The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer's disease: A comparative neuropsychological study.

The authors compared age-matched groups of patients with the frontal and temporal lobe variants of frontotemporal dementia (FTD; dementia of frontal type [DFT] and semantic dementia), early Alzheimer's disease (AD), and normal controls (n?=?9 per group) on a comprehensive neuropsychological battery. A distinct profile emerged for each group: Those with AD showed a severe deficit in episodic memory with more subtle, but significant, impairments in semantic memory and visuospatial skills; patients with semantic dementia showed the previously documented picture of isolated, but profound, semantic memory breakdown with anomia and surface dyslexia but were indistinguishable from the AD group on a test of story recall; and the DFT group were the least impaired and showed mild deficits in episodic memory and verbal fluency but normal semantic memory. The frontal and temporal presentations of FTD are clearly separable from each other and from early AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease

OBJECTIVE: Cerebral parietal hypometabolism and left-right asymmetry occur early in the course of Alzheimer disease (AD), and the apolipoprotein E type 4 allele (APOE epsilon 4) is a risk factor for familial AD. To determine if APOE epsilon 4 is associated with lowered brain function in nondemented relatives at risk for familial AD, we studied 12 relatives with APOE epsilon 4 and 19 relatives without APOE epsilon 4. We also compared them with seven patients with probable AD. DESIGN: After grouping subjects according to diagnosis and genotype, brain function measures were compared among groups. SETTING: University medical center. PATIENTS: At risk subjects had mild memory complaints, normal cognitive performance, and at least two relatives with AD. Subjects with APOE epsilon 4 did not differ from those without APOE epsilon 4 in mean age at examination (56.4 vs 55.5 years) or in neuropsychological performance (mean Mini-Mental State Examination score, 28.8 vs 29.3). MAIN OUTCOME MEASURES: Cerebral glucose metabolism was measured using positron emission tomography and fludeoxyglucose F 18. RESULTS: Parietal metabolism was significantly lower and left-right parietal asymmetry was significantly higher in at-risk subjects with APOE epsilon 4 compared with those without APOE epsilon 4. Patients with dementia had significantly lower parietal metabolism than did at-risk subjects with APOE epsilon 4. CONCLUSIONS: These results suggest that the inheritance of APOE epsilon 4 is associated with reduced cerebral parietal metabolism and increased asymmetry in non-demented relatives at risk for probable AD. Longitudinal study will determine if glucose metabolic measures provide a means to monitor experimental treatment responses during the early phases of the disorder.     

Fluency and memory differences between ischemic vascular dementia and Alzheimer's disease.

This study compared 32 patients with ischemic vascular dementia (IVD) to 32 patients with probable Alzheimer's disease (AD) on select language and verbal memory tests. The IVD and AD patients were individually matched on the basis of age, dementia severity, years of education, and gender. The IVD patients had poorer verbal fluency, but better free recall, fewer recall intrusions, and better recognition memory than the AD patients. Relationships between the neuropsychological measures and radiological indexes of cortical and subcortical pathology were also examined. Number of infarcts, white-matter lucency, and ventricular enlargement correlated with some of the neuropsychological measures; cortical atrophy correlated with most of the measures. The findings suggest that neuropsychological deficits in IVD may be related to dysfunction of frontal-subcortical circuits, although an associated degenerative cortical process may also be involved. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological, psychiatric, and cerebral blood flow findings in vascular dementia and Alzheimer's disease

BACKGROUND AND PURPOSE: Psychiatric, neuropsychological, and cerebral blood flow differences between patients with ischemic vascular dementia (IVD) or Alzheimer's disease (AD) were examined. METHODS: A consecutive series of patients who met either the criteria of the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association for probable AD or the State of California AD Diagnostic and Treatment Centers criteria for probable IVD were included in the study. Twenty consecutive patients with IVD were matched for age, sex, and Mini-Mental State Examination scores with 40 consecutive patients with probable AD. Patients underwent a psychiatric interview, a neuropsychological assessment, and single-photon emission CT imaging with 99mTc-hexamethylpropyleneamine oxime. RESULTS: Patients with IVD showed significantly more severe anosognosia (P<.05) and emotional lability (P<.01) than AD patients, but no significant between-group differences were found in the frequency and severity of depression. IVD patients showed significantly more severe deficits in tests of planning, sequencing (P<.05), and verbal fluency (P<.05) as well as significantly more severe cerebral blood flow deficits in the basal ganglia (P<.01) and the frontal lobes (P<.001) than AD patients. CONCLUSIONS: Patients with IVD showed a relatively more severe dysfunction of the frontal lobes as demonstrated by single-photon emission CT and expressed in specific psychiatric and neuropsychological changes than AD patients matched for age, sex, and severity of dementia.     

