Kentaro Hirao

Voxel-based morphometry to discriminate early Alzheimer's disease from controls.

We assessed the accuracy of voxel-based morphometry (VBM) using a three-dimensional T1-weighted MRI in discriminating Alzheimers disease (AD) in the very early stage of amnestic type of mild cognitive impairment and age-matched healthy controls. We randomly divided these subjects into two groups. The first group comprising 30 AD patients and 41 controls was used to identify the area with the most significant gray matter loss in patients compared to normal controls based on the voxel-based analysis of a group comparison. The second group comprising 31 patients and 41 controls was used to determine the discrimination accuracy of VBM. A Z-score map for a gray matter image of a subject was obtained by comparison with mean and standard deviation gray matter images of the controls for each voxel after anatomical standardization and voxel normalization to global mean using the following equation; Z-score=([control mean]-[individual value])/(control S.D.). Receiver operating characteristic curves for a Z-score in the bilateral medial temporal areas including the entorhinal cortex with the most significant loss in the first group showed a high discrimination accuracy of 87.8%. This result would open up a possibility for early diagnosis of AD using VBM.

Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease

To test the effects of the PPAR-γ agonist pioglitazone on cognition, regional cerebral blood flow (rCBF), and plasma levels of Aβ40 and Aβ42, we conducted a 6-month, randomized, open-controlled trial in patients with mild Alzheimer disease (AD) accompanied with type II diabetes mellitus. We randomly assigned 42 patients to either the group treated with 15-30 mg pioglitazone daily (n=21, pioglitazone group) or not (n=21, control group). The pioglitazone group improved cognition and rCBF in the parietal lobe, while the control group showed no such improvement. The plasma Aβ40/Aβ42 ratio increased in the control group, but showed no significant change in the pioglitazone group. Both groups showed good control of diabetes during the study. In addition, pioglitazone treatment resulted in a decrease in fasting plasma insulin levels, indicating enhanced insulin sensitivity. The results of this pilot study demonstrated that pioglitazone exhibited cognitive and functional improvements, and stabilization of the disease in diabetic patients with AD. Pioglitazone may offer a novel strategy for the treatment of AD.

The prediction of rapid conversion to Alzheimer's disease in mild cognitive impairment using regional cerebral blood flow SPECT

Mild cognitive impairment (MCI) comprises a heterogeneous group with a variety of clinical outcomes and they are at risk for developing Alzheimers disease (AD). The prediction of conversion from MCI to AD using the initial neuroimaging studies is an important research topic. We investigated the initial regional cerebral blood flow (rCBF) measurements using single photon emission computed tomography (SPECT) in individuals with 76 amnesic MCI (52 subjects converted to AD and 24 subjects did not convert to AD at 3-year follow-up) and 57 age- and gender-matched controls. We sought functional profiles associated with conversion to AD, then evaluated the predictive value of the initial rCBF SPECT. As compared with controls, AD converters demonstrated reduced blood flow in the bilateral parahippocampal gyri, precunei, posterior cingulate cortices, bilateral parietal association areas, and the right middle temporal gyrus. Non-converters also demonstrated significant reduction of rCBF in the posterior cingulated cortices and the right caudate nucleus when compared to controls. As compared with non-converters, converters showed reductions of rCBF in the bilateral temporo-parietal areas and the precunei. The logistic regression model revealed that reduced rCBF in the inferior parietal lobule, angular gyrus, and precunei has high predictive value and discriminative ability. Although a cross-validation study is needed to conclude the usefulness of rCBF SPECT for the prediction of AD conversion in individuals with MCI, our data suggest that the initial rCBF SPECT studies of individuals with MCI may be useful in predicting who will convert to AD in the near future.

Comparative value of brain perfusion SPECT and [123I]MIBG myocardial scintigraphy in distinguishing between dementia with Lewy bodies and Alzheimer’s disease

PurposeBoth decreased occipital perfusion on brain single-photon emission computed tomography (SPECT) and reduction in cardiac 123I-metaiodobenzylguanidine (MIBG) uptake are characteristic features of dementia with Lewy bodies (DLB), and potentially support the clinical diagnosis of DLB. The aim of this study was to compare the diagnostic value of these two methods for differentiation of DLB from Alzheimer’s disease (AD).MethodsThe study population comprised 19 patients with probable DLB and 39 patients with probable AD who underwent both SPECT with N-isopropyl-p-[123I]iodoamphetamine and MIBG myocardial scintigraphy. Objective and quantitative measurement of perfusion in the medial occipital lobe, including the cuneus and lingual gyrus, was performed by the use of three-dimensional stereotactic surface projections.ResultsMedial occipital perfusion was significantly decreased in the DLB group compared with the AD group. The mean heart/mediastinum ratios of MIBG uptake were significantly lower in the DLB group than in the AD group. Although SPECT failed to demonstrate significant hypoperfusion in the medial occipital lobe in five patients with DLB, marked reduction of MIBG uptake was found in all patients with DLB. Receiver operating characteristic analysis revealed that MIBG myocardial scintigraphy enabled more accurate discrimination between DLB and AD than was possible with perfusion SPECT.ConclusionMIBG myocardial scintigraphy may improve the sensitivity in the detection of DLB. In particular, this method may provide a powerful differential diagnostic tool when it is difficult to distinguish cases of DLB from AD using brain perfusion SPECT.

