Erin Moran

Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.

Cerebrovascular deposition of β‐amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the β‐amyloid–binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes.

Imaging amyloid deposition in Lewy body diseases

Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; H&Y = Hoehn and Yahr; MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

Cognition, reserve, and amyloid deposition in normal aging.

To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.

Single photon emission computed tomography perfusion differences in mild cognitive impairment

Objective: To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI). Methods: Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc-HMPAO. Clinical outcome after a 5-year follow-up period was heterogeneous. Results: Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer’s disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer’s disease within the follow-up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer’s disease were also included for purposes of comparison. The group of patients with Alzheimer’s disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion. Conclusions: These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.

Psychosis of Alzheimer's disease: Gender differences in regional perfusion

We sought to determine whether the presence of psychotic symptoms in patients with Alzheimers disease is associated with abnormal regional cerebral function. Perfusion single photon emission computed tomography images from 51 AD patients with psychotic symptoms were compared to images of 52 AD patients without such symptoms. Group comparisons were made with a voxel-based method, Statistical Parametric Mapping. We found that perfusion was lower in female patients with psychotic symptoms in right infero-lateral prefrontal cortex and in inferior temporal regions compared to female patients without such symptoms. In contrast, perfusion was higher in male patients with psychotic symptoms in the right striatum compared to male patients without such symptoms. Comparison groups did not differ in age or in dementia severity, as estimated by the Mini-Mental State Examination (MMSE). These results support the role of right hemisphere prefrontal and lateral temporal cortex in the psychosis of AD in women but not in men, and raise the possibility that these dysfunctional processes have a gender-specific regional pathophysiology in AD.

Intelligence quotient-adjusted memory impairment is associated with abnormal single photon emission computed tomography perfusion

Cognitive reserve among highly intelligent older individuals makes detection of early Alzheimers disease (AD) difficult. We tested the hypothesis that mild memory impairment determined by IQ-adjusted norms is associated with single photon emission computed tomography (SPECT) perfusion abnormality at baseline and predictive of future decline. Twenty-three subjects with a Clinical Dementia Rating (CDR) score of 0, were reclassified after scores were adjusted for IQ into two groups, 10 as having mild memory impairments for ability (IQ-MI) and 13 as memory-normal (IQ-MN). Subjects underwent cognitive and functional assessments at baseline and annual follow-up for 3 years. Perfusion SPECT was acquired at baseline. At follow-up, the IQ-MI subjects demonstrated decline in memory, visuospatial processing, and phonemic fluency, and 6 of 10 had progressed to a CDR of 0.5, while the IQ-MN subjects did not show decline. The IQ-MI group had significantly lower perfusion than the IQ-MN group in parietal/precuneus, temporal, and opercular frontal regions. In contrast, higher perfusion was observed in IQ-MI compared with IQ-MN in the left medial frontal and rostral anterior cingulate regions. IQ-adjusted memory impairment in individuals with high cognitive reserve is associated with baseline SPECT abnormality in a pattern consistent with prodromal AD and predicts subsequent cognitive and functional decline.

P2-268: Amyloid deposition in presymptomatic familial Alzheimer’s disease

these parameters in brain and CSF and the influence of APOE genotype. Objectives: The aim of this study was to investigate the influence of APOE 4 genotype on brain functional changes in AD patients measured as cerebral glucose metabolism (CMRglc) and CSF levels of A 1-42 and Tau. Methods: The AD patient group, matched for age and education, consisted of 21 heterozygous and homozygous carriers (age 69.2 7.7, MMSE score 24.5 3.5, education 9.7 3.5 years, mean SD) and 13 non-carriers (age 68.0 9.2, MMSE score 26.0 4.3, education 11.1 3.0) of the APOE 4 allele. The AD patients were recruited from the Department of Geriatric Medicine at Karolinska University Hospital Huddinge, Stockholm, Sweden, where they underwent assessment for memory problems. They fulfil the diagnosis of probable AD according to NINCDS-ADRDA. CSF was obtained by lumbar puncture. For APOE 4 genotyping genomic DNA was extracted from peripheral blood and determined by standard PCR techniques. All subjects underwent F-flourodeoxyglucose (FFDG) PET scans at the Uppsala PET Centre, Uppsala. The PET data were analyzed using Patlak analysis in different Regions Of Interest (ROI). Results: AD patients with APOE 4 allele showed significantly lower levels of A 1-42 (329.43 131.50 pg/ml) compared to non-carriers (421.77 115.92 pg/ml, mean SD, p 0.05). No significant difference in CSF Tau was evinced in APOE 4 carriers (605.10 242.08 pg/ml) compared to non-carriers (531.23 233.60 pg/ml). A significant positive correlation was observed in 4 allele carriers between CMRglc in left inferior parietal cortex and A 1-42 in CSF (correlation factor 0.45, p 0.05) while no correlation between CMRglc and A 1-42 levels was observed in APOE 4 non-carriers. No significant correlation was observed between CMRglc and Tau in neither APOE 4 carriers nor in APOE 4 non-carriers. Conclusions: Combined studies of CSF and in vivo by brain PET can provide important information for early diagnostic markers of AD.

IC-103-03: Amyloid deposition in presymptomatic familial Alzheimer’s disease

Keith A. Johnson, Daniel Pollen, Dorene Rentz, Erin Moran, John Alex Becker, Majaz Moonis, Joan Swearer, Brad Hyman, Dennis Selkoe, Reisa Sperling, Steven DeKosky, Chet Matthis, William Klunk, Alan Fischman, Massachusetts General Hospital, Boston, MA, USA; University of Massachusetts, Worcester, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; University of Pittsburgh, Pittsburgh, PA, USA. Contact e-mail: kajohnson@partners.org