Regional cerebral blood flow difference between dementia with Lewy bodies and AD

Methods.

Fourteen patients with probable DLB, 14 patients with probable AD, and 14 healthy individuals were included in this study. The patients with DLB or AD were selected from the Hyogo Institute for Aging Brain and Cognitive Disorders (HI-ABCD) Dementia Registry and were matched for age, sex, and best Mini-Mental State Examination (MMSE) score (in repeated measures). All patients were examined by neurologists and psychiatrists and were given standard neuropsychological examinations, routine laboratory tests, EEG, and cranial MRI, the results of which were incorporated into the diagnosis. The clinical and investigative data were collected and entered into the HI-ABCD Dementia Registry. Staff physicians closely monitored the fluctuation of cognitive functions over a 1-month admission in terms of MMSE performance, activities of daily living, and episodic confusion. Diagnosis of probable DLB was based on CDLBIW criteria.2 These criteria include three core features: fluctuating cognitive functions, recurrent visual hallucinations, and spontaneous parkinsonism. Two of them are necessary for a diagnosis of probable DLB. Diagnosis of probable AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA). The control group consisted of 14 neurologically and cognitively normal subjects who volunteered to undergo a SPECT study for examination of their relatively unimportant neurologic complaints.

The mean (± SD) age was 73.4 ± 4.8 years for the DLB group, 73.6 ± 6.1 years for the AD group, and 71.0 ± 9.1 years for the control group. Each group consisted of seven women and seven men. The mean MMSE score was 18.3 ± 4.5 for the DLB group, 18.0 ± 2.4 for the AD group, and 28.1 ± 2.2 for the control group. Clinical data of the patients with DLB are summarized in table 1. None of the AD patients showed any of the three features (that is, none fulfilled the criteria for possible DLB). Visuospatial and visuoperceptual deficits were not evident in the AD group, including Balint syndrome, unilateral spatial neglect, and visual agnosia. Visuoconstructive disability was noted in eight patients.

SPECT images were obtained with a rotating dual-headed gamma camera. Twenty minutes after the injection of 111 MBq of ¹²³I-IMP, the SPECT scan was started. The SPECT acquisition was done in 60 steps, each step lasting 30 seconds. Data were collected in 64 × 64 matrices and were reconstructed in transaxial sections parallel to the frontal pole–occipital pole plane with 8 mm thickness. Statistical parametric mapping 95 software (MRC Cyclotron Unit, London, UK) was used for analysis. To eliminate the low-intensity background and remove the brain-edge halo caused by partial volume error, the cutoff threshold was set at 30% of the maximum pixel value. Then the data were transformed into a standard stereotactic space, the images were smoothed with an isotropic Gaussian filter (16 mm full width half maximum), and each individual global CBF was normalized by proportional scaling across the entire data set to a mean of 50 mL/100 mL/min.8 The normalized data set was compared among the groups by computing a voxel-by-voxel t statistic. The t statistic was transformed to a normal statistic yielding a z-score for each voxel, and the subset of voxels exceeding a threshold of p < 0.025 (corrected) was displayed as a volume image rendered in three orthogonal projections.

All procedures followed the Clinical Study Guidelines of the Ethics Committee of HI-ABCD and were approved by the Internal Review Board. Written consent was obtained from the subjects after a complete description of the study to all the individuals and their relatives.

Results.

In patients with DLB and AD, parietotemporal and posterior cingulate CBFs were lower than those in control subjects. CBFs in the primary visual cortex and left frontal association cortex were also significantly lower in patients with DLB than in control subjects. The results of the comparison of the relative CBF between the DLB and AD groups are given in table 2 and the figure. Relative CBF was lower in the occipital lobes and higher in the right medial temporal lobe in the DLB group than in the AD group. In patients with DLB, CBF was lower in the bilateral occipital lobes and higher in the right medial temporal lobe than in those with AD. FIGURE

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Figure. Statistical parametric mapping projections show areas with significantly high cerebral blood flow (CBF) (p < 0.025, corrected) in a comparison of 14 patients with dementia with Lewy bodies (DLB) and 14 patients with AD. (A) Specific voxels in which CBF was significantly lower in the DLB group than in the AD group. (B) Specific voxels in which it was significantly higher. Relative CBF was lower in the occipital lobes and higher in the right medial temporal lobe in the DLB group than in the AD group.

Discussion.

We found a significant difference in the CBF pattern between DLB and AD, which was consistent with the differences demonstrated in previous PET glucose metabolism studies.2-4 Statistical parametric mapping analysis demonstrated that medial temporal CBF was significantly different only in the right side, probably because of a Type II error in the left side. Hypometabolism in the occipital lobes in patients with DLB has also been demonstrated in studies using FDG PET.2-4

The mechanism of occipital hypometabolism/hypoperfusion is highly speculative, as Lewy bodies hardly affect the occipital lobes. Borght et al.9 attributed the hypometabolism in the occipital visual cortices to dopaminergic systems in the visual pathway, and abnormal visual input from the retina might explain the hypometabolism, referencing the retinal dopamine deficiency. An involvement of the occipital cholinergic system has also been assumed.4 Reduced occipital perfusion/metabolism has been observed in patients with PD, both with and without dementia. This suggests that the mechanism of occipital hypoperfusion/hypometabolism is related to a common pathologic state in PD and DLB regardless of manifestation of dementia, although some patients in the above studies would be classified as having DLB under the current concept. Kuhl et al.,10 using SPECT and ¹²³I-iodobenzovesamicol, an in vivo marker of the vesicular acetylcholine transporter, found that the presynaptic cholinergic terminal density was reduced in the parietal and occipital cortices in PD without dementia. Further studies are needed to determine whether occipital involvement predicts future development of dementia in PD patients.

Concerning the medial temporal cortex, the relatively well preserved CBF in DLB is likely attributable to less involvement of the medial temporal memory system, including the hippocampus, in DLB. This finding is also compatible with the pathologic and neuropsychological findings in DLB: low density of neurofibrillary tangles in the limbic system despite the preferential appearance of Lewy bodies in the limbic structures, and relatively well preserved memory function.