Telomere length shortening in patients with dementia with Lewy bodies.

BACKGROUND AND PURPOSE: Shortened telomere length has been considered to be associated with various age-related diseases, especially in dementia such as Alzheimer's disease and vascular dementia. However, changes in telomere length in dementia with Lewy bodies (DLB) remain unclear. To elucidate these changes, we set out to determine telomere length in peripheral leukocytes as well as the level of urinary 8-hydroxy-deoxyguanosine (8-OHdG) as a marker of oxidative stress in DLB. METHODS: Blood samples were obtained from 33 patients with a clinical diagnosis of probable DLB and 35 age-matched, non-demented elderly controls (NEC). Telomere length was assessed by quantitative real-time polymerase chain reaction of genomic DNA extracted from leukocytes, whereas oxidative stress was assessed on the basis of urine 8-OHdG level, which was measured using high-performance liquid chromatography. RESULTS: Telomere length was significantly shorter in the DLB group than in the NEC group. Urinary 8-OHdG levels were significantly higher in the DLB group than in the NEC group. There was a negative correlation between telomere length and age in the DLB group; however, there were no significant relationships between telomere length and clinical findings including disease duration, severity of cognitive decline, presence or absence of fluctuation in cognitive function, visual hallucinations, and Parkinsonism. In both groups, the correlation between telomere length and urinary 8-OHdG levels was not significant. CONCLUSIONS: These findings indicate that the etiopathology of DLB is considered to be an accelerated aging process.

Regional cerebral blood flow changes in patients with idiopathic REM sleep behavior disorder.

BACKGROUND: Recent studies have shown an association between rapid eye movement sleep behavior disorder (RBD) and neurodegenerative disorders, especially alpha-synucleinopathies. OBJECTIVE: We investigated regional cerebral blood flow (rCBF) changes using single photon emission computed tomography (SPECT) in patients with idiopathic RBD (iRBD), to determine functional brain alterations associated with the disorder. METHODS: The SPECT data of 24 patients with iRBD were compared with those of 18 age-matched normal controls using statistical parametric mapping 2. RESULTS: We found decreased rCBF in the parietooccipital lobe (precuneus), limbic lobe, and cerebellar hemispheres in patients with iRBD, which is commonly seen in patients with Lewy body disease (Parkinson's disease and dementia with Lewy bodies) or multiple system atrophy. CONCLUSION: Our SPECT study suggests that iRBD can be a presymptomatic stage of alpha-synucleinopathies.

Differences in clinical course between dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND AND PURPOSE: To investigate whether there may be differences in the clinical course and changes in cognitive progression between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: We compared the time from the first visit to endpoints (discontinuation of visits because of admission, death, or institutionalization) between 56 patients with DLB and 111 patients with AD. Mini-Mental State Examination (MMSE) scores of patients were every 12 months examined up to 60 months. RESULTS: Dementia with Lewy bodies had a significantly shorter time to reaching endpoints than those with AD (median time; 40 months vs. 52 months, P < 0.0001). The proportion of admission (or death) was significantly higher in DLB than in AD (30% vs. 14%, P < 0.05), while the difference in institutionalization in nursing homes did not reach statistical significance (25% vs. 17%). Rates of longitudinal MMSE score decline for DLB and AD groups were equivalent. CONCLUSION: Dementia with Lewy bodies had a greater risk of admission (or death) because of most commonly fall-related injuries and bronchopneumonia than AD, but the two groups did not differ in rate of cognitive decline.

Deep gray matter hyperperfusion with occipital hypoperfusion in dementia with Lewy bodies.

Although decreased occipital perfusion is a characteristic feature of dementia with Lewy bodies (DLB), not all patients with DLB show a significant decreased perfusion in the occipital lobe. We explored characteristics of perfusion changes to improve the identification of DLB, in addition to occipital hypoperfusion. Statistical image analysis of single photon emission computed tomography data was performed on 22 patients with DLB and 25 patients with Alzheimer's disease (AD). A significant decreased perfusion in the occipital lobe was found in 16 patients with DLB (72%) and three patients with AD (12%), while a significant increased perfusion in the deep gray matter (striatum and/or thalamus) was found in 18 patients with DLB (81%) and eight patients with AD (31%), respectively. Either occipital hypoperfusion or deep gray matter hyperperfusion was found in 21 patients with DLB (95%), while in nine patients with AD (35%), indicating a sensitivity of 95% and a specificity of 65% in discriminating DLB from AD. Our results suggest that the addition of deep gray matter hyperperfusion to occipital hypoperfusion may be useful in the clinical differentiation of DLB and AD.