The progression of cognitive deterioration and regional cerebral blood flow patterns in Alzheimer's disease: A longitudinal SPECT study

BACKGROUND AND PURPOSE The progression of cognitive deterioration in patients with Alzheimers disease (AD) is considerably variable. The ability to predict the progression rate is important for clinicians to treat and manage patients with AD. We examined the possible relationship between the rate of cognitive deterioration and regional cerebral blood flow (rCBF) patterns in patients with AD. METHODS We followed 48 patients with AD for an average of 37 months. They were subsequently divided into the rapidly progressing group (n=24) and slowly progressing group (n=24) based on an annual Mini-Mental State Examination (MMSE) score change. Initial and follow-up rCBF were assessed using single photon emission CT (SPECT) and the SPECT data were analyzed by 3D-stereotactic surface projections. RESULTS At initial evaluation, the rapidly progressing group had greater rCBF deficits mainly in the parietotemporal and frontal regions, and left posterior cingulate than did the slowly progressing group. When compared with initial SPECT, follow-up SPECT showed a significant rCBF reduction in widespread regions, including parietotemporal and frontal lobes, of the rapidly progressing group, while showed in the scattered and small regions of hemispheres of the slowly progressing group. CONCLUSION Our longitudinal SPECT study suggests a significant association between rCBF deficits in the parietotemporal, posterior cingulate, and frontal regions and subsequent rapid cognitive and rCBF deterioration.

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).

The role of 123I-metaiodobenzylguanidine myocardial scintigraphy in the diagnosis of Lewy body disease in patients with dementia in a memory clinic.

Reduction in cardiac 123I-metaiodobenzylguanidine (MIBG) uptake is a characteristic feature of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and is useful in distinguishing them from other neurodegenerative disorders. The aim of this study was to investigate the role of this method of scintigraphy in the differential diagnosis of dementia in our Memory Clinic. We performed MIBG scintigraphy in patients with dementia referred to the Memory Clinic and compared the heart-to-mediastinum (H/M) ratio of MIBG uptake. Thirty out of 32 patients with DLB and all 9 PD with dementia patients had reduced H/M ratios, whereas 37 out of 40 patients with Alzheimer’s disease had normal H/M ratios. Most patients with vascular dementia, frontotemporal dementia, and other dementias had normal H/M ratios. The overall sensitivity to positively identify patients with Lewy body disease (including DLB and PD with dementia) was 95%, and the specificity to distinguish them from patients with other types of dementias was 87%. MIBG scintigraphy showed a high sensitivity for the detection of Lewy body disease, and also a high specificity for discrimination from other types of dementia. The scintigraphy may provide a valuable and adjunctive method in the diagnosis of Lewy body disease and a differential diagnostic tool for patients with dementias.

MR features of the substantia innominata and therapeutic implications in dementias.

We measured the thickness of the substantia innominata using magnetic resonance imaging in 122 patients with Alzheimers disease (AD), 31 patients with dementia with Lewy bodies (DLB) and 34 patients with vascular dementia (VaD), and examined the correlates of cognitive response to donepezil. Although all dementia groups showed significant atrophy of the substantia innominata compared to 28 age-matched controls, atrophy was greater in the DLB group, but less in the VaD group than the AD group. Mini-Mental State Examination score changes at 12 weeks after donepezil administration inversely and significantly correlated with the thickness of the substantia innominata in patients with AD (n=103, r=-0.43, p<0.0001) and in patients with DLB (n=24, r=-0.57, p<0.01), but not in patients with VaD (n=12, r=-0.22, p>0.1). There may be some differences in cholinergic impairment among AD, DLB and VaD, reflecting cholinergic neuropathology. Clinical response to cholinergic therapy may be partly attributable to damaged cholinergic neurons in AD and DLB, but not in VaD, suggesting differences in the therapeutic implication of cholinergic system degeneration.

Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer's disease and cerebrovascular disease: a pilot study.

Aim:  It remains unknown whether antiplatelet agents have a preventive effect on cognitive decline in patients with Alzheimers disease (AD). We investigated the effects of cilostazol, an antiplatelet agent and cyclic adenosine monophosphate phosphodiesterase 3 inhibitor, on cognition and regional cerebral blood flow (rCBF) in elderly patients with AD and cerebrovascular disease (CVD).

Neuroanatomical correlates of unawareness of memory deficits in early Alzheimer's disease.

Background/Aims: To investigate neuroanatomical substrates of unawareness of memory deficits in patients with early Alzheimer’s disease (AD). Methods: We compared regional perfusion deficits between AD patients with awareness (n = 19) and unawareness (n = 19). SPECT data were analyzed by statistical brain imaging method. Results: Statistical maps demonstrated a more extensive and severe reduction in perfusion in the unaware group than in the aware group. Quantitative analysis demonstrated a significant difference between the groups in the right subcallosal, anterior cingulate and cingulate gyri and left orbital, subcallosal, and anterior cingulate gyri. Conclusion: Functional damage to the inferior, medial and orbital frontal lobes as well as the anterior cingulate gyri may be associated with the lack of awareness in patients with early AD.