Noradrenergic cardiac denervation is associated with gait velocity in Parkinson disease: a dual ligand PET study.

PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.

Body Composition, Falls, and Freezing of Gait in Parkinson's Disease: Gender-Specific Effects.

BACKGROUND: Postural instability and gait difficulties (PIGD) are a significant cause of mobility loss and lower quality of life in Parkinson's disease (PD). When PD progresses, patients may experience falls and freezing of gait (FoG) resulting in fear of falling and increasing sedentariness. Sedentary behavior results in sarcopenia associated with other changes in body composition, especially in older patients becoming frail. Previous studies have shown gender-specific changes in body composition with aging as well as gender disparities in symptoms and progression of PD, yet the association between gender-specific body composition and PIGD symptoms such as FoG along with falls, remains unexplored. OBECTIVE: This study aimed to investigate the association between gender-specific changes in body composition, FoG and falls assessment. METHODS: 136 PD subjects underwent detailed clinical test batteries and had whole-body composition assessed using dual-energy X-ray absorptiometry (DXA). Multivariate logistic forward stepwise regression was performed to define body composition associations for FoG and falls. RESULTS: Multivariate regression analysis revealed that in males with PD, lower leg lean mass was significantly associated with the presence of FoG (OR, 0.429; 95% CI, 0.219-0.839; p=0.013) but not with falls. In females with PD, higher leg adipose mass was significantly associated with falls (OR, 4.780; 95% CI, 1.506-15.174; p=0.008) but not with FoG. CONCLUSION: These observations suggest gender specific associations between body composition and FoG vs. falls in PD. Future research should explore the impact of interventions on body composition in individuals with PD by paying specific attention to gender differences.

Cardiac sympathetic denervation and anxiety in Parkinson disease.

BACKGROUND: Anxiety in Parkinson disease (PD) negatively impacts quality of life. While research predominantly focuses on central nervous system changes, some evidence suggests a connection between peripheral autonomic dysfunctions and PD-related anxiety. The role of the peripheral autonomic nervous system in this context may be overlooked. OBJECTIVES: This study explores the link between anxiety symptoms and cardiac sympathetic denervation in PD using 11C-meta-hydroxyephedrine ([11C]HED) PET cardiac imaging. METHODS: We studied 34 non-demented PD subjects, assessing anxiety levels through the Spielberg Anxiety State-Trait test trait section (STAI-T). Patients underwent comprehensive assessments along with [11C]HED cardiac and [11C]DTBZ brain PET. To identify subdimensions of STAI-T, we employed principal components analysis (PCA). We examined associations between the anxiety subdimensions and two measures of cardiac sympathetic denervation from [11C]HED PET. We utilized correlation and linear regression models for these analyses. RESULTS: PCA revealed two STAI-T results components: anxiety-depressive and pure anxiety subcomponents. Only pure anxiety significantly correlated with measures of cardiac sympathetic denervation (rhos -0.40, p = 0.018; 0.35, p = 0.043). Regression models confirmed a significant association, with cardiac sympathetic denervation explaining ∼20 % of pure anxiety variance, independent of sex, dopaminergic impairment, and anxiolytic treatments. DISCUSSION: This study provides preliminary evidence of peripheral autonomic nervous system abnormalities contributing to PD-related anxiety, suggesting dysregulation in peripheral autonomic functions influencing anxiety perception.

Resting state connectivity within the basal ganglia and gait speed in older adults with cerebral small vessel disease and locomotor risk factors.

BACKGROUND AND AIM: The basal ganglia are critical for planned locomotion, but their role in age-related gait slowing is not well known. Spontaneous regional co-activation of brain activity at rest, known as resting state connectivity, is emerging as a biomarker of functional neural specialization of varying human processes, including gait. We hypothesized that greater connectivity amongst regions of the basal ganglia would be associated with faster gait speed in the elderly. We further investigated whether this association was similar in strength to that of other risk factors for gait slowing, specifically white matter hyperintensities (WMH). METHODS: A cohort of 269 adults (79-90 years, 146 females, 164 White) were assessed for gait speed (m/sec) via stopwatch; brain activation during resting state functional magnetic resonance imaging, WMH, and gray matter volume (GMV) normalized by intracranial volume via 3T neuroimaging; and risk factors of poorer locomotion via clinical exams (body mass index (BMI), muscle strength, vision, musculoskeletal pain, cardiometabolic conditions, depressive symptoms, and cognitive function). To understand whether basal ganglia connectivity shows distinct clusters of connectivity, we conducted a k-means clustering analysis of regional co-activation among the substantia nigra, nucleus accumbens, subthalamic nucleus, putamen, pallidum, and caudate. We conducted two multivariable linear regression models: (1) with gait speed as the dependent variable and connectivity, demographics, WMH, GMV, and locomotor risk factors as independent variables and (2) with basal ganglia connectivity as the dependent variable and demographics, WMH, GMV, and locomotor risk factors as independent variables. RESULTS: We identified two clusters of basal ganglia connectivity: high and low without a distinct spatial distribution allowing us to compute an average connectivity index of the entire basal ganglia regional connectivity (representing a continuous measure). Lower connectivity was associated with slower gait, independent of other locomotor risk factors, including WMH; the coefficient of this association was similar to those of other locomotor risk factors. Lower connectivity was significantly associated with lower BMI and greater WMH. CONCLUSIONS: Lower resting state basal ganglia connectivity is associated with slower gait speed. Its contribution appears comparable to WMH and other locomotor risk factors. Future studies should assess whether promoting higher basal ganglia connectivity in older adults may reduce age-related gait slowing.

Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study.

BACKGROUND AND PURPOSE: The diagnosis of Parkinson disease (PD) is made typically on the basis of motor abnormalities. PD is now recognized to have both motor and non-motor manifestations, indicating a need for the development of reliable non-motor diagnostic tests for PD. The aim of the present study was to compare the accuracy of various clinical motor and non-motor tests for the diagnosis of PD. METHODS: Forty-five PD patients (Hoehn and Yahr stages 1-3; mean age 59.5 +/- 10.0 years) and 45 healthy controls matched for gender and age completed a clinimetric motor test battery to assess limb bradykinesia, tremor and balance. Non-motor tests consisted of depression, anxiety and smell identification ratings. Area under the receiver operator characteristic curve (AUC) analysis was used. RESULTS: We found that smell identification was the most accurate predictor of the presence of PD within the overall group of patients and matched control subjects (AUC = 0.886) and also in the subgroups of mild severity (Hoehn and Yahr stages 1-1.5; AUC = 0.923), young-onset (AUC = 0.888) and female PD patients (AUC = 0.797). The second best diagnostic test was the grooved pegboard test for the clinically most affected body side. CONCLUSIONS: We conclude that olfactory function is the most accurate diagnostic predictor within a heterogeneous sample of patients with PD.

Striatal dopaminergic denervation and gait in healthy adults.

Parkinsonian-like motor impairments are common in the elderly. The etiology of these symptoms in the absence of clinically diagnosable Parkinson's disease (PD) is unknown. The aim of this study was to evaluate associations between striatal dopaminergic neuron losses that occur with aging and gait in healthy adults. Forty healthy subjects aged 21-85 years old underwent [(11)C]-beta-CFT dopamine transporter (DAT) positron emission tomography (PET). Subjects were also asked to walk in a gait laboratory at their own pace. Gait variables of interest included average general spatiotemporal characteristics of walking patterns and their standard deviation reflecting gait variability. Segmented nonlinear models were used to investigate the relationship between striatal DAT activity and gait while controlling for age. Gait speed, cadence, and single and double support durations were significantly slower than age-based predictions in adults with lower striatal DAT activity (P < 0.05). After controlling for age, striatal DAT activity was not significantly associated with average step length and step width and with gait variability. We conclude that dopaminergic physiology influences certain aspects of gait independent of age-related changes. The findings of this study may augur novel therapeutic approaches to treating gait disorders in the elderly.

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.

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease.

OBJECTIVES: Dopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. METHODS: PD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. RESULTS: Mean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036). CONCLUSIONS: Impaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.

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.

Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease.

RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.

A controlled trial with vasopressin analogue (DGAVP) on cognitive recovery immediately after head trauma.

Recent evidence suggests that the vasopressin analogue desglycinamide-arginine8-vasopressin (DGAVP) might specifically benefit mild brain trauma patients. We investigated the effect of intranasal DGAVP treatment in 32 patients who had sustained a mild head injury for 3 months in a double-blind, placebo-controlled, matched-pairs study. DGAVP did not have a positive effect on cognitive recovery in this group of mildly affected patients.

Reversible MRI findings in a patient with Hashimoto's encephalopathy.

Diffuse subcortical MRI signal abnormalities were seen during a subacute exacerbation in a patient with Hashimoto's encephalopathy. The patient had an excellent clinical response to corticosteroids. Clinical recovery paralleled normalization of MRI abnormalities and lowering of thyroid microsomal antibody titer.

Prior blood transfusions and Alzheimer's disease.

We performed a population-based, case-control study to evaluate prior blood transfusion as a potential risk factor for Alzheimer's disease (AD). All cases were incident cases of AD from 1975 to 1984 with residence for 40 years or more in Olmsted County, Minnesota, prior to their onset of dementia (N = 252). There was one age- and gender-matched control for each case. We ascertained the number of blood transfusions prior to the age of onset of dementia and the corresponding year in each control. Sixty-five cases and 55 controls had at least one prior blood transfusion. We did not find a significantly increased risk of AD for the events of at least one, three, or six blood transfusions.

Motor correlates of occipital glucose hypometabolism in Parkinson's disease without dementia.