Comparison of neuropsychological functioning in Alzheimer's disease and frontotemporal dementia

Neuropsychological changes distinguishing mild Alzheimer's disease (AD) from frontotemporal dementia (FTD) have been described, but empirical verification of differential cognitive characteristics is lacking. Archival neuropsychological data on 15 FTD patients, 16 AD patients, and 16 controls were compared. Controls outperformed both patient groups on measures of verbal and nonverbal memory, executive ability, and constructional skill, with AD patients showing more widespread memory decline. No differences were found between the 3 groups in confrontation naming, recognition memory, or basic attention. Patient groups differed only in nonverbal memory, with FTD patients performing significantly better than AD patients. However, patient groups also differed in pattern of performance across executive and memory domains. Specifically, AD patients exhibited significantly greater impairment on memory than executive tasks, whereas the opposite pattern characterized the FTD group. These findings suggest that examination of relative rankings of scores across cognitive domains, in addition to interpretation of individual neuropsychological scores, may be useful in differential diagnosis of FTD versus AD.     

Hippocampal sclerosis contributes to dementia in the elderly

OBJECTIVE: To assess the relevance of hippocampal sclerosis (HS) to dementia in the elderly. BACKGROUND: HS is a prominent pathologic finding in some demented elderly, but the anatomic substrate and cognitive profiles of this dementia have not been well established. DESIGN/METHODS: An autopsy series, including dot-immunobinding assay to estimate neocortical synaptic density, of eight patients (three men, five women) with HS on whom extensive antemortem neuropsychological testing was available. RESULTS: Mean age at onset was 72.0 (+/-9.8) (range, 59 to 89) with a mean duration of symptoms of 6.5 (+/-2.9) years. Patients were only mildly impaired with a mean MMSE of 20.9 (+/-4.9) and a mean DRS of 103.1 (+/-12.5) at presentation. Cardiovascular disease was present in 88%, with a mean Hachinski score of 3.4 (+/-2.2). No patient had a history of seizures. Sixty-three percent had depression or depressive symptoms. Neuropsychologically, most patients presented with prominent memory and language deficits and became progressively demented. Neuropathologically, isolated HS was a rare finding; many patients had either very mild or neocortical "plaque only or plaque predominant" Alzheimer's disease (AD) in addition to HS changes. Midfrontal neocortical synaptophysin counts were significantly reduced in all HS patients compared with controls (p = 0.0006). CONCLUSIONS: In the elderly, HS can be a neuropathologic substrate of dementia. Clinically, it can be associated with a course that is difficult to distinguish from AD although cardiac disease and depression are frequent concomitants. Deterioration of cognitive function in these subjects may relate to other pathologic features such as neocortical synapse loss.     

Neuropsychological effects of closed head injury in older adults: A comparison with Alzheimer's disease.

In this study, neuropsychological profiles of 14 older adult patients with mild or moderate closed head injury (CHI). 14 patients with probable Alzheimer's disease (AD), and 14 community residing elderly controls were compared. The groups were similar in demographic features, and the CHI and AD patients had comparable Mini-Mental State Examination scores. Tests of verbal learning and memory, letter and category fluency, and naming were administered. Relative to the CHI group, AD patients exhibited more devastated memory and did not show a normal facilitation on the category retrieval task. The patient groups exhibited similar levels of categorical clustering and naming accuracy for both high- and low-frequency words. These results suggest that neuropsychological markers of memory and semantic processing may be useful in differentiating the cognitive effects from AD versus early recovery from CHI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Heterogeneity of protein profiles of Helicobacter pylori isolated from individual patients