Magnetisation transfer measurements of the subcortical grey and white matter in Parkinson's disease with and without dementia and in progressive supranuclear palsy.

We measured the magnetisation transfer ratio (MTR) in the subcortical grey and white matter of 11 patients with idiopathic Parkinson's disease (PD) without dementia, six with PD with dementia (PDD), six with progressive supranuclear palsy (PSP), and 12 elderly control subjects to assess regional differences in structural brain damage. There were no significant differences in MTR in any region between PD and controls. However, patients with PDD had significantly lower MTR in the subcortical white matter, including the frontal white matter and the genu of the corpus callosum than the controls, whereas PSP had significantly lower MTR in the subcortical grey matter, including the putamen, globus pallidus and thalamus, in addition to the subcortical white matter. This suggests that regional patterns of structural brain damage can be detected using the magnetisation transfer technique. Measurement of MTR in the subcortical grey and white matter may be useful in differential diagnosis.

Magnetization transfer measurements of the hippocampus in the early diagnosis of Alzheimer's disease.

We measured magnetization transfer ratios (MTRs) of the hippocampus in 38 patients with Alzheimer's disease (AD), including very mild (Clinical Dementia Rating [CDR] 0.5, n=12), mild (CDR 1, n=14), and moderate stages (CDR 2, n=12), and in 21 healthy elderly control subjects. Medial temporal lobe atrophy was graded subjectively on a five-point scale by two observers blinded to clinical data. Compared with the controls, each of the AD groups, including the very mild group, had significant atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus. Logistic regression analysis revealed that the overall discrimination rate with MTR measurement and visual analysis of the atrophy was 85% and 73% between the control group and the CDR 0.5 group, 89% and 80% between the control group and the CDR 1 group, and 100% and 91% between the control group and the CDR 2 group, respectively. MTR measurements may provide additional information in detecting structural damage of the hippocampus of AD and be helpful in providing improved diagnosis and early detection of AD.

[Diagnosis of Alzheimer's disease using brain SPECT with three-dimensional stereotactic surface projections].

We compared the diagnostic usefulness of three-dimensional stereotactic surface projection (3D-SSP) with that of standard transaxial images in brain SPECT in patients with Alzheimer's disease (AD). The subjects consisted of 69 patients with AD and 60 patients with non-AD, including vascular dementia, Parkinson's disease with dementia, frontotemporal dementia, other dementing diseases and neuropsychiatric diseases. Standard transaxial section and 3D-SSP SPECT images with N-isopropyl-p-[123I] iodoamphetamine were blindly interpreted by three examiners and were classified into the following three patterns: typical AD, atypical AD, and not indicative AD patterns. The 3D-SSP images demonstrated reductions of cerebral blood flow in the parieto-temporal association cortex and posterior cingulate gyrus more clearly and easily than the standard transaxial images. The diagnostic sensitivity and specificity were 93% and 85% with 3D-SSP and 83% and 82% with standard transaxial section respectively. 3D-SSP was especially useful for early or atypical AD which showed no characteristic perfusion abnormalities on standard transaxial images. These results suggest that SPECT with 3D-SSP provides an sensitive as well as accurate tool for the diagnosis of AD.

Magnetization transfer measurements of the hippocampus in patients with Alzheimer's disease, vascular dementia, and other types of dementia.

BACKGROUND AND PURPOSE: Although atrophy of structures in the medial temporal lobe has been considered an indication of Alzheimer's disease (AD), atrophic changes on MR images have also been associated with other dementing diseases and are not specific to AD. This study was undertaken to determine whether characteristic alterations in the hippocampus of patients with AD are detectable with magnetization transfer (MT) imaging. METHODS: Coronal MT imaging was performed in 35 patients with probable AD, in 14 patients with vascular dementia, in 13 patients with other types of dementia, and in 23 control subjects to measure MT ratios of the hippocampus. Medial temporal lobe atrophy was graded subjectively on a five-point scale. RESULTS: Scores of medial temporal lobe atrophy in all dementia groups were significantly higher than those in control subjects, but no differences were found among the dementia groups. MT ratios in the hippocampus were significantly lower in patients with AD than in those with non-AD dementia and in the control subjects; however, no differences were found between the non-AD dementia patients and the control subjects. MT ratio measurements were better than visual analysis of atrophy for differentiating AD patients from those with non-AD dementia (an overall discrimination rate of 77% versus 65%). MT ratios significantly correlated with scores on the Mini-Mental State Examination and with medial temporal lobe atrophy in AD patients but not in patients with non-AD dementia. CONCLUSION: MT measurements may be more specific than visual analysis in detecting structural damage of the hippocampus in AD patients and might be useful in discriminating AD from vascular dementia and other types of dementia.

