Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia.

AIM: To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson's disease (PD) and parkinsonian dementia (PDem). METHODS: Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [11C]methyl-4-piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD). RESULTS: Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = -0.5, p = 0.007. This correlation remained significant after controlling for Mini-Mental State Examination scores. CONCLUSION: Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.

White matter hyperintensities and cortical acetylcholinesterase activity in parkinsonian dementia.

OBJECTIVE: To investigate the relationship between the severity of white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity in parkinsonian dementia (PDem). METHODS: PDem (n = 11) and control subjects (n = 14) underwent [11C]methyl-4-piperidinyl propionate (11C-PMP) AChE brain positron emission tomography and magnetic resonance (MR) imaging. Presence of WMH on proton density and T2 MR images was scored using a modified version of the semi-quantitative rating scale by Scheltens et al. [J Neurol Sci114 (1993)]. RESULTS: Analysis demonstrated significantly lower mean cortical (11)C-PMP k3 hydrolysis rates in PDem (-19.9%) when compared with control subjects (P < 0.0001). PDem subjects had higher mean severity of WMH (+20.1%) when compared with control subjects (P < 0.05). When WMH severity was entered into the analysis of variance model, there was no significant co-variate effect on cortical AChE activity (F = 0.24, ns). CONCLUSIONS: The concomitant presence of mild to moderate WMH in patients with PDem does not have a significant effect on cortical AChE activity.

Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia.

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer's disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson's disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (-20.9%) and PD (-12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = -0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease.

OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Right prosubiculum amyloid plaque density correlates with anosognosia in Alzheimer's disease.

BACKGROUND: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions. OBJECTIVE: To investigate pathological correlates of anosognosia in Alzheimer's disease. DESIGN: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and -Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 -Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC). RESULTS: SP density was greater in the right PRO region of -Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of -Aware subjects than in the other regions (F = 12.72, p = 0.002). CONCLUSIONS: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease.

OBJECTIVE: To describe the effect of cholinesterase inhibitors (CEIs) on the natural course of Alzheimer's disease (AD). METHODS: The short and long term effects of CEIs were evaluated in 135 patients with probable Alzheimer's disease relative to 135 patients who were never exposed to CEIs matched by age, education, duration of the symptoms, and cognitive status. We measured 1 year change in cognitive and functional performance, and the likelihood of arriving at each of four end points: (1) mini mental state examination (MMSE) of 9 or lower, (2) Blessed dementia rating scale for activities of daily living of 12 or higher, (3) nursing home admission, and (4) death, over an average 3 years of observation (36.7 (SD 21.5) months). RESULTS: Patients on CEIs were better cognitively and functionally after 1 year compared with those patients who never used CEIs. A proportional hazard analysis with CEI use as a time dependent covariate showed that the use of CEIs decreased the risk of nursing home admission. There was no association, however, between use of CEIs and time to cognitive and functional end points, or to death. CONCLUSIONS: This observational study showed that there was an initial cognitive and functional benefit from the use of CEIs in Alzheimer's disease, which waned as the disease progressed. However, the results suggest that there is a long term beneficial effect of the use of CEIs, as indicated by the delay in admission to nursing homes.

Long-term care in dementia: patients and caregivers.

General principles of managing chronic, age-associated diseases apply as much to Alzheimer's disease (AD) and other late-life dementing disorders as they do to congestive heart failure or osteoarthritis. Beyond efforts to maintain residual tissue or organ function, important physician roles include promoting general well-being and helping patients and their caregivers adjust to disease-related limitations. Physicians provide essential information to patients and their families about the disease, its social and legal ramifications, and community resources to facilitate care. Therefore, physicians must be knowledgeable about broadly intersecting medical, legal, financial, and ethical issues surrounding the long-term management of AD and other dementias. The many challenges faced by patients with dementia and their caregivers over time underscore the need for an ongoing diagnostic and therapeutic alliance with primary care physicians. This article reviews salient aspects of long-term care for patients with AD and other dementias, highlighting the vital and varied roles of physicians in managing these chronic brain disorders.

The use of herbal alternative medicines in neuropsychiatry. A report of the ANPA Committee on Research.

Growing numbers of people throughout the United States (40% in 1998) are using various forms of alternative therapies. A MEDLINE literature search of journals from the past three decades and an Internet database query were performed to determine the types and frequency of alternative therapies used, with special attention given to the herbal medicines used in neuropsychiatric disorders. Clinical effects, mechanisms of action, interactions, and adverse reactions of the herbal treatments are detailed. Objective controlled trials will be needed to establish safety and efficacy of herbal supplements. Knowledge of the properties of these therapies can improve the care of neuropsychiatric patients.

Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory.

