Dennis Chan

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimers disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimers disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimers disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimers disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimers disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442

Automatic differentiation of anatomical patterns in the human brain: Validation with studies of degenerative dementias

We compared voxel-based morphometry (VBM) with independent accurate region-of-interest (ROI) measurements of temporal lobe structures in order to validate the usefulness of this fully automated and unbiased technique in Alzheimers disease (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses appear more sensitive to left middle and inferior temporal gyrus volume loss, whereas VBM appears more sensitive to regional hippocampal volume loss. In addition the significance of volume reductions was generally less in VBM owing to more stringent corrections for multiple comparisons. In conclusion, the automated technique detects a general trend of atrophy similar to that of expertly labeled ROI measurements in AD and SD, although there are discrepancies in the ranking of severity and in the significance of volume reductions that are more marked in AD.

Long-term retrograde amnesia… the crucial role of the hippocampus

For patients with hippocampal pathology, disagreement exists in the literature over whether retrograde amnesia is temporally limited or very extensive depending on whether the anatomical damage is restricted to this structure or also involves additional temporal cortex. We report a comprehensive assessment of retrograde and anterograde memory functions of a severely global amnesic patient (VC). We found that he presented with a remarkably extensive and basically ungraded retrograde amnesia. This impairment profoundly affected four decades preceding the onset of his amnesia and encompassed both non personal and personal facts and events. VC also presented with a severe anterograde amnesia and a deficit in the acquisition of new semantic knowledge in the post-morbid period. Detailed MRI volumetric measurements revealed gross abnormalities in both hippocampi which were markedly shrunken. Of relevance to the debate on retrograde amnesia were the observations that the volumes of both entorhinal cortices and the remainder of both temporal lobes were normal. These data suggest that the hippocampus is critical not only for the efficient encoding and hence normal recall of new information but also for the recall of episodic information acquired before the onset of amnesia. Our results are compatible with the view that retrograde amnesia is both extensive and ungraded when the damage is limited to the hippocampus.

Rates of global and regional cerebral atrophy in AD and frontotemporal dementia

Objective: Serial registered MRI provides a reproducible technique for detecting progressive cerebral atrophy in vivo and was used to determine if there were differences between the rates of cerebral atrophy in AD and frontotemporal dementia (FTD). Methods: Eighty-four patients with dementia (54 AD and 30 FTD) and 27 age-matched control subjects each had at least two volumetric MR scans. Serial scans were positionally matched (registered), and brain volume loss was determined by calculation of the brain boundary shift integral. Results: There was a difference between the rates of whole-brain atrophy in patients (mean annual volume loss 2.7% of total brain volume) and in control subjects (mean annual volume loss 0.5%). AD and FTD were associated with different rates of atrophy (mean annual losses 2.4 and 3.2%). The range of atrophy rates in the FTD group (0.3 to 8.0%) greatly exceeded that in the AD group (0.5 to 4.7%). Frontal-variant FTD was associated with a wider range of atrophy rates than temporal-variant FTD. Analysis of regional brain atrophy rates revealed that there was widespread symmetrically distributed cerebral volume loss in AD, whereas in frontal FTD there was greater atrophy anteriorly and in temporal FTD the atrophy rate was greatest in the left anterior cerebral cortex. Conclusions: Both AD and FTD patients had increased rates of brain atrophy. Whereas the patients with AD were associated with a relatively restricted spread of atrophy rates, the greater spread of rates observed in the patients with FTD may reflect the heterogeneity of disease in FTD, with differences observed between frontal and temporal FTD. Increased rates of whole-brain atrophy did not discriminate AD from FTD, but analysis of regional atrophy rates revealed marked differences between patient groups.

Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study

The extent to which cerebral atrophy in Alzheimers disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimers disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimers disease.

Assessing the onset of structural change in familial Alzheimer's disease.

