Neural and behavioral substrates of disorientation in mild cognitive impairment and Alzheimer's disease

Abstract

Background: The neural and cognitive substrates of measures of orientation as used in clinical trials and examinations have not been comprehensively examined.

Methods: We studied 473 subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD) at baseline in Alzheimer's Disease Neuroimaging Initiative. Regression analyses at baseline were conducted to find significant predictors of orientation score among cognitive, brain morphometry, and glucose metabolism measures. Mixed model longitudinal analysis was performed to examine consequences of orientation on functional decline, and Cox hazard models examined the risk of conversion to AD in the MCI group.

Results: In MCI and AD subjects, orientation was predicted by poorer neurocognitive performance on immediate and delayed episodic memory and attention and processing speed. Among magnetic resonance imaging measures, orientation was predicted by entorhinal cortex thickness, hippocampal volume, and inferior temporal cortex thickness. Glucose metabolism in both middle-inferior temporal cortex and hippocampus were also predictive of orientation score. Functioning was significantly lower in disoriented subjects after 4 years of follow-up, and MCI patients who also were disoriented showed a higher rate of conversion to AD with a hazard ratio of 1.5.

Conclusions: Orientation is associated with medial temporal lobe structure, temporal lobe glucose metabolism, and episodic memory function. In MCI individuals orientation was a risk factor for progression to AD, also associated with rapid functional decline and worse prognosis. Thus, orientation may serve as a surrogate for episodic memory in clinical examination. These results have direct implications for the use of orientation in MCI and AD clinical trials including ceiling effects in healthy controls and issues of redundancy with measures of memory, when both are used in composite scores.

Keywords: Alzheimer's disease; FDG-PET; Memory; Mild cognitive impairment; Structural magnetic resonance imaging.

Fig. 1

Magnetic resonance imaging (MRI) morphometric predictors of orientation in individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Brain areas that significantly predicted orientation are highlighted in red. The overall significance of the predictive model was: F_{7, 294} = 12.583, P < .0001, adjusted R² = 0.212. (A) Decreased entorhinal cortex thickness predicted poorer orientation, accounting for 17% of the variance (adjusted R² = 0.174); individual estimates: b = 0.523 (confidence interval or CI 0.067–0.979), t = 2.26, P = .025, standardized b = 0.175, variance inflation factor or VIF = 2.298. (B) Smaller hippocampal volume predicted disorientation, accounting for 2% of the variance (adjusted R² = 0.025); individual estimates: b = 0.0005 (CI 0.0001–0.001), t = 2.43, P = .015, standardized b = 0.177, VIF = 2.015. (C) Decreased thickness of the inferior temporal cortex predicted disorientation, explaining 1% of the variance (adjusted R² = 0.014); individual estimates: b = 1.307 (CI 0.470–2.145), t = 3.07, P = .002, standardized b = 0.207, VIF = 1.726. (D) Represents both entorhinal and inferior-temporal cortices from a basal plane, illustrating the importance of medial temporal lobe areas in disorientation. NB: The colored area represents the region under study; it is not a heat map.

Fig. 2

Fluorodeoxyglucose positron emission tomography (FDG-PET) measures of glucose metabolism predictors of orientation in individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Brain areas that significantly predicted orientation are highlighted in red. The overall significance of the predictive model was: F_{6, 183} = 9.314, P < .0001, R² adjusted = 0.214. (A) Glucose hypometabolism in the middle and inferior temporal cortex was predictive of disorientation, explaining almost 18% of the variance (adjusted R² = 0.186); individual estimates: b = 3.934 (confidence interval or CI 2.474–5.393), t = 5.32, P < .0001, standardized b = 0.375, variance inflation factor or VIF = 1.154. (B) Glucose hypometabolism in the hippocampus was also predictive of disorientation, explaining almost 3% of the variance (adjusted R² = 0.028); individual estimates: b = 2.185 (CI 0.602–3.768), t = 2.72, P = .007, standardized b = 0.194, VIF = 1.178. NB: The colored area represents the region under study; it is not a heat map.

Fig. 3

Kaplan-Meier estimates of the rate of progression to Alzheimer's disease (AD) in mild cognitive impairment (MCI) patients who were either oriented or disoriented at baseline. MCI patients with disorientation converted to AD at a higher rate than MCI patients with intact orientation ability. The blue line represents oriented MCI individuals and the red line represents disoriented MCI individuals. The X-axis represents time and the Y-axis represents conversion from MCI to AD.