The patient began exhibiting recurrent dream enactment behavior around age 50. The frequency and severity of the behaviors gradually increased over many years, but injuries rarely occurred. His cognitive decline became apparent at the age 66 and over the following year he developed obvious signs of parkinsonism, leading to a diagnosis of DLB. By age 72 recurrent visual hallucinations, fluctuations in cognition, visual illusions, and auditory hallucinations became apparent. A comprehensive evaluation at age 76 was notable for a Kokmen Short Test of Mental Status [Kokmen, et al.,1987
] score of 28/38, hypokinetic dysarthria, and moderate symmetric parkinsonism. Polysomnography demonstrated increased electromyographic tone and flailing limb movements during REM sleep, thereby confirming the presence of REM sleep behavior disorder (RBD). He showed clear deficits in attention and processing speed (unable to complete Trail Making Test A or B, semantic fluency at the 2nd percentile), and visual construction (Rey-Osterreith Complex figure was severely distorted, <1st percentile), with far less impairment or normal performance on confrontation naming and delayed recall on verbal memory measures.
MRI showed mild atrophy of the hippocampi and mild periventricular white matter hyperintensities. Abnormal glucose metabolism was present in the temporoparietal cortices and prefrontal cortex on 18
F-FDG PET consistent with the typical pattern in AD. PiB retention was most significant in the frontal lobes where as the occipital lobes were relatively spared. The abundant PiB retention in the white matter was comparable to the non-specific PiB retention typically seen in the white matter, which was masked out of the cortical GM ROI analysis and global PiB retention ratio through partial volume correction of CSF and tissue compartments using the co-registered 3D- MRI [Jack, et al.,2008
] (). The global PiB retention ratio was 1.68, which would be classified as “PiB positive” according to the typically used cut-off of 1.50 [Jack, et al.,2008
Representative slices from PiB-PET and FDG-PET images
The patient underwent numerous pharmacologic manipulations with cholinesterase inhibitors, levodopa, dopamine agonists, memantine, psychostimulants, and atypical neuroleptics, but these never resulted in any obvious clinical benefits. He died at age 77.
At autopsy, the brain weighed 1020g, had moderate to severe cortical atrophy, mild to moderate hippocampal atrophy, moderate lateral ventricular enlargement, and pallor of the substantia nigra. H&E showed severe nigral degeneration but no other abnormalities. Bielschowsky silver stained showed NFT were moderate in the hippocampus and entorhinal cortices, and absent in neocortical regions; and neuritic plaques were sparse in the midfrontal, middle temporal, and inferior parietal cortices corresponding to a Braak stage III neurofibrillary pathology and low likelihood of AD by NIA-Reagan criteria (). LB were found in the substantia nigra, entorhinal, anterior cingulate, midfrontal, middle temporal and inferior parietal cortices, consistent with a pathological diagnosis of DLB – neocortical type.
PiB retention ratio and the distribution and magnitude of AD and LB pathology in different brain regions of interest*
Aβ was more sensitive to plaques, compared to Bielshowsky silver stain (, ). Overall, the density of Aβ was greatest in the frontal lobes and lowest in the hippocampus (). Amyloid angiopathy was mild in the middle hippocampus, inferior parietal and lateral temporal cortex and absent in other regions. NFT density was greatest in the posterior hippocampus followed by middle hippocampus, entorhinal cortex and amygdala. LB were also most numerous in limbic regions but unlike NFT, were also widespread in the neocortex ().
Aβ plaques in midfrontal cortex sections
α-synuclein immunoreactive LBs and PHF-tau immunoreactive NFTs
Among the analyzed ROIs we identified the greatest PiB retention (PiB retention ratio >1.90), and Aβ density in the frontal lobe and medial parietal ROIs (). There was a strong correlation between PiB retention and Aβ density in the 17 ROIs that were analyzed on pathological examination using Spearman rank order correlation (r=0.899; p<0.0001) (). There was no correlation between LB density and PiB retention (r=0.13; p=0.66) (); nor between tau density and PiB retention (r=−0.36; p=0.17).
Correlation between Cortical PiB retention ratio and Aβ density
Correlation between Cortical PiB retention ratio and LB density