OBJECTIVE: To determine whether occipital reduction in regional cerebral glucose metabolism in PD reflects retinal versus nigrostriatal dopaminergic degeneration. We hypothesized that occipital glucose metabolic reduction should be symmetric if parkinsonian retinopathy is responsible for the reduction. METHODS: PD patients without dementia (n = 29; age 63 +/- 10 years) and normal controls (n = 27; age 60 +/- 12 years) underwent [18F]fluorodeoxyglucose PET imaging. Regional cerebral glucose metabolic rates were assessed quantitatively. RESULTS: When compared with normal controls, PD patients showed most severe glucose metabolic reduction in the primary visual cortex (mean -15%, p < 0.001). Occipital glucose metabolic reduction was greater in the hemisphere contralateral to the side of the body affected initially or more severely in PD. There was an inverse correlation between side-to-side asymmetries in finger-tapping performance and occipital glucose metabolic reduction (r = -0.45, p < 0.05; n = 28). The correlation was strongest in patients with a relatively early stage of PD with more unilateral motor impairment (Hoehn and Yahr stage I, r = -0.74, p < 0.01; n = 10). CONCLUSION: The results indicate a pathophysiologic association between nigrostriatal dysfunction and occipital glucose metabolic reduction in PD.

(+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis.

Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.

Striatal presynaptic monoaminergic vesicles are not increased in Tourette's syndrome.

BACKGROUND: Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). OBJECTIVE: To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. METHODS: We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). RESULTS: We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. CONCLUSIONS: There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.

Decreased striatal monoaminergic terminals in Huntington disease.

OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.

Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus.

Traditional side-by-side visual interpretation of ictal and interictal single-photon emission computed tomography (SPECT) scans can be difficult in identifying the surgical focus, particularly in patients with extratemporal or otherwise unlocalized intractable epilepsy. Computer-aided subtraction ictal SPECT co-registered to MRI (SISCOM) may improve the clinical usefulness of SPECT in localizing the surgical seizure focus. We studied 51 consecutive intractable partial epilepsy patients who had interictal and ictal scans. The SPECT studies were blindly reviewed and classified as either localizing to 1 of 16 sites in the brain or as nonlocalizing. SISCOM images were localizing in 45 of 51 (88.2%) compared with 20 of 51 (39.2%) for traditional side-by-side inspection of ictal and interictal SPECT images (p < 0.0001). Inter-rater agreement for two independent reviewers was better for SISCOM (84.3% versus 41.2%, kappa = 0.83 versus 0.26; p < 0.0001). Concordance of seizure localization with the more established tests was also higher for SISCOM. Late injection of the radiotracer (> 45 seconds), but not secondary generalization of the seizure, was associated with a falsely localizing or nonlocalizing SISCOM. Epilepsy surgery patients whose SISCOM localization was concordant with a falsely localizing or nonlocalizing SISCOM. Epilepsy surgery patients whose SISCOM localization was concordant with the surgical site were more likely to have excellent outcome than patients with nonconcordant or nonlocalizing findings (62.5% [10/16] versus 20% [2/10]; p < 0.05). On the other hand, seizure localization by the traditional method of SPECT inspection had no significant association with postsurgical outcome. We conclude that SISCOM improves the sensitivity and the specificity of SPECT in localizing the seizure focus for epilepsy surgery. Concordance between SISCOM localization and site of surgery is predictive of postsurgical improvement in seizure outcome.

Alzheimer's disease and cumulative exposure to anesthesia: a case-control study.

OBJECTIVE: To evaluate prior exposure to general anesthesia as a potential risk factor for Alzheimer's disease (AD). DESIGN: A retrospective, population-based, case-control study. SETTING: The Rochester Epidemiology Resource. PATIENTS: Cases were all incident cases of AD from 1975 to 1984 who resided for 40 years or more in Olmsted County prior to the onset of their dementia (n = 252). One age- and gender-matched control for each case was selected from all registrations for care at Mayo Clinic during the year of onset in the incident case. The case and control groups each had 252 individuals. Of these, 208 cases and 199 controls had at least one exposure to general anesthesia prior to the year of onset of dementia in the matched AD patient. MEASUREMENTS: The cumulative duration of anesthesia and the total number of general anesthetic exposures prior to the age of onset of dementia and the corresponding year in each matched control were ascertained. RESULTS: There was no significant difference in mean cumulative exposure (in minutes) to general anesthesia (patients vs controls: 188.4 vs 170.5 minutes, ns). Neither exposure to six or more episodes of general anesthesia (OR = 1.44; 95% CI: 0.77-2.71) nor cumulative exposure to 600 minutes or more of general anesthesia (OR = 1.63; 95% CI: 0.53-5.04) were associated with a significantly increased risk of AD. CONCLUSION: It is unlikely that multiple exposures to general anesthesia increase the risk of AD.