Subcortical hyperintensities in Alzheimer's disease: associated clinical and metabolic findings

The authors measured subcortical hyperintensities (SH) on magnetic resonance images (MRI) in 18 patients with probable Alzheimer's disease and examined the relationships of SH severity with cortical metabolic function and clinical symptoms. Severity of SH was not correlated with absolute metabolic rates in cortical lobes. However, anterior SH severity was inversely correlated with frontal/ parietal metabolic ratios after covarying for cognitive impairment. SH severity in some areas was associated with the severity of global neuropsychiatric symptoms, but marked effects on individual symptoms were not apparent. The small sample size and multiple variables limit conclusions that can be drawn. These preliminary findings indicate that subcortical MRI hyperintensities may play a role in the pathophysiology and clinical expression of Alzheimer's disease.     

Subcortical hyperintensities in the cholinergic system are associated with improvements in executive function in older adults with coronary artery disease undergoing cardiac rehabilitation

Objective

Coronary artery disease (CAD) is frequently accompanied by white matter hyperintensities and executive dysfunction. Because acetylcholine is important in executive function, these symptoms may be exacerbated by subcortical hyperintensities (SH) located in cholinergic (CH) tracts. This study investigated the effects of SH on cognitive changes in CAD patients undergoing a 48‐week cardiac rehabilitation program.

Methods

Fifty patients (age 66.5 ± 7.1 years, 84% male) underwent the National Institute of Neurological Disorders and Stroke – Canadian Stroke Network neurocognitive battery at baseline and 48 weeks. Patients underwent a 48‐week cardiac program and completed neuroimaging at baseline. Subcortical hyperintensities in CH tracts were measured using Lesion Explorer. Repeated measures general linear models were used to examine interactions between SH and longitudinal cognitive outcomes, controlling for age, education, and max VO₂ change as a measure of fitness.

Results

In patients with SH in CH tracts, there was a significant interaction with the Trail Making Test (TMT) part A and part B over time. Patients without SH improved on average 16.6 and 15.0% on the TMT‐A and TMT‐B, respectively. Patients with SH on average showed no improvements in either TMT‐A or TMT‐B over time. There were no significant differences in other cognitive measures.

Conclusion

These results suggest that CAD patients with SH in CH tracts improve less than those without SH in CH tracts, over 48 weeks of cardiac rehabilitation. Thus, SH in CH tracts may contribute to longitudinal cognitive decline following a cardiac event and may represent a vascular risk factor of cognitive decline. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.     

Apathy and executive function in Alzheimer's disease.

Apathy is a common behavioral disturbance in patients with Alzheimer's disease (AD). Recent studies have linked the presence of apathy to alterations in frontal lobe functions, but few studies have explored the relationship using standard neuropsychological measures in patients with AD. We administered a comprehensive battery of neuropsychological tests and a behavior rating scale to 80 patients with AD. We explored the relationship of apathy to executive dysfunction. AD patients with apathy performed significantly worse on tests of executive function (WAIS-R Digit Symbol, Trail-Making, Stroop Color Interference Test) than AD patients without apathy. The presence of dysphoria did not modify these results and no significant relationships were found between tests of executive functions and dysphoria. Performance on executive measures as a group were effective in correctly classifying patients as apathetic or nonapathetic with 75% accuracy. Neuropsychological measures not dependent on executive functions were unrelated to apathy. Apathy is associated with executive dysfunction and not with other neuropsychological deficits. Apathy is distinct from dysphoria.     

Statistical parametric mapping of brain SPECT perfusion abnormalities in patients with Alzheimer's disease

Brain perfusion in 20 patients with mild Alzheimer's disease (AD), 20 patients with moderate AD and 20 control subjects (matched for age, gender and education) were assessed by single photon emission computed tomography (SPECT) using technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO). SPECT images were transformed to a standard size and shape for group comparisons by the voxel-based t test of the statistical parametric mapping techniques. Cerebral hypoperfusion in the left lower parietal area was found in mild AD patients. In moderate AD patients, significant cerebral hypoperfusion was located in bilateral posterior parietotemporal cortices, contiguous anterior occipital lobes, posterior cingulate gyri and, to a lesser extent, in frontal areas.     