[Relation between hippocampal damage and cerebral cortical function in Alzheimer's disease].

We investigated the relation between hippocampal damage and cerebral cortical dysfunction in Alzheimer's disease (AD) using MRI and SPECT. Nineteen patients with AD and 10 control subjects were studied. Hippocampal damage (including hippocampal formation, entorhinal cortex, and parahippocampal white matter) was assessed to evaluate the severity of atrophy and the magnetization transfer ratio (MTR) and cerebral cortical dysfunction was evaluated by quantitative cerebral blood flow (CBF) measurements using SPECT with 99mTc-ECD. Compared with controls, patients with AD had significantly more atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus and parahippocampus. There were significant correlations between the severity of hippocampal damage and regional CBF in temporoparietal lobes. Mini-Mental State Examination scores significantly correlated with the severity of hippocampal damage and regional CBFs in temporoparietal lobes. These results suggest that the functional effect of hippocampal damage occurs in temporoparietal lobes in AD, probably due to neuronal disconnections between hippocampal areas (including the entorhinal cortex) and temporoparietal lobes.

[Is hippocampal atrophy a specific change for Alzheimer's disease?].

Although detection of hippocampal atrophy has been proposed for the diagnosis of Alzheimer's disease (AD), atrophic changes in MRI can be found in other dementia diseases. This study was undertaken to determine whether hippocampal atrophy was a specific change for AD. Coronal T 1-weighted images were performed in 36 patients with AD, 40 patients with non-AD including vascular dementia, frontemporal dementia, Parkinson's disease with dementia, dementia with Lewy bodies, progressive supranuclear palsy, and normal pressure hydrocephalus, 9 patients with age-associated memory impairment (AAMI), and 24 control subjects. Hippocampal atrophy was graded subjectively on a 5-point scale. Scores of hippocampal atrophy for AD (2.11 +/- 0.95) and non-AD (1.80 +/- 0.91) were significantly higher than those for controls (0.79 +/- 0.72). Scores for AD were also significantly higher than those for AAMI (1.11 +/- 0.160), but no difference was found between AD and non-AD. These results suggest that hippocampal atrophy is not a specific marker for AD and appears to be a common phenomenon in dementia syndromes.

Diffusion-weighted and magnetization transfer imaging of the corpus callosum in Alzheimer's disease.

We investigated structural changes of the corpus callosum in patients with Alzheimer's disease (AD) using sagittal diffusion-weighted (DW) and magnetization transfer (MT) imaging. Patients with AD (n=23) had a significantly decreased area only in the posterior portion of the corpus callosum. Apparent diffusion coefficient (ADC) values perpendicular to the commisural fiber orientation were significantly higher in the anterior portion of the corpus callosum without definite atrophy, as well as in the posterior portion with significant atrophy, in patients with AD than in controls (n=16) and thus diffusion in these regions showed a significantly lower degree of anisotropy in patients than in controls. MT ratios were also significantly lower in patients with AD in the anterior and posterior portions of the corpus callosum than in controls. These findings probably reflect structural changes in the corpus callosum including axonal loss and/or demyelination. DW and MT imagings may be useful in detecting degeneration of the corpus callosum in AD.

Magnetization transfer ratio in cerebral white matter lesions of Binswanger's disease.

We measured the magnetization transfer (MT) ratios in white matter lesions of Binswanger's disease (BD) and compared them with BD and with similar-appearing changes in non-demented elderly subjects and cerebral infarction. Four subject groups were studied: 30 patients with BD and periventricular hyperintensity (PVH) on MRI, 29 patients with ischemic cerebrovascular event with PVH but no dementia, 17 patients with old cerebral infarction, and 26 elderly control subjects. MT ratios were calculated for areas of PVH in BD and non-demented subjects, of infarction, and of normal-appearing white matter in controls. The decrease in MT ratios for areas in PVH of non-demented subjects and BD and in infarction compared with normal white matter in controls was 12, 20, and 35%, respectively. The MT ratio in PVH of BD was significantly lower than that in PVH of non-demented subjects, but not to the levels seen in areas of infarction. There was a significant high correlation between the Mini-Mental State Examination score and MT ratio for area of PVH (r = 0.790). MT ratio distinguishes PVH in BD patients from those in non-demented subjects, suggesting underlying histopathological differences. Tissue damage in white matter lesions of BD may be more severe than that in non-demented subjects, but not as much as with complete infarction.