Regional and global cerebral atrophy are inevitable features of Alzheimers disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3–28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0–7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7–7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms. Ann Neurol 2003;53:000–000

Atrophy patterns in Alzheimer's disease and semantic dementia: A comparison of FreeSurfer and manual volumetric measurements

Alzheimers disease (AD) and semantic dementia (SD) are characterized by different patterns of global and temporal lobe atrophy which can be studied using magnetic resonance imaging (MRI). Manual delineation of regions of interest is time-consuming. FreeSurfer is a freely available automated technique which has a facility to label cortical and subcortical brain regions automatically. As with all automated techniques comparison with existing methods is important. Eight temporal lobe structures in each hemisphere were delineated using FreeSurfer and compared with manual segmentations in 10 control, 10 AD, and 10 SD subjects. The reproducibility errors for the manual segmentations ranged from 3% to 6%. Differences in protocols between the two methods led to differences in absolute volumes with the greatest differences between methods found bilaterally in the hippocampus, entorhinal cortex and fusiform gyrus (p<0.005). However, good correlations between the methods were found for most regions, with the highest correlations shown for the ventricles, whole brain and left medial-inferior temporal gyrus (r>0.9), followed by the bilateral amygdala and hippocampus, left superior temporal gyrus, right medial-inferior temporal gyrus and left temporal lobe (r>0.8). Overlap ratios differed between methods bilaterally in the amygdala, superior temporal gyrus, temporal lobe, left fusiform gyrus and right parahippocampal gyrus (p<0.01). Despite differences in protocol and volumes, both methods showed similar atrophy patterns in the patient groups compared with controls, and similar right-left differences, suggesting that both methods accurately distinguish between the three groups.

Topographical Short-Term Memory Differentiates Alzheimer's Disease From Frontotemporal Lobar Degeneration

We used a recently developed test of spatial memory—the Four Mountains Test—to investigate the core cognitive processes underpinning topographical disorientation in patients with amnestic mild cognitive impairment (a‐MCI) and mild Alzheimers disease (AD). Performance of these clinical groups was compared with age‐matched controls, patients with frontotemporal lobar degeneration (FTLD), and patients with subjective memory impairments. We investigated the perception (concurrent match‐to‐sample) and short‐term retention (2‐s delayed match‐to‐sample) of the configuration of topographical features in computer‐generated landscapes shown from different viewpoints. Thirty‐one patients were tested (7 AD, 6 a‐MCI, 7 temporal variant FTLD, 5 frontal variant FTLD, 6 subjective memory impairment) and 25 age‐ and gender‐matched controls. Brain MRI was available for 27 patients; medial temporal lobe atrophy was assessed using a visual rating scale. Patients with a‐MCI or mild AD were impaired on topographical short‐term memory, but not perception. No other group differences were found on the topographical subtests. Notably, patients with temporal variants of FTLD performed normally, regardless of the laterality of damage. Subtests for the perception and retention of nonspatial aspects of the landscapes (weather conditions, seasonal and daily variations in lighting and color) were poor at differentiating the patient groups. These results indicate a core deficit in representing topographical layout, even for very short durations, within the context of more general long‐term memory impairments found in AD, and suggest that this function is particularly sensitive to the earliest stages of the disease.

Epilepsy presenting as AD: Neuroimaging, electroclinical features, and response to treatment

Three patients with progressive memory impairment initially attributed to AD underwent serial neuropsychometry, MRI, and EEG. Registered serial MRI volumetric analysis showed no loss of whole or regional brain volume. EEG revealed temporal lobe spike activity and antiepileptic treatment was optimized. Memory functions improved with antiepileptic medication in all three patients. The demonstration of temporal lobe spike activity in patients with progressive memory impairment is an indication for a trial of antiepileptic medication.

EEG abnormalities in frontotemporal lobar degeneration

The EEG appearances in patients with frontotemporal lobar degeneration (FTLD) were compared with those in patients with Alzheimer disease (AD). EEG abnormalities were found in 61% of FTLD patients, with the degree of EEG abnormality increasing with dementia severity. There was no significant difference in the severity of EEG abnormality between the FTLD and AD patient groups. These data suggest a need for reappraisal of the role of the EEG in the diagnostic differentiation of FTLD from AD.