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.     

Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis

Alzheimer's disease (AD) is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. These behavioral disorders contribute to the clinical heterogeneity of the disease and probably express different pathophysiological processes. Apathy is one of the most frequent behavioral disorders in AD. The aim of this study was to evaluate brain perfusion of AD patients with and without apathy (as determined by the Neuropsychiatric Inventory) compared with that in healthy elderly subjects. A total of 15 AD patients without apathy (AD/NA; mean age 76.6) and 15 AD patients with apathy (AD/A; mean age 77.6) were studied. Brain perfusion was measured by 99mTc-labeled bicisate (ECD) single-photon emission tomography (ECD SPECT). The images of the two AD subgroups were compared by means of statistical parametric mapping (SPM 99) to corresponding images of 11 healthy elderly control subjects (obtained from the Society of Nuclear Medicine database). Compared with the healthy elderly subjects, the apathy-free AD subgroup had significantly lower perfusion of inferior temporal regions (left fusiform gyrus, left parahippocampal area) and occipital regions (left gyrus lingualis). The apathy subgroup had significantly decreased perfusion of the left anterior cingulate, the right inferior and medial gyrus frontalis, the left orbitofrontal gyrus and the right gyrus lingualis. The differences in the brain areas with reduced perfusion between the apathy-free subjects (mainly the posterior regions) and the apathetic subjects (mainly the anterior regions) indicate that behavioral disorders such as apathy participate in the heterogeneity of brain perfusion in AD.     

Association between apathy/depression and executive function in patients with Alzheimer's disease

ABSTRACTBackground: Apathy and depression may be strongly associated with executive dysfunction in Alzheimer's disease (AD). The Frontal Assessment Battery (FAB) is an instrument for assessing executive function. The dual task paradigm is also useful for assessing divided attention. However, the association between apathy/depression and these tasks is unclear.Methods: Both the FAB and the dual task were used to evaluate AD patients. A two-way analysis of variance was then conducted between the FAB and dual task results and the absence versus the presence of depression or the absence versus the presence of apathy.Results: Of 88 patients with AD, 26 had both apathy and depression, 26 had depression only, 18 had apathy only, and 18 had neither. Total FAB scores and dual task scores differed significantly between the AD patients with depression and those without depression; the scores were also different between those with apathy and those without apathy. Also, a significant interaction between depression and apathy was noted for the total FAB and dual task scores.Conclusions: The deficits in the total FAB and dual task scores were larger in AD patients with both apathy and depression compared with patients with either apathy or depression alone. AD patients with both symptoms may have greater deficits in frontal lobe function relative to AD patients with either apathy or depression alone.     

阿尔茨海默病额叶白质损害的DTI与临床执行功能的关系

目的 分别应用磁共振扩散张量成像(diffusion tensor imaging,DTI)及额叶功能评定量表(frontal assessment battery,FAB)评价阿尔茨海默病(Alzheimer disease,AD)患者额叶白质损害与执行功能,并对两者的关系进行研究.方法 对15例AD组和15例对照组应用FAB测得评分,并且进行DTI扫描,测量额叶白质的部分各向异性(fractional anisotropy,FA)和半均扩散系数(average diffusion coefficient,ADC)值,对两组额叶白质区域的FA值和ADC值及FAB评分进行比较,并评价额叶白质的FA值和ADC值与临床执行功能评分之间的相关关系.结果 AD患者FAB值及额叶白质FA值均较对照组显著降低,额叶白质FA值与FAB值呈正相关(r=0.678,P=0.003).结论 FAB能够实用且有效的检测AD患者额叶执行功能的改变,FA值可反映AD患者额叶白质受损程度及其与执行功能的关系.     

