Guy B. Williams

Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia

Objective: To characterize and quantify the patterns of temporal lobe atrophy in AD vs semantic dementia and to relate the findings to the cognitive profiles. Medial temporal lobe atrophy is well described in AD. In temporal variant frontotemporal dementia (semantic dementia), clinical studies suggest polar and inferolateral temporal atrophy with hippocampal sparing, but quantification is largely lacking. Methods: A volumetric method for quantifying multiple temporal structures was applied to 26 patients with probable AD, 18 patients with semantic dementia, and 21 matched control subjects. Results: The authors confirmed the expected bilateral hippocampal atrophy in AD relative to controls, with involvement of the amygdala bilaterally and the right parahippocampal gyrus. Contrary to expectations, patients with semantic dementia had asymmetric hippocampal atrophy, more extensive than AD on the left. As predicted, the semantic dementia group showed more severe involvement of the temporal pole bilaterally and the left amygdala, parahippocampal gyrus (including the entorhinal cortex), fusiform gyrus, and the inferior and middle temporal gyri. Performance on semantic association tasks correlated with the size of the left fusiform gyrus, whereas naming appeared to depend upon a wider left temporal network. Episodic memory measures, with the exception of recognition memory for faces, did not correlate with temporal measures. Conclusions: Hippocampal atrophy is not specific for AD but is also seen in semantic dementia. Distinguishing the patients with semantic dementia was the severe global but asymmetric (left > right) atrophy of the amygdala, temporal pole, and fusiform and inferolateral temporal gyri. These findings have implications for diagnosis and understanding of the cognitive deficits in AD and semantic dementia.

Abnormal Brain Structure Implicated in Stimulant Drug Addiction

Nature or Drug Abuse? There are significant structural changes in striatal and prefrontal brain regions of stimulant drugdependent individuals. However, it is not clear if these brain abnormalities predate drug-taking, rendering individuals vulnerable for the development of dependence, or if these changes are the effect of many years of drug use. Ersche et al. (p. 601; see the Perpective by Volkow and Baler) investigated brain abnormalities in both drug-dependent individuals and in their biological siblings who have never taken drugs of abuse and compared them with matched healthy volunteers. The brain abnormalities in the sibling pairs were associated with significant impairments in the regulation of behavior; an ability known to be compromised in drug dependence. Because these neural changes were observed in family members who do not take drugs, the changes are likely to represent neurological markers of vulnerability to addiction rather than consequences of chronic drug abuse. A neurological marker of addiction vulnerability occurs in sibling pairs who do not take drugs. Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual’s health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates

Objective To investigate the effect of hyperventilation on cerebral blood flow in traumatic brain injury. Design A prospective interventional study. Setting A specialist neurocritical care unit. Patients Fourteen healthy volunteers and 33 patients within 7 days of closed head injury. Interventions All subjects underwent positron emission tomography imaging of cerebral blood flow. In patients, Paco2 was reduced from 36 ± 1 to 29 ± 1 torr (4.8 ± 0.1 to 3.9 ± 0.1 kPa) and measurements repeated. Jugular venous saturation (Sjvo2) and arteriovenous oxygen content differences (AVDO2) were monitored in 25 patients and values related to positron emission tomography variables. Measurements and Main Results The volumes of critically hypoperfused and hyperperfused brain (HypoBV and HyperBV, in milliliters) were calculated based on thresholds of 10 and 55 mL·100g−1·min−1, respectively. Whereas baseline HypoBV was significantly higher in patients (p < .05), baseline HyperBV was similar to values in healthy volunteers. Hyperventilation resulted in increases in cerebral perfusion pressure (p < .0001) and reductions in intracranial pressure (p < .001), whereas Sjvo2 (>50%) and AVDO2 (<9 mL/mL) did not exceed global ischemic thresholds. However, despite these beneficial effects, hyperventilation shifted the cerebral blood flow distribution curve toward the hypoperfused range, with a decrease in global cerebral blood flow (31 ± 1 to 23 ± 1 mL·100g−1·min−1;p < .0001) and an increase in HypoBV (22 [1–141] to 51 [2–428] mL;p < .0001). Hyperventilation-induced increases in HypoBV were apparently nonlinear, with a threshold value between 34 and 38 torr (4.5–5 kPa). Conclusions Hyperventilation increases the volume of severely hypoperfused tissue within the injured brain, despite improvements in cerebral perfusion pressure and intracranial pressure. Significant hyperperfusion is uncommon, even at a time when conventional clinical management includes a role for modest hyperventilation. These reductions in regional cerebral perfusion are not associated with ischemia, as defined by global monitors of oxygenation, but may represent regions of potentially ischemic brain tissue.

Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 ± 69 vs. 2 ± 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 ± 63 mL (mean ± 95% CI), which equates to 13 ± 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (ρ = −0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this “traumatic penumbra” is poorly detected by bedside clinical monitors and has significant associations with outcome.

The human perirhinal cortex and semantic memory

Studies in macaque monkeys indicate that the perirhinal cortex in the temporal lobe participates in object memory. This function may be analogous to aspects of human semantic memory (knowledge of objects, concepts, faces and words). To date, the status of perirhinal cortex has not specifically been investigated in patients with semantic deficits as seen in semantic dementia, the temporal lobe variant of frontotemporal dementia. High‐resolution three‐dimensional magnetic resonance imaging was performed in subjects with semantic dementia and Alzheimers disease (characterized in its early stages by selective episodic memory impairment) and in healthy age‐matched controls. Hippocampal, perirhinal, temporopolar and entorhinal cortex volumes were measured by outlining areas on successive scan slices according to recognized landmarks. The entorhinal and hippocampal regions were further subdivided into anterior and posterior parts. In keeping with the hypothesized contribution of the perirhinal cortex to semantic memory function, we found greater involvement of this region, together with the temporopolar and anterior entorhinal cortices, in semantic dementia than in either Alzheimers disease patients or control subjects. Performance on a range of semantic tests also correlated with perirhinal volume. Bilateral reduction in hippocampal volume compared with controls was seen in Alzheimers disease. In conclusion, atrophy of the human perirhinal cortex, and of directly connected areas, was associated with semantic memory impairment but not episodic memory impairment, as predicted from the primate work.

Diffusion tensor imaging in chronic head injury survivors: correlations with learning and memory indices

Diffusion tensor imaging (DTI) provides a unique insight into the cellular integrity of the brain. While conventional magnetic resonance imaging underestimates the extent of pathology following closed head injury, diffusion-weighted imaging has been shown to more accurately delineate the extent of cerebral damage. There have only been a few case studies of DTI in chronic head injury survivors. This study used DTI to investigate changes in anisotropy and diffusivity in survivors of head injury at least 6 months after their injury. The relationship between cognition and diffusion abnormality was also investigated. The voxel-based analysis revealed significant bilateral decreases in anisotropy, in major white matter tracts and association fibers in the temporal, frontal, parietal and occipital lobes. Statistically significant increases in diffusivity were also found in widespread areas of the cortex. A significant positive correlation was found between diffusivity and impairment of learning and memory in the left posterior cingulate, left hippocampal formation and left temporal, frontal and occipital cortex. The common pattern of abnormality despite heterogeneous injury mechanism and lesion location in the group suggests that these cellular changes reflect secondary insults. The importance of diffusion abnormalities in head injury outcome is emphasized by the significant correlation between a learning and memory index and diffusivity in areas known to subserve this cognitive function.

How Reliable Is Perfusion MR in Acute Stroke?: Validation and Determination of the Penumbra Threshold Against Quantitative PET

Background and Purpose— Perfusion magnetic resonance imaging (pMR) is increasingly used in acute stroke, but its physiologic significance is still debated. A reasonably good correlation between pMR and positron emission tomography (PET) has been reported in normal subjects and chronic cerebrovascular disease, but corresponding validation in acute stroke is still lacking. Methods— We compared the cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) maps generated by pMR (deconvolution method) and PET (15O steady-state method) in 5 patients studied back-to-back with the 2 modalities at a mean of 16 hours (range, 7 to 21 hours) after stroke onset. We also determined the penumbra thresholds for pMR-derived MTT, time to peak (TTP), and Tmax against the previously validated probabilistic PET penumbra thresholds. Results— In all patients, the PET and pMR relative distribution images were remarkably similar, especially for CBF and MTT. Within-patient correlations between pMR and PET were strong for absolute CBF (average r2=0.45) and good for MTT (r2=0.35) but less robust for cerebral blood volume (r2=0.24). However, pMR overestimated absolute CBF and underestimated MTT, with substantial variability in individual slopes. Removing individual differences by normalization to the mean resulted in much stronger between-patient correlations. Penumbra thresholds of ≈6, 4.8, and 5.5 seconds were obtained for MTT delay, TTP delay, and Tmax, respectively. Conclusions— Although derived from a small sample studied relatively late after stroke onset, our data show that pMR tends to overestimate absolute CBF and underestimate MTT, but the relative distribution of the perfusion variables was remarkably similar between pMR and PET. pMR appears sufficiently reliable for clinical purposes and affords reliable detection of the penumbra from normalized time-based thresholds.