A standardized neuropsychological test battery was administered to 167 patients with different forms of mild-to-moderate dementia: probable Alzheimer dementia (AD: n = 49), multi-infarct dementia (n = 43), idiopathic Parkinson disease with dementia (n = 35), depressive pseudodementia (n = 26), and progressive supranuclear palsy (n = 14). Results obtained were used (a) to analyze the profiles of cognitive impairment shown by the different dementia groups; (b) to assess the incidence of some neuropsychological patterns that we hypothesized to be more characteristic of AD, in the various groups; and hence (c) to evaluate the reliability of these patterns as diagnostic markers of AD. Four of the patterns investigated were derived from a verbal learning task (Rey's Auditory Verbal Learning test): (1) absence of the primacy effect; (2) tendency to produce intrusion errors during free recall of a word list; (3) absolute decay of memory trace; and (4) tendency to produce false alarms during delayed recognition of the same word list. Two additional patterns were derived from visual-spatial tasks (copying drawings and Raven's Coloured Progressive Matrices): (5) occurrence of the closing-in phenomenon in copying drawings; and (6) tendency to choose globalistic or odd responses in Raven's matrices. Though all the six patterns were somewhat useful for identifying AD patients, no pattern met the criteria of being both highly sensitive and highly specific, which should characterize an ideal marker. In fact, intrusions and false alarms were observed in many AD patients, but also in patients affected by other forms of dementia. The absence of the primacy effect, the closing-in phenomenon, and the absolute decay of memory trace were more specific, but could be observed in only one-third of AD patients. We also computed the number of positive patterns shown by each patient and assumed the presence of two or more patterns as a global index suggestive of a dementia of the Alzheimer type. With this cumulative method, a higher level of sensitivity and specificity was achieved in the identification of AD patients.     

Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease

Brain lesions have been reported with increasing frequency in the delusional misidentification syndromes (DMS). This is the first controlled study to describe DMS regional cerebral metabolic rates of glucose (rCMRglc). We compared rCMRglc (using positron emission tomography) and neuropsychological data in 9 patients with DMS and Alzheimer dementia (AD), 15 AD patients without DMS, and 17 healthy controls. The DMS group differed from the AD group without DMS in having significant hypometabolism in paralimbic (orbitofrontal and cingulate areas bilaterally) and left medial temporal areas, and significant bilateral normalized hypermetabolism in sensory association cortices (superior temporal and inferior parietal) without right left asymmetry. Compared to healthy controls, both AD groups had significant dorso lateral frontal hypometabolism bilaterally. No specific DMS neuropsychological profile was identified. Dysfunctional connections among multimodal association areas, paralimbic structures, and dorsolateral frontal cortex are proposed as the predisposing neural deficit underlying DMS, causing cognitive-perceptual-affective dissonance, which under specific conditions results in "positive" delusion formation.     

Perseverative behavior in Alzheimer's disease and subcortical ischemic vascular dementia.

Perseverative behavior has not been extensively studied in patients with dementia. In this study, perseverative behavior was elicited with the dementia version of the Graphical Sequence Test. A control group and participants with Alzheimer's disease (AD) and subcortical ischemic vascular dementia (IVD) were studied. A factor analysis revealed a 3-factor model consisting of perseverations related to semantic knowledge, motor functioning, and a third, intermediary factor. IVD participants made more total perseverations than did AD participants. Perseverations made by AD participants were correlated with deficits on tests of semantic knowledge, whereas the perseverations made by IVD participants were correlated with motor and frontal systems tests. Results are consistent with the view that perseverative behavior is hierarchically arranged in terms of specific levels of cognitive complexity and the overall pattern of cognitive deficits associated with each type of dementia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory in mild Alzheimer's disease and early Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) impair working memory (WM). It is unclear, however, whether the deficits seen early in the course of these diseases are similar. To address this issue, the authors compared the performance of 22 patients with mild AD, 20 patients with early PD and without dementia, and 112 control participants on tests of inhibition, short-term memory, and 2 commonly administered tests of WM. The results suggest that although mild AD and early PD both impair WM, the deficits may be related to the interruption of different processes that contribute to WM performance. Early PD disrupted inhibitory processes, whereas mild AD did not. The WM deficits seen in patients with AD may be secondary to deficits in other cognitive capacities, including semantic memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory evaluation in Alzheimer's disease. Caregivers' appraisals and objective testing

