William W. Barker

Cerebral metabolic effects of a verbal fluency test: A PET scan study

Sixteen normal volunteers were studied with [F-18] fluorodeoxyglucose and positron emission tomography scans during behavioral activation with a verbal fluency test, and 35 age-matched controls were studied with resting-state scans. There was an overall increase of the cerebral glucose metabolic rate of 23.3% during verbal fluency activation, compared to the resting state, with the greatest activation in bilateral temporal and frontal lobes. A negative correlation between test performance scores and indices of metabolism was found in frontal, temporal, and parietal regions. Damage to the left frontal lobe maximally affects scores on verbal fluency tests, but performing the test activates a network of regions, of which the left frontal lobe is only one. Proficient performance in verbal fluency seems to require less metabolic activation than poor performance, perhaps because of the efficiency of cognitive strategies employed.

Sensitivity of Cerebral Glucose Metabolism to Age, Gender, Brain Volume, Brain Atrophy, and Cerebrovascular Risk Factors

In 76 normal volunteers studied by positron emission tomography, with [18F]fluorodeoxyglucose, CMRglu was significantly lower in the elderly as compared with young subjects and significantly higher in females relative to males. However, in 58 of these subjects who also had magnetic resonance imaging scans, age and gender were found to be unrelated to CMRglu, when the effects of brain volume and brain atrophy on CMRglu were partialed out using covariate analyses. Individually, brain volume was found to have a significant effect on CMRglu, explaining ∼17% of the variability in CMRglu measures and brain atrophy explaining ∼8% of the variance in CMRglu. Together these two measures accounted for ∼21% of the variance. Cerebrovascular risk factors in normal subjects were not found to affect mean CMRglu or the variability of CMRglu measures. In this study almost 80% of the variance in CMRglu could not be explained by any of the factors that had been considered. This implies a lack of sensitivity of absolute values of global CMRglu to the mild effects of brain dysfunction. Although some of the unexplained variance is probably methodological in origin, physiological factors that are difficult to quantify, such as the state of arousal, are likely to be contributory as well.

Sensitivity and Specificity of Positron Emission Tomography and Magnetic Resonance Imaging Studies in Alzheimer’s Disease and Multi-Infarct Dementia

Positron emission tomographic (PET) scans using [18F]-fluorodeoxyglucose and magnetic resonance imaging (MRI) scans were quantitatively analyzed for metabolic and structural abnormalities in normal subjects and patients classified as having Alzheimers disease (AD), mixed dementia and multi-infarct dementia (MID) according to Hachinski ischemic scores. MRI-detected abnormalities in the periventricular white matter and in subcortical locations increased in incidence with age in normals and increased markedly in AD and especially in MID. Upper limits for the severity of these white matter lesions could be defined only for normal young and elderly subjects, but not for AD, mixed or MID patients. PET scan abnormalities occurred in about 90% of demented patients and in 54% of elderly and 34% of young normals. There was no characteristic pattern of abnormality that distinguished MID from AD patients. It is concluded that PET and MRI studies in demented patients are useful ancillary tests especially in evaluating the mild, questionably demented subject and for assessing the functional impact of structural disease.

Semantic Interference in Mild Alzheimer Disease: Preliminary Findings

OBJECTIVEnThe authors evaluated the usefulness and psychometric properties of the Semantic Interference Test (SIT) in patients with mild Alzheimer disease (AD).nnnMETHODSnSubjects were first presented with 10 common objects to be learned over three trials. Proactive interference was assessed by having subjects recall 10 new objects that were semantically related to the previous ones. Retroactive interference was assessed by having subjects recall the original 10 objects.nnnRESULTSnControlling for overall memory impairment, very mildly impaired AD patients demonstrated significantly greater proactive and retroactive interference effects than the normal, community-dwelling comparison group. The proactive score alone and the combined proactive-plus-retroactive score index were more effective than traditional neuropsychological measures of delayed recall in distinguishing between the very mildly impaired AD group and the normal-comparison group.nnnCONCLUSIONnThe authors discuss the potential usefulness of the SIT in identifying vulnerability to semantic interference in early AD.

Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness

BACKGROUNDnAccumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimers disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory.nnnOBJECTIVESnWe focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI).nnnMETHODSnThirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions.nnnRESULTSnSI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models.nnnCONCLUSIONnSemantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.

Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment

Objective Semantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition. Methods Eighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy−), or other neurological/psychiatric diagnosis (Amy−). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning). Results SIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP. Conclusions SIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy− participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.