The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for evaluating psychopathology in dementia. The authors developed a brief questionnaire form of the NPI (NPI-Q), intended for use in routine clinical practice, and cross-validated it with the NPI in 60 Alzheimer's patients. Test-retest reliability of the NPI-Q was acceptable. The prevalence of analogous symptoms reported on the NPI and NPI-Q differed on average by 5%; moderate or severe symptom ratings differed by less than 2%. The NPI-Q provides a brief, reliable, informant-based assessment of neuropsychiatric symptoms and associated caregiver distress that may be suitable for use in general clinical practice.

Predictors of progression in patients with AD and Lewy bodies.

OBJECTIVE: To examine the differences in the pattern of progression between AD and AD with Lewy bodies (AD+LB). METHODS: The authors examined predictors of functional and cognitive disability, institutionalization, and death, as well as time to the development of psychosis (e.g., delusions, hallucinations), extrapyramidal signs (EPS), diurnal hypersomnia, and depression in 185 patients with definite AD and 60 with autopsy-confirmed AD+LB. In addition, they analyzed a selected group of patients who did not have comorbid systemic or CNS disease that may have affected progression of the disease (AD = 98 versus AD+LB = 44). The mean follow-up was 58.91 +/- 35.2 months. RESULTS: All cases: Patients with AD+LB had faster time to the development of EPS and diurnal hypersomnia, but not to the development of psychosis or depression. The rate of cognitive and functional decline, time to institutionalization, and physical survival was not different between AD+LB and AD. Selected cases: Patients with AD+LB developed earlier EPS and diurnal hypersomnia than AD patients, and there was a trend to develop earlier major depression, but no differences were noted in time to psychosis. Patients with AD+LB had a faster time to institutionalization than those with AD. The rate of cognitive and functional decline and physical survival was not different between AD+LB and AD in these selected cases. CONCLUSION: Patients with AD+LB can develop EPS and diurnal hypersomnia earlier and have faster time to institutionalization than those with AD alone, but cognitive and functional decline and physical survival are similar between these two entities.

Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies.

OBJECTIVE: 1) To examine the clinical differences between AD and AD with Lewy bodies (AD+LB); and 2) to determine the accuracy of Consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) at different levels of dementia severity. METHODS: The authors examined the clinical characteristics of 185 patients with pathologically diagnosed AD alone and 60 with AD+LB. The relationship between clinical symptoms and AD+LB was determined by multivariate analyses, controlled by age, duration of symptoms, presence of cerebrovascular disease, and dementia severity. RESULTS: Mild dementia syndrome: No specific clinical symptom was associated with the presence of AD+LB. The sensitivity of the diagnosis of DLB was 62% and specificity was 54%. Moderate dementia syndrome: Extrapyramidal signs (EPS), especially cogwheel rigidity, and major depression were associated with AD+LB. The sensitivity for DLB was 82% and specificity was 31%. Severe dementia syndrome: Cogwheel rigidity and diurnal hypersomnia were associated with AD+LB. The sensitivity for DLB was 93% and specificity was 16%. CONCLUSIONS: The presence of EPS is not useful in differentiating AD+LB from AD in patients with mild dementia. However, as the disease progressed, they emerge as defining features, especially cogwheel rigidity. The accuracy of AD+LB diagnosis varies according the severity of the dementia syndrome. The low sensitivity and specificity in AD+LB patients with mild dementia suggest that in early stages AD+LB patients do not present the clinical characteristics of DLB. By contrast, the high sensitivity and low specificity for the diagnosis of DLB in moderate/severe dementia stages suggests that AD patients can also have characteristic symptoms of DLB. These results indicate that the antemortem diagnosis of AD+LB is difficult in all dementia stages, and better clinical and biologic differentiations of these entities are needed.

Psychotic symptoms in Alzheimer's disease are not associated with more severe neuropathologic features.

Psychotic symptoms in Alzheimer's disease (AD) have been associated with increased rates of cognitive impairment and functional decline. Prior studies have been conflicting with regard to whether AD patients with psychosis (AD+P) have evidence of more severe neuropathologic findings at postmortem exam. We examined the severity of neuritic plaques and neurofibrillary tangles in six brain regions--middle frontal cortex, hippocampus, inferior parietal cortex, superior temporal cortex, occipital cortex, and transentorhinal cortex-in 24 AD+P subjects and 25 matched AD subjects without psychosis (AD-P). All analyses controlled for the presence of cortical Lewy bodies, and corrected for multiple comparisons. We found no significant associations between neuritic plaque and neurofibrillary tangle severity and AD+P, and no significant associations with any individual psychotic symptom. The association of AD+P with a more rapidly progressive course of AD appears to be mediated by a neuropathologic process other than increased severity of plaque and tangle formation.

