John A. Becker

Preclinical prediction of Alzheimer's disease using SPECT

Background Regional cerebral perfusion measured by single photon emission computed tomography (SPECT) was examined as a preclinical predictor of the development of Alzheimers disease (AD). Methods Singular value decomposition was used to produce 20 SPECT factors (known as vectors) (n = 152). Vector scores were then computed for four groups (n = 136), differing in cognitive status: Group 1-normal controls at both baseline and follow-up; Group 2-subjects with “questionable” AD at both baseline and follow-up; Group 3-subjects with questionable AD at baseline who converted to AD on follow-up (Converters); Group 4-subjects with AD at baseline. All SPECT data in the analyses were gathered at baseline. Results The four groups could be distinguished on the basis of their baseline SPECT data (p < 0.00005; hit rate = 83%). Regional decreases in perfusion were most prominent among Converters in the hippocampal-amygdaloid complex, the posterior cingulate, the anterior thalamus, and the anterior cingulate. Inclusion of apolipoprotein E status did not significantly improve the discrimination. Conclusions SPECT data gathered and analyzed in this manner may be useful as one aspect of the preclinical prediction of AD. Three of the four brain regions important for discriminating Converters from normal controls involve a distributed brain network pertaining to memory, suggesting that this network may be selectively affected in the earliest stages of AD.

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.

Spatial Relation between Microbleeds and Amyloid Deposits in Amyloid Angiopathy

Advanced cerebrovascular β‐amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. We used T2*‐weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On coregistered positron emission tomography (PET) and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p = 0.002) and declined with increasing distance from the microbleed (p < 0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition. Ann Neurol 2010

Cognitive Profile of Amyloid Burden and White Matter Hyperintensities in Cognitively Normal Older Adults

Amyloid burden and white matter hyperintensities (WMH) are two common markers of neurodegeneration present in advanced aging. Each represents a potential early indicator of an age-related neurological disorder that impacts cognition. The presence of amyloid is observed in a substantial subset of cognitively normal older adults, but the literature remains equivocal regarding whether amyloid in nondemented populations is deleterious to cognition. Similarly, WMH are detected in many nondemented older adults and there is a body of evidence indicating that WMH are associated with decreased executive function and other cognitive domains. The current study investigated amyloid burden and WMH in clinically normal older adult humans aged 65–86 (N = 168) and examined each biomarkers relation with cognitive domains of episodic memory, executive function, and speed of processing. Factors for each domain were derived from a neuropsychological battery on a theoretical basis without reference to the relation between cognition and the biomarkers. Amyloid burden and WMH were not correlated with one another. Age was associated with lower performance in all cognitive domains, while higher estimated verbal intelligence was associated with higher performance in all domains. Hypothesis-driven tests revealed that amyloid burden and WMH had distinct cognitive profiles, with amyloid burden having a specific influence on episodic memory and WMH primarily associated with executive function but having broad (but lesser) effects on the other domains. These findings suggest that even before clinical impairment, amyloid burden and WMH likely represent neuropathological cascades with distinct etiologies and dissociable influences on cognition.

Detection of isolated cerebrovascular β-amyloid with pittsburgh compound B†

Imaging of cerebrovascular β‐amyloid (cerebral amyloid angiopathy) is complicated by the nearly universal overlap of this pathology with Alzheimers pathology. We performed positron emission tomographic imaging with Pittsburgh Compound B on 42‐year‐old man with early manifestations of Iowa‐type hereditary cerebral amyloid angiopathy, a form of the disorder with little or no plaque deposits of fibrillar β‐amyloid. The results demonstrated increased Pittsburgh Compound B retention selectively in occipital cortex, sparing regions typically labeled in Alzheimers disease. These results offer compelling evidence that Pittsburgh Compound B positron emission tomography can noninvasively detect isolated cerebral amyloid angiopathy before overt signs of tissue damage such as hemorrhage or white matter lesions. Ann Neurol 2008;64:587–591

Reversible cerebral hypoperfusion in Lyme encephalopathy

Lyme encephalopathy (LE) presents with subtle neuropsychiatric symptoms months to years after onset of infection with Borrelia burgdorferi. Brain magnetic resonance images are usually normal. We asked whether quantitative single photon emission computed tomography (SPECT) is a useful method to diagnose LE, to measure the response to antibiotic therapy, and to determine its neuroanatomic basis. In 13 patients with objective evidence of LE, SPECT demonstrated reduced cerebral perfusion (mean perfusion defect index [PDI] = 255), particularly in frontal subcortical and cortical regions. Six months after treatment with 1 month of intravenous ceftriaxone, perfusion significantly improved in all 13 patients (mean PDI = 188). In nine patients with neuropsychiatric symptoms following Lyme disease, but without objective abnormalities (e.g., possible LE), perfusion was similar to that of the treated LE group (mean PDI = 198); six possible LE patients (67%) had already received ceftriaxone prior to our evaluation. Perfusion was significantly lower in patients with LE and possible LE than in 26 normal subjects (mean PDI = 136), but 4 normal subjects (15%) had low perfusion in the LE range. We conclude that LE patients have hypoperfusion of frontal subcortical and cortical structures that is partially reversed after ceftriaxone therapy. However, SPECT cannot be used alone to diagnose LE or determine the presence of active CNS infection.

Age and amyloid-related alterations in default network habituation to stimulus repetition.

The neural networks supporting encoding of new information are thought to decline with age, although mnemonic techniques such as repetition may enhance performance in older individuals. Accumulation of amyloid-β, one hallmark pathology of Alzheimers disease (AD), may contribute to functional alterations in memory networks measured with functional magnetic resonance imaging (fMRI) prior to onset of cognitive impairment. We investigated the effects of age and amyloid burden on fMRI activity in the default network and hippocampus during repetitive encoding. Older individuals, particularly those with high amyloid burden, demonstrated decreased task-induced deactivation in the posteromedial cortices during initial stimulus presentation and failed to modulate fMRI activity in response to repeated trials, whereas young subjects demonstrated a stepwise decrease in deactivation with repetition. The hippocampus demonstrated similar patterns across the groups, showing task-induced activity that decreased in response to repetition. These findings demonstrate that age and amyloid have dissociable functional effects on specific nodes within a distributed memory network, and suggest that functional brain changes may begin far in advance of symptomatic Alzheimers disease.

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.