OBJECTIVES: To evaluate if caregivers are reliable informants concerning memory deficits in patients with Alzheimer's disease (AD). DESIGN: Responses of caregivers of patients with probable AD and responses of healthy control subjects on a standardized memory questionnaire were compared with objective measures of cognition (Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery) and with clinical estimates of activities of daily living, depression, and psychopathology (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] clinical assessment battery) using the Self-report Memory Questionnaire. SETTING: A federally funded AD research center. SUBJECTS: The referred sample included 117 patients with probable AD, their informants, and 41 healthy control subjects age-matched to the patients. Patients and control subjects were between the ages of 58 and 85 years, had between 9 and 19 years of education, and were in good health. EXCLUSIONS: Patients who did not meet NINCDS-ADRDA criteria of probable AD. MAIN OUTCOME MEASURE: The optimal number of questionnaire items yielding the best combination of sensitivity and specificity. RESULTS: An abbreviated version of the scale, renamed the Short-Memory Questionnaire, had excellent specificity and sensitivity for identifying dementia. Positive and negative predictive values were 63.5% and near 100%, respectively. The Short-Memory Questionnaire showed good reliability, internal consistency, and external validity. Caregiver appraisals of memory deficits significantly correlated with objective measures of memory and also with generalized cognitive dysfunction. CONCLUSIONS: Caregivers of patients with AD are reliable informants of their relatives' deficits. The Short-Memory Questionnaire is an easily administered, informant-based scale that may be useful in clinical settings or epidemiologic studies to screen out persons with memory difficulties.     

Utility of ischemic scores in the differential diagnosis of Alzheimer's disease and ischemic vascular dementia

Despite new developments in the concept of vascular dementia, the Hachinski Ischemic Score (HIS) and its modified versions continue to be widely used in the clinical differentiation of Alzheimer's disease (AD) and ischemic vascular dementia (IVD). The sensitivity of the HIS and two modified versions in the diagnosis of AD, IVD, and single infarcts in a large, geriatric population with mild cognitive impairment (N = 100) was evaluated. Sensitivity for identification of AD was greater than 90% but was less than 70% for IVD. Over one third of patients with one or more infarcts on computed tomographic brain scans and 63% of mixed cases were classified as having probable AD. It is concluded that ischemic scores may be useful at predicting prevalence rates if individual case accuracy is ignored. Despite being sensitive to identifying AD, ischemic scores are insensitive to both cerebral infarction and IVD and cannot reliably exclude IVD. Finally, patients with mixed dementia should not be expected to have intermediate scores.     

Do neuropsychological tests detect preclinical Alzheimer's disease: Individual-test versus cognitive-discrepancy score analyses.

Attempts to identify cognitive markers of a preclinical phase of Alzheimer's disease (AD) have yielded inconsistent findings. The problem may stem in part from methodologies that are insensitive to potential subgroups within the at-risk, preclinical AD population (PCAD). The present study investigated the utility of asymmetric cognitive profiles in identifying individuals at risk for AD. Twenty elderly adults who were later diagnosed with AD (PCAD) and 20 matched control participants were compared on measures of cognitive asymmetry derived from difference scores on tests of verbal and visuospatial ability. Although both groups performed similarly on the individual tests, comparisons using difference scores revealed significantly larger discrepancies between naming and visuoconstruction skills in the PCAD group. Ile PCAD group also had a higher frequency of asymmetric cognitive profiles relative to a normative group. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visuoconstructional problems in dementia: Contribution of executive systems functions.

Visuoconstructional ability was assessed by asking patients diagnosed with Alzheimer's disease (AD), ischaemic vascular dementia (IVD), and Parkinson's disease (PD) and a normal control group (NC) to copy a modification of the Rey–Osterrieth Complex Figure (M–ROCF). The drawings of the NC group were superior to all dementia participants. AD patients generally outperformed LVD and PD patients; however, there were few differences between LVD and PD groups. Nonetheless, the drawings of LVD and PD patients were very fragmented and contained numerous perseverations and omissions. Despite these errors, patients with LVD and PD obtained higher delayed recognition memory scores than AD patients. Correlational analyses among dementia patients between neuropsychological tests and the copy of the M–ROCF found that accurate figure copy was most consistently correlated with tests of working memory, that is, tests requiring patients to monitor their behavior and sustain a complex mental set while performing mental manipulations. By contrast, no relationship between executive function tests related to measures of response selection/inhibition or other domains of neuropsychological functioning was found. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Performance of everyday actions in mild Alzheimer's disease.