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

OBJECTIVE: To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. BACKGROUND: Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. RESULTS: The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. CONCLUSION: Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades: II.

OBJECTIVE: To describe the experience of a research clinic diagnosing possible AD during the last two decades. BACKGROUND: The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for possible AD are generally used to indicate that a patient has AD in association with another disease process that could by itself cause dementia. There are no studies describing how these criteria should be applied, and there are no descriptions of functional and cognitive progression or survival in possible AD. METHODS: The authors examined the clinical characteristics of 267 patients diagnosed with possible AD at the AD Research Center of Pittsburgh from 1983 to 2000 and the likelihood of arriving at four endpoints: Mini-Mental State Examination score of /= 12, nursing home admission, and death. RESULTS: The possible AD classification has been simplified in six categories: possible AD with cerebrovascular disease (CVD) (69%), with history of alcohol abuse (15%), with history of depression (7%), with thyroid disease (4%), with history of head trauma (6%), with vitamin B12 deficiency (6%), and with other disease process that may have affected the clinical presentation of AD (4%). The presence of CVD, history of alcohol abuse, and history of depression concomitant with the onset of dementia were associated with time to death. Neither thyroid disease, history of head trauma, nor vitamin B12 deficiency were associated with any of the four endpoints. CONCLUSION: This cohort showed that comorbid conditions that can affect cognition delineate clearly defined subgroups in AD. The presence of environmental or other brain disorders sufficient to produce dementia appears to affect physical survival in patients with AD, but not functional and cognitive decline or institutionalization.

Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias.

OBJECTIVE: To evaluate the inter-rater reliability and validity of clinical diagnostic criteria for neurodegenerative dementias. BACKGROUND: Inter-rater accuracy of the diagnosis of AD has been explored, but there are few accuracy studies for progressive supranuclear palsy (PSP) and frontotemporal lobe dementia (FTD). Furthermore, there have been no simultaneous accuracy studies in a mixed sample of patients with cortical and subcortical neurodegenerative processes. METHODS: Four experienced clinicians reviewed first-visit clinical data abstracted from the records of 40 pathologically diagnosed demented subjects. They were asked to apply the NINCDS-ADRDA criteria for AD, the NINDS-SPSP clinical criteria for PSP, the Lund and Manchester criteria for FTD, and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB). RESULTS: The generalized K for AD was 0.73, for PSP 0.82, for FTD 0.75, and for DLB 0.37. The K pool test showed a statistically significant difference between DLB and the other disease processes, and no differences were observed among AD, FTD, and PSP. The mean sensitivity for AD was 95%, for PSP 75%, for FTD 97%, and for DLB 34%. The mean specificity for AD was 79%, for PSP 98.5%, for FTD 97%, and for DLB 94%. CONCLUSIONS: We found improved inter-rater reliability for the diagnosis of AD among clinicians compared with earlier studies. Similarly, there was a near-perfect and substantial inter-rater agreement for the diagnosis of PSP and FTD. The sensitivity for the diagnosis of AD was high, although clinicians overdiagnosed this condition. However, there was a reasonable accuracy for the diagnosis of PSP and FTD. Heterogeneity of the clinical presentation of DLB significantly affected inter-rater agreement and accuracy. The use of multiple diagnostic criteria for cortical and subcortical dementia increases the level of clinical diagnostic accuracy.

Cholinergic therapy for neuropsychiatric symptoms in neurologic disorders.

Acetylcholine is a modulatory central nervous system (CNS) neurotransmitter involved in diverse brain processes. Historically, drugs that increase CNS cholinergic transmission have been investigated primarily for relieving cognitive symptoms in Alzheimer"s disease (AD). Emerging from these efforts are recent findings that several cholinesterase-inhibitor agents also have a beneficial effect on selected noncognitive symptoms in AD, such as apathy, psychosis, and purposeless motor behaviors. The broad psychotropic effects of cholinergic agents observed in AD and other degenerative conditions highlight potential symptom-based therapeutic indications for these drugs across a variety of neurologic disorders.

Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale.