Chemical control of Haematobia irritans with 0.5% topical ivermectin solution in cattle.

A field trial was conducted to evaluate the efficacy of a topical formulation of ivermectin administered at the dose of 500 micrograms/kg against horn flies (Haematobia irritans) in cattle. Eighty-eight cattle in four herds naturally exposed to horn flies were used in the trial. Replicates were formed of two herds. Within replicates, one herd was randomly allocated to the untreated control and the other to the ivermectin treatment group. Horn fly counts were taken on the treatment day (Day 0) and on Days 7, 14, 21, 28, and 35 post-treatment. There were no horn flies on any cattle in the treatment group, whereas all the control cattle were continuously infested by horn flies on each examination day.

Regional differences in diffusion abnormality in cerebral white matter lesions in patients with vascular dementia of the Binswanger type and Alzheimer's disease.

We investigated changes in water diffusion in the cerebral white matter of 14 patients with vascular dementia of the Binswanger type (VDBT) and ten patients with Alzheimer's disease (AD) with periventricular hyperintensity (PVH) lesions using diffusion-weighted magnetic resonance imaging (MRI) and studied the pathophysiological differences between white matter lesions found in these two conditions. Apparent diffusion coefficients (ADCs) in the anterior and posterior white matter and the genu and splenium of the corpus callosum were significantly higher in both groups of patients than in the 12 age-matched controls, and ADC values in VDBT and AD groups were almost the same. ADC ratios, defined as diffusion restricted perpendicular to the direction of nerve fibers, were also significantly higher in the patients than in the control subjects. However, there were regional differences in ADC ratios in the two conditions, with ratios in VDBT being higher in the anterior portions of the white matter but ratios in AD were higher in the posterior portions. The diffusion-weighted MRI technique may be useful in the differential diagnosis of VDBT and AD with white matter lesions.

[Magnetization transfer imaging of periventricular white matter lesions in patients with multi-infarct dementia].

Using magnetization transfer (MT) imaging, we studied the underlying pathological conditions of periventricular hyperintense (PVH) white matter changes seen on T2-weighted MR images of patients with multi-infarct dementia. Twenty-two patients with multiple lacunar infarcts and PVH lesions, including 11 with dementia (diagnosed as multi-infarct dementia) and 11 without dementia, and 10 control subjects (with multiple lacunes, but no PVH lesion) were studied using the MT technique. MT ratios (MTRs) were calculated for PVH lesions (normal-appearing frontal white matter in controls) and the genu of the corpus callosum. Signal intensities on T2-weighted images in PVH lesions of patients were significantly higher than those in normal-appearing white matter of controls, while there were no significant differences in signal intensity in the genu of the corpus callosum among the dementia, non-dementia and control groups. However, MTRs in patients with PVH lesions were significantly lower than those in controls, and MTRs in demented patients were significantly lower than those in non-demented patients. Moreover, MTRs in the genu of the corpus callosum of demented patients were significantly lower than in those in non-demented patients and controls. MTRs in PVH lesions and the genu of the corpus callosum significantly correlated with Hasegawa's dementia scale score. These results suggest that there is some difference in histopathologic changes of PVH lesions between demented and non-demented patients and that the pathological substrate in the corpus callosum may play a role in inducing cognitive decline. Studies with MT imaging may allow the characterization of different pathological conditions that cannot be visualized by conventional MRI.

Diffusion-weighted magnetic resonance and magnetization transfer imaging in the assessment of ischemic human stroke.

We compared characteristic features in ischemic stroke lesions from the hyperacute to the chronic stage on diffusion-weighted (DW) and magnetization transfer (MT) images with those on T2-weighted (T2W) images, and assessed changes in apparent diffusion coefficient (ADC), MT effect (MTe), and T2 ratios (infarct/normal) over time. DW images were particularly useful for detecting hyperacute infarcts within 6 hours of onset and in distinguishing acute lesions from chronic lesions. ADC ratios were lower within 7 days after onset and rose toward 1.0 in the subacute phase, becoming relatively isotense on ADC maps, but elevated thereafter. Although MTe ratios were unchanged or only subtly changed in the acute stage, they became significantly lower in the subacute and chronic stages. These combined magnetic resonance (MR) techniques were useful in the assessment of ischemic stroke and facilitated the determination of the age of cerebral infarct.

Diffusion-weighted MR imaging of the hippocampus and temporal white matter in Alzheimer's disease.