Early neuropsychological deficits associated with mild Alzheimer's disease (AD) have been characterized as memory deficits and impaired executive function or attention. The functional impact of early impairment was investigated by evaluating performance of everyday actions in older adults with mild AD (n = 15) as compared with healthy age-matched controls (n = 16). Everyday actions were familiar activities, for example, making a cup of tea, but were varied in complexity (simple, complex) and were performed under varied attention demand (single task, dual task). Although both participant groups responded to increasing task complexity by making more errors, the AD group made more errors under dual-task conditions regardless of the complexity of the task. Furthermore, a task requiring strategic retrieval of semantic information from long-term memory and manipulation of attention online (category fluency) was able to account for a large proportion of the group-related variance in everyday task performance. Results are discussed in relation to the role of components of working memory in performance of everyday actions in mild AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cognitive loss in dementia with Lewy bodies and Alzheimer disease

BACKGROUND: Dementia with Lewy bodies (DLB) is emerging as a common cause of degenerative dementia. Some preliminary evidence exists that the pattern of cognitive impairment in DLB is different from that in Alzheimer disease (AD). OBJECTIVE: To delineate features of cognitive impairment of DLB on standardized neuropsychological tests. METHODS: We performed neuropsychological assessments of 26 patients with probable DLB (based on criteria of the consortium on DLB international workshop) and of 52 patients with probable AD (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke [now the National Institute of Neurological Disorders and Stroke])-Alzheimer's Disease and Related Disorders Association) who were matched to the patients with DLB 2:1 by age, sex, education, and Mini-Mental State Examination score. RESULTS: Compared with the group with probable AD, the group with probable DLB scored significantly lower on the picture arrangement, block design, object assembly, and digit symbol substitution subtests of the Wechsler Adult Intelligence Scale-Revised and on the Raven Colored Progressive Matrices test and significantly higher on the Mini-Mental State Examination locational orientation subtest and the Alzheimer's Disease Assessment Scale word recall subtest. A discriminant analysis revealed that the word recall score on the Alzheimer's Disease Assessment Scale and the block design score on the Wechsler Adult Intelligence Scale-Revised were the best discriminant factors. CONCLUSIONS: The disproportionately severe visuoperceptual, visuoconstructive, and visuospatial dysfunction and the disproportionately mild memory impairment in DLB compared with AD, which likely reflect the distribution of the pathologic changes in DLB, can help to differentiate DLB from AD.     

Age at onset and language disturbances in Alzheimer's disease

This study examined the effect of age at symptom onset of Alzheimer's disease (AD) on the pattern of language disturbance. We assessed 150 consecutive patients with a clinical diagnosis of mild-to-moderate AD using the Western Aphasia Battery and a 100-item picture-naming test. A multivariate linear regression analysis examined the effect of age at onset after controlling for gender, education, severity of dementia and duration of the disease. Patients with early onset performed significantly worse than did patients with late onset on the word comprehension and sequential commands subtests. On the other hand, late-onset patients performed more poorly than early-onset patients on the picture-naming test in a subgroup with mild language deficits. However, the trend disappeared in other subgroups with more degraded language function. We consider that the concomitant effects of normal aging worsened the picture-naming deficits in the late-onset patients, and the rapid decline of naming ability in the early-onset patients masked the aging effect with the progression of language deficits. The deterioration of word comprehension and the rapid decline of naming ability are the characteristics of early-onset patients. The different patterns of language deficits between early- and late-onset patients may correspond to the genetic heterogeneity of AD.     

Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia

OBJECTIVE: To compare the evolution of Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia by cognitive domain. SETTING: The University of Western Ontario Dementia Study, which is a registry of cases of dementia seen for secondary and tertiary assessment in a university memory disorders clinica with extensive follow-up data and histopathological confirmation of clinical diagnoses. PATIENTS: One hundred twenty-nine patients with definite or probable AD, 12 patients with definite or probable VaD, and 36 patients with definite or probable mixed dementia. METHODS: Patients were grouped as having an early, moderate, or advanced stage of disease according to the extended scale for dementia (ESD). The ESD was subdivided into cognitive domains, and the domain scores were compared for each stage of disease by diagnostic category with the use of a 2-way analysis of variance with repeated measures. RESULTS: As expected, the scores in all domains decreased significantly with increasing severity. There was a significant difference in the decline in memory among the diagnostic groups (P = .02) that was mostly attributable to the difference between AD and mixed dementia (P = .03), with the difference between AD and VaD only approaching significance (P = .06). There was a similar finding for praxis. The interaction between diagnosis (AD and VaD) and severity was significant only for memory (P = .02), showing a less severe memory deficit at onset but a proportionately more rapid progression in VaD and arithmetic ability (AD and mixed dementia [P = .03]). CONCLUSIONS: Alzheimer disease, VaD, and mixed dementia evolve similarly as assessed using cognitive domains obtained by subdivision of the ESD in a patient population derived from a memory clinic and by analyzing VaD as a single entity. Only memory impairment evolves differently between AD and VaD, with this depending on the severity. Memory is more severely impaired in the early stage of AD; however, with increasing severity of dementia, memory impairment in VaD accelerates and catches up with AD at the level of moderate impairment. The differences between AD and mixed dementia are greater than those between mixed dementia and VaD, suggesting an important role for the ischemic component of mixed dementia. Simple neuropsychological tools (eg, the ESD) may be incapable of distinguishing between AD and VaD, and more focused instruments may be required. Inherent bias in case selection may prevent extrapolation of these results to VaD in general, but the neuropsychological criteria for VaD may need to vary, depending on the severity.     

Cortical variability and asymmetry in normal aging and Alzheimer's disease

The onset of Alzheimer's disease (AD) is accompanied by a complex and distributed pattern of neuroanatomic change, difficult to distinguish clinically from dynamic alterations in normal aging. Extreme variations in the sulcal patterns of the human cortex have made it difficult to identify diffuse and focal variations in cortical structure in neurodegenerative disease. We report the first comprehensive 3D statistical analysis of deep sulcal structure in vivo, in both normal aging and dementia. High-resolution 3D T1-weighted fast SPGR (spoiled GRASS) MRI volumes were acquired from 10 patients diagnosed with AD (NINCDS-ARDRA criteria; age: 71.9 +/- 10.7 years) and 10 normal subjects matched for age (72.9 +/- 5.6 years), gender, educational level and handedness. Scans were digitally transformed into Talairach stereotaxic space. To determine specific patterns of cortical variation in dementia patients, 3D average and probabilistic maps of primary deep sulci were developed for both normal and AD groups. Major sulci (including supracallosal, cingulate, marginal, parieto-occipital, anterior and posterior calcarine sulci, and Sylvian fissures) were modeled as complex systems of 3D surfaces using a multi-resolution parametric mesh approach. Variations and asymmetries in their extents, curvature, area and surface complexity were evaluated. Three-dimensional maps of anatomic variability, structural asymmetry and local atrophy indicated severe regionally selective fiber loss in AD. A midsagittal area loss of 24.5% at the corpus callosum's posterior midbody (P < 0.025) matched increases in structural variability in corresponding temporo-parietal projection areas. Confidence limits on 3D cortical variation, visualized in 3D, exhibited severe increases in AD from 2 to 4 mm at the callosum to a peak SD of 19.6 mm at the posterior left Sylvian fissure. Normal Sylvian fissure asymmetries (right higher than left; P < 0.0005), mapped for the first time in three dimensions, were accentuated in AD (P < 0.0002), and were greater in AD than in controls (P < 0.05). Severe AD-related increases in 3D variability and asymmetry may reflect disease-related disruption of the commissural system connecting bilateral temporal and parietal cortical zones, regions known to be at risk of early metabolic dysfunction, perfusion deficits and selective neuronal loss in AD.