Hyperventilation following head injury : Effect on ischemic burden and cerebral oxidative metabolism

Objective:To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. Design:A prospective interventional study. Setting:A specialist neurocritical care unit. Patients:Ten healthy volunteers and 30 patients within 10 days of closed head injury. Interventions:Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36 ± 3 and 29 ± 2 torr. Measurements and Main Results:We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17 ± 22 vs. 2 ± 3 mL; p ≤ .05), with worse matching of oxygen delivery to demand (p < .001). Hyperventilation consistently reduced cerebral blood flow (p < .001) and resulted in increases in oxygen extraction fraction and ischemic brain volume (17 ± 22 vs. 88 ± 66 mL; p < .0001), which were undetected by SjO2 monitoring. Mean CMRO2 was slightly increased following hyperventilation, but responses were extremely variable, with 28% of patients demonstrating a decrease in CMRO2 that exceeded 95% prediction intervals for zero change in one or more regions. CMRO2 correlated with cerebral electrophysiology, and cortical somatosensory evoked potential amplitudes were significantly increased by hyperventilation. Conclusions:The acute cerebral blood flow reduction and increase in CMRO2 secondary to hyperventilation represent physiologic challenges to the traumatized brain. These challenges exhaust physiologic reserves in a proportion of brain regions in many subjects and compromise oxidative metabolism. Such ischemia is underestimated by common bedside monitoring tools and may represent a significant mechanism of avoidable neuronal injury following head trauma.

White Matter Abnormalities in Patients With Obsessive-Compulsive Disorder and Their First-Degree Relatives

OBJECTIVE Obsessive-compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysconnectivity of large-scale brain systems. The extent of white matter abnormalities in OCD is unknown, and the genetic basis of this disorder is poorly understood. The authors used diffusion tensor imaging, a magnetic resonance imaging technique, for examining white matter abnormalities in brain structure through quantification of water diffusion, to confirm whether white matter abnormalities exist in OCD. They also explored whether such abnormalities occur in healthy first-degree relatives of patients, indicating they may be endophenotypes representing increased genetic risk for OCD. METHOD The authors used diffusion tensor imaging to measure fractional anisotropy of white matter in 30 patients with OCD, 30 unaffected first-degree relatives, and 30 matched healthy comparison subjects. Regions of significantly abnormal fractional anisotropy in patients in relation to healthy comparison subjects were identified by permutation tests. The authors assessed whether these abnormalities were also evident in the first-degree relatives. A secondary region-of-interest analysis was undertaken to assess the extent of replication between our data and previous relevant literature. RESULTS Patients with OCD demonstrated significantly reduced fractional anisotropy in a large region of right inferior parietal white matter and significantly increased fractional anisotropy in a right medial frontal region. Relatives also exhibited significant abnormalities of fractional anisotropy in these regions. CONCLUSIONS These findings indicate that OCD is associated with white matter abnormalities in parietal and frontal regions. Similar abnormalities in unaffected first-degree relatives suggest these may be white matter endophenotypes for OCD.

Neural correlates of semantic and behavioural deficits in frontotemporal dementia

Patients with frontotemporal dementia (FTD) can present with the clinical syndrome of semantic dementia due to a progressive loss of semantic knowledge or a neuropsychiatric syndrome characterised by aberrant social behaviours although frequently both co-exist. It has been assumed that the former is underpinned by damage to the temporal lobes and the latter, predominantly, by damage to the frontal lobes. Using the technique of voxel-based morphometry, we studied a group of FTD cases (n = 18) with a range of cognitive and neuropsychiatric features to correlate loss of semantic knowledge (as measured by the sum of two semantic tests) and aberrant behaviour (as measured by the neuropsychiatric inventory, NPI) with regional loss of grey matter volume. Semantic breakdown correlated with extensive loss of grey matter volume throughout the left anterior temporal lobe and less significantly with right temporal pole and subcallosal gyrus. Aberrant behaviour correlated with loss of grey matter volume in the dorso-mesial frontal lobe--paracingulate region, Brodmann areas 6/8/9--more so on the right. The frontal paracingulate correlation suggests that damage to this region may significantly contribute to the genesis of the behavioural syndrome seen in FTD.