group, an excessive decrease of perfusion was found in the left middle frontal gyrus of the PD with SCI patients. CONCLUSIONS: Our findings suggest that perfusion deficits in the middle frontal area may play an important role in the pathophysiology of SCI in PD.

Long-Term Efficacy of Memantine in Parkinson' Disease Dementia: An 18-Month Prospective Perfusion Single Photon Emission Computed Tomography Preliminary Study

BACKGROUND AND PURPOSE: Although the treatment efficacy of memantine in Parkinson's disease dementia (PDD) has been reported after several weeks of administration, the long-term effects on brain perfusion and clinical symptoms remain unclear. The current study aimed to follow-up PDD patients after 18 months of memantine treatment using (99m)Tc hexamethylpropylene amine oxime single photon emission computed tomography (SPECT). METHODS: A total of 15 patients with PDD and 11 healthy participants were recruited into this study and they were assessed with brain SPECT, Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), and Neuropsychiatric Inventory (NPI). Differences in regional cerebral blood flow (rCBF) between the two groups were evaluated at baseline. After 18 months of memantine administration, changes in brain perfusion, severity of dementia, cognition, and neuropsychiatric disturbances were examined in the patients with PDD. RESULTS: The PDD group showed hypoperfusion in most of the cortical, subcortical, and cerebellar areas compared to healthy controls at baseline. At the follow-up, changes in rCBF, CDR (p=0.32), sum of box of CDR (p=0.49), MMSE (p=0.61), GDS (p=0.79), and NPI (p=0.23) were not significant in the PDD patients. CONCLUSIONS: Our findings implicate that memantine may delay the progression of brain perfusion deficits and clinical symptoms of PDD in the long term.

The Relationships between Homocysteine Levels and Memory in Early Alzheimer's Disease Patients

BACKGROUND: Alzheimer's disease (AD) is a representative neurodegenerative disorder associated with memory disturbance. Recent research has shown that risk factors for cerebrovascular disorders are also causes of dementia. Of these risk factors, hyperhomocysteinemia is well known to be positively correlated with all types of dementias including AD. But it is not clear if there is a difference in the concentration of homocysteine according to subtypes of memory impairment of AD. We performed this study to explore the relationship between homocysteine and memory. METHODS: A total of 54 patients (male: 15 patients) to the dementia clinic at our hospital were recruited for this study. All subjects underwent neuropsychological tests including detailed memory function tests and brain magnetic resonance images. The plasma homocysteine level was measured routinely in all patients. RESULTS: Verbal and visual memories in AD were significantly associated with the concentration of plasma homocysteine. The plasma homocysteine level was significantly correlated with delayed recalls of verbal and visual memories and recognition of visual memory. However, there was no relationship between plasma homocysteine and working memory. CONCLUSIONS: This study showed that plasma homocysteine level was related to the consolidation and retrieval stage of memory in AD. Therefore, we cautiously assumed that control of plasma homocysteine level could contribute to management for the prevention of cognitive impairment.

Clinical Characteristics and Outcome of Isolated Fetal Hydronephrosis / 대한산부인과학회지

OBJECTIVE: Routine maternal ultrasonography has revealed a very high incidence of fetal hydronephrosis. However, there is little data available, in Korea, on the natural progress of prenatal hydronephrosis. Therefore, to help in the management of patients, the antenatal course and neonatal follow-up data of isolated fetal hydronephrosis were analyzed. METHODS: Prenatal diagnosis, etiologies, clinical characteristics, and outcome were studied retrospectively in 77 cases of unilateral and bilateral prenatal hydronephrosis from January 2000 to March 2004. Cases were classified as mild (7 mm > or =, , ) prenatal hydronephrosis as depending on the renal pelvis anteroposterior diameter. Fisher's exact test and Chi-square test were used for statistical analysis. RESULTS: The etiologies of prenatal hydronephrosis were ureteropelvic junction obstruction 45 (58.4%), vesicoureteral reflux 2 (2.6%), ureterocele 1 (1.3%), and urethra obstruction 1 (1.3%). At delivery, 18 cases were normal kidneys, and during the follow-up periods, 10 cases resolved spontaneously. Mild, moderate, and severe hydronephrosis were present in 30 (38.9%), 38 (49.4%), and 9 (11.7%) respectively. Operations were performed in 2/38 (5.3%) of moderate cases, and 7/9 (77.8%) of severe cases. CONCLUSION: Most of prenatal hydronephrosis diagnosed by ultrasonography disappeared postnatally and the needs for postnatal operations were rare. It is suggested that hydronephrosis in the fetus or neonate dose not necessarily imply the presence of an obstructive uropathy or a significant functional abnormality and the reassurance of parents and follow up evaluation of the neonate during perinatal period may be needed.