We investigated the changes in water diffusion in the hippocampus and the temporal white matter (the temporal stem) in eight patients with possible Alzheimer's disease (AD), 10 patients with probable AD, and 10 age-matched controls, using coronal diffusion-weighted magnetic resonance (MR) imaging. Apparent diffusion coefficients (ADCs) were derived for the three orthogonal axes and an index of diffusion anisotropy (IDA = ADC(max-min)/ADC(mean)) was then calculated. Although no significant differences were found in ADC and IDA values in the hippocampal body between controls and patients, vertical (superior-inferior) ADC values and ADC(mean) values in the temporal stem of patients with AD were significantly higher than those in controls, and IDA values were therefore significantly lower in patients with possible or probable AD than those in controls. Moreover, IDA values in the temporal stem were significantly correlated with the clinical severity. These results suggest that decreased fiber density, such as the disruption and loss of axonal membranes or myelin, occur early in the temporal stem, probably due to secondary degeneration related to grey matter pathology including the medial temporal lobe.

[Atrophy and magnetization transfer ratio of the corpus callosum in patients with Alzheimer's disease].

We compared atrophy and magnetization transfer ratio (MTR) in the corpus callosum in patients with Alzheimer's disease and age-matched normal subjects. Fifteen patients with Alzheimer's disease and fourteen normal subjects received MRI. The corpus callosum was divided into three parts (anterior, middle, and posterior portions) on midsagittal slice, and their areas on T2-weighted reversed images and MTR on magnetization transfer contrast images in each portion were measured. The area and MTR decreased significantly in the posterior portion in patients with Alzheimer's disease. In the anterior portion, MTR decreased significantly, but although the area showed no significant change. In the middle portion, the area and MTR showed no significant change. MTR and the area was correlated in each portion in patients with Alzheimer's disease. The score of Hasegawa dementia scale-revised (HDS-R) and the area of the middle, posterior and total of corpus callosum were significantly related. The score of HDS-R and MTR in the anterior portion of corpus callosum were significantly related. The present study revealed decreases in MTR in the anterior portion of the corpus callosum of patients with Alzheimer's disease although the area showed no significant change, and this change suggests the increase in free water and/or the decrease in bound water in tissues, probably due to demyelination and axonal degeneration.

[Single photon emission computed tomography in the diagnosis of Alzheimer's disease].

Studies with single photon emission computed tomography (SPECT) have shown temporoparietal (TP) hypoperfusion in patients with Alzheimer's disease (AD). We evaluated the utility of this findings in the diagnosis of AD. SPECT images with 123I-iodoamphetamine were analyzed qualitatively by a rater without knowledge of the subject's clinical status. Sixty-seven of 302 consecutive patients were judged as having TP hypoperfusion by SPECT imaging. This perfusion pattern was observed in 44 of 51 patients with AD, in 5 with mixed dementia, 8 with cerebrovascular disease (including 5 with dementia), 4 with Parkinson's disease (including 2 with dementia), 1 with normal pressure hydrocephalus. 1 with slowly progressive aphasia. 1 with progressive autonomic failure, 2 with age associated memory impairment, and 1 with unclassified dementia. The sensitivity for AD was 86.3% (44 of 51 AD), and the specificity was 91.2% (229 of 251 non-AD). Next, we looked for differences in perfusion images between patients with AD and without AD. Some patients without AD had additional hypoperfusion beyond TP areas: deep gray matter hypoperfusion and diffuse frontal hypoperfusion, which could be used to differentiate them from the patients with AD. Other could not be distinguished from patients with AD by their perfusion pattern. Although patients with other cerebral disorders occasionally have TP hypoperfusion, this finding makes the diagnosis of AD very likely.

[Age-related changes of diffusional anisotropy in the cerebral white matter in normal subjects].

To investigate age-related changes of diffusional anisotropy in the cerebral white matter, we performed diffusion-weighted MRI studies in 21 normal subjects aged 25 to 96 years. The anisotropic rations (ARs), defined as the apparent diffusion coefficients perpendicular to the nerve fibers to those parallel to the nerve fibers, were significantly higher in elderly than in young subjects in the anterior and posterior white matter surrounding the lateral ventricle. Moreover, significant correlation between age and AR was found in the anterior white matter. The ventricular index (VI) measured on MRI, as a quantitative indicator of brain atrophy, was significantly higher in elderly than younger subjects, and significantly correlated with AR in the anterior white matter. Multiple regression analysis demonstrated that the VI showed the highest correlation for AR. On the other hand, there was no significant correlations between ARs in the corpus callosum and age. These results suggest that morphological changes in the myelin and axon in the white matter occur in elderly normal subjects, probably due to neuronal loss with aging.