OBJECTIVES: To develop an adjunct scale to the Neuropsychiatric Inventory (NPI) for assessing the impact of neuropsychiatric symptoms in Alzheimer's disease (AD) patients on caregiver distress. DESIGN: Cross-sectional descriptive and correlational study. SETTING: University out-patient memory disorders clinics. PARTICIPANTS: Eighty-five AD subjects and their caregivers (54 spouses, 31 children). MEASUREMENTS: The NPI and NPI Caregiver Distress Scale (NPI-D) were used to assess neuropsychiatric symptoms in AD patients and related caregiver distress, respectively. Criterion validity of the NPI-D was examined (N = 69) by comparison with an abridged version of the Relatives' Stress Scale (RSS'), a general measure of caregiver stress, using item clusters that had previously been correlated to behavioral disturbances in demented patients. Test-retest (n = 20) and inter-rater reliability (n = 16) of the NPI-D were also assessed. RESULTS: Test-retest and interrater reliability of the NPI-D were both adequate. Overall, caregiver NPI-D distress ratings were correlated significantly with the RSS' (r = .60, P < .001). RSS' ratings correlated strongly with NPI scores (r = .64, P < .001), even after controlling for degree of cognitive impairment based on the Mini-Mental State Exam (MMSE) score (r = .61). MMSE scores showed a moderate correlation to RSS' ratings (-.30, P = .02), but this association was markedly attenuated when controlling for the degree of neuropsychiatric disturbance based on the NPI score (r = -. 14). NPI-D ratings for 9 of 10 NPI symptom domains correlated most strongly with either NPI symptom severity or total (frequency x severity) scores. Agitation, dysphoria, irritability, delusions, and apathy were the symptoms most often reported to be severely distressing to caregivers. CONCLUSIONS: The NPI-D provides a reliable and valid measure of subjective caregiver distress in relation to neuropsychiatric symptoms measured by the NPI. Neuropsychiatric alterations are more strongly associated than cognitive symptoms to caregiver distress. The NPI-D may be useful in both clinical and research settings for assessing the contribution to caregiver distress of neuropsychiatric symptoms in AD patients.

The apolipoprotein E epsilon 4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease.

The objective of our study was to examine the relationship between the presence of the apolipoprotein E (apo E) epsilon 4 allele, psychiatric symptoms, and extrapyramidal signs (EPS) in probable Alzheimer's disease (AD). The apo E epsilon 4 allele modifies the risk and age at onset of AD. However, it still needs to be determined whether it is a marker for specific clinical subgroups. The frequency of clinical signs and symptoms was examined in 194 AD patients with the apo E epsilon 3/3 (N = 79), epsilon 3/4 (N = 96), and epsilon 4/4 (N = 19) genotypes participating in a longitudinal study of dementia. Each patient was assessed with semistructured psychiatric and neurologic examinations. Patients with the epsilon 4/4 genotype had an earlier age at onset of dementia (p = 0.03). However, no individual psychiatric symptom or neurologic sign was associated with the presence of the apo E epsilon 4 allele, including major depression (odds ratio [OR], 1.14; CI, 0.50 to 2.45; p = 0.78), psychosis (e.g., delusions and hallucinations) (OR, 0.66, CI, 0.35 to 1.25; p = 0.20), and EPS (in neuroleptic-free patients) (OR, 0.82, CI, 0.45 to 1.49; p = 0.52), after controlling by age at onset, duration of the symptoms, education, and severity of dementia. The presence of the apo E epsilon 4 allele has limited utility in the characterization of neurologic and psychiatric subgroups in probable AD patients. The apo E epsilon 4/4 genotype appears to be related to age at onset of AD, consistent with previous findings.

Midline cerebral morphometry distinguishes frontotemporal dementia and Alzheimer's disease.

We investigated and contrasted midline cerebral structures in frontotemporal dementia (FTD) and Alzheimer's disease (AD). FTD and AD may be difficult to distinguish clinically. FTD typically affects frontal and anterior temporal regions, whereas AD tends to involve more posterior temporal and parietal areas. We hypothesized that disease-specific cerebral alterations would be differentially reflected in corresponding regions of the corpus callosum (CC), pericallosal CSF space (PCS), or their ratio (CC:PCS). Regions-of-interest (ROIs) from midsagittal MRIs in 17 AD, 16 FTD, and 12 elderly control (EC) subjects were analyzed. ROIs were divided into four regions using an anatomic landmark-based computer algorithm and were adjusted for head size variation. FTD subjects had a much smaller anterior CC region and significantly larger PCS area, particularly in anterior regions. AD and EC subjects did not differ significantly in any total or regional ROI measure. Total and anterior CC:PCS ratios were markedly lower in FTD patients. Across groups, total CC:PCS correlated significantly with midsagittal cerebral area and was similarly associated with Mini-Mental State Examination score. Anterior CC (AD) and PCS (FTD) regions exhibited disease-specific relationships to these variables. A discriminant model using two ROI variables correctly classified 91% of AD and FTD patients, comparing favorably with blind clinical MRI diagnostic ratings. Midline cerebral structural alterations reflect differential patterns of cerebral degeneration in AD and FTD, yielding morphometric indices that may facilitate the study of brain-behavior relationships and differential diagnosis of dementia.