Subcortical infarcts, Alzheimer's disease pathology, and memory function in older persons

OBJECTIVE: Examine the effects of subcortical infarcts with Alzheimer's disease (AD) pathology on dementia, episodic memory, and other cognitive abilities in older persons. METHODS: Participants included 148 autopsied subjects of the Rush Memory and Aging Project (mean age, 88.0 years), a longitudinal clinicopathological study. Cognition was assessed yearly with 21 neuropsychological tests. Infarcts were visualized on coronal slabs, and plaques and neurofibrillary tangles were counted and standardized to form a composite measure of AD pathology. Multiple regression analyses were used controlling for age, sex, and education. RESULTS: Fifty-three (35.8%) subjects had cerebral infarcts. After accounting for AD pathology, infarcts increased the odds of dementia by 5.1-fold (95% confidence interval, 1.98-12.92) and lowered cognitive function by 0.50 standard unit (p = 0.001). After controlling for cortical infarcts and AD pathology, subcortical infarcts, present in 39 of 53 (73.6%) subjects with infarcts, increased the odds of dementia by almost 4-fold and reduced cognitive function by more than a third of a unit (parameter estimate = -0.37; p = 0.03). In analyses with cognitive abilities, subcortical infarcts were associated with lower episodic, semantic, and working memory (p < or = 0.05), and had an interaction with AD pathology to further worsen working memory (p = 0.02). INTERPRETATION: Subcortical infarcts add to deleterious effects of AD pathology by increasing the odds of dementia and lowering memory function.     

Visual attention deficits in Alzheimer's disease: relationship to HMPAO SPECT cortical hypoperfusion

Patients with Alzheimer's disease (AD) display a multiplicity of cognitive deficits in domains such as memory, language, and attention, all of which can be clearly linked to the underlying neuropathological alterations. The typical degenerative changes occur early on in the disease in the temporal-parietal lobes, with other brain regions, such as the frontal cortex, becoming more affected as the disease progresses. In light of the importance of the parietal cortex in mediating visuospatial attentional processing, in the present study, we investigated a deficit in covert orienting of visual attention and its relationship to cortical hypoperfusion in AD. We characterized the visual attentional profile of 21 AD patients, relative to that of 26 matched normal individuals, and then assessed the correspondence between behavior and hypoperfusion, as measured by regional cerebral blood flow using SPECT. Relative to controls, the AD group demonstrated a unilateral attentional deficit, with disproportionate slowing in reorienting attention to targets in the left compared to the right hemispace, especially following an invalid peripheral cue. Furthermore, even in the presence of bilateral pathology typical of AD, there was a positive correlation between this unilateral attentional disorder and the magnitude of the right superior parietal lobe hypoperfusion. The association of the altered attentional processing profile (i.e., greater difficulty disengaging attention from right-sided stimuli) with right-hemisphere-predominant hypoperfusion not only confirms the critical role of the right parietal lobe in covert attentional orienting but, more importantly, identifies a potential locus of the behavioral alterations in visuospatial processing in AD.     

SPECT findings in Alzheimer's disease and Parkinson's disease with dementia

We examined, with single photon emission tomography (SPECT) and (^99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD) and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non-demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD.     

Functional ability in executive variant Alzheimer's disease and typical Alzheimer's disease

A frontal, or executive, variant of Alzheimer's disease (EAD) has been described in the literature in which frontal dysfunction accompanies temporal and parietal changes in the early stages of the illness. However, no study has empirically investigated associated aspects, such as neuropsychiatric symptoms, instrumental activities of daily living, or caregiver burden in this EAD subgroup. We compared the performance of two subgroups of mild Alzheimer's disease patients (e.g., EAD and typical Alzheimer's disease; TAD) on neuropsychological and associated measures. Results revealed that the EAD group, selected based on poor executive scores, did not significantly differ from the TAD group on nonexecutive neuropsychological tests of intelligence, language, verbal and nonverbal memory, or visual-spatial abilities. However, the EAD group evidenced more severe neuropsychiatric symptoms, impaired activities of daily living