A Case of Limb-body Wall Complex / 대한산부인과학회잡지

Limb-body wall complex, also known short umbilical cord syndrome and body stalk anomaly, is a complex set of disruptive abnormalities consisting of failure of ventral body wall to close, short umbilical cord, disruption of lateral body wall, distinctive scoliosis of spine, limb defects, facial defects and cranial defects. This disorder has similar findings to amnioitic band syndrome. but limb-body wall complex appears severe scoliosis of spine, herniation of internal organs, absent or short umbilical cord. Recently, we present a case of limb-body wall complex which found at 32+1 weeks. A case was diagnosed with ultrasonography, so we report a case of limb-body wall complex with brief review of literature.

Normal Variation and Predictive Value for Pregnancy Outcome of Fetal Heart Rate in the Early First Trimester / 대한산부인과학회잡지

OBJECTIVE: The purpose of this study was to define the normal variation of fetal heart rate (FHR) and to analyze whether first-trimester fetal heart rate (FHR) are useful in predicting pregnancy outcome. METHODS: We prospectively studied 162 singleton pregnancies with gestational ages ranging from 5 to 10 weeks between Mar. 1999 and Jan. 2003 visting our hospital. Color doppler sonography was used to calculate the fetal heart rate in beats per minute as the mean of 3 waves. RESULTS: The following results were obtained. 1. Overall, 149 pregnancies reached viability and 13 resulted in fetal loss before 13 weeks' gestation. 2. A significantly higher number of viable pregnancies, compared with fetal losses, had FHR within one (73.1% compared with 38.5%, p<0.001) and two (94.6% compared with 69.2%, p<0.001) standard deviations of the mean for viable pregnancies at corresponding gestational ages. 3. A significant correlation was seen between gestational age and fetal heart rate (p<0.001). The regressing equation for heart rate was as follows: heart rate = 3.40 X gestational age (days)-30.15 (r = 0.87). 4. There was no significant difference in the fetal heart rates between male and female embryos during this early stage of pregnancy. CONCLUSION: First-trimester FHR can be helpful to predict pregnancy outcome. Women with FHR outside the reference range from the mean for viable pregnancies at corresponding gestational ages may be at risk for eventual pregnancy loss.

A Study of Successful Prognostic Factors in Vaginal Birth after Cesarean Sections / 대한산부인과학회잡지

OBJECTIVE: Recently, with rising rates of repeat cesarean sections, enormous amount of the studies about trial of labor after cesarean section have been reported to decrease the rate of cesarean section. The purpose of this study is to provide data regarding the safety and the successful prognostic factors of VBAC (vaginal birth after cesarean section). METHODS: This retrospective study was performed based on 194 pregnant women who tried vaginal delivery after cesarean section at Eulji University Hospital from March 1997 to February 2002. The age of mother, gestational age, estimated fetal body weight by ultrasonography, neonatal body weight, cervical effacement, cervical dilatation, Bishop score, the number of previous vaginal delivery, and spontaneous labor were analyzed between successful group (177 patients) and failure group (17 patients) with trial of labor. Student T-test and Chi-square test were used for statistical analysis. RESULTS: 177 cases (91.24%) in 194 cases succeeded in VBAC and 17 cases (8.76%) failed. There was no maternal death or uterine rupture in the cases of trial of labor. The gestational age, estimated fetal body weight by ultrasonography, neonatal body weight, cervical effacement, cervical dilatation, Bishop score, the number of previous vaginal delivery, spontaneous labor had notable differences between the successful group and the failure group. But, There was no significant difference in maternal age. CONCLUSION: The trial of labor after cesarean section is relatively safe method of delivery if it is performed under strict indication. Above findings can be used as possible prognostic factors for the success of VBAC and may reduce the risk and complication of VBAC. The following studies with large populations and performed by multi-centers will be needed for the evaluation of safety and successful prognostic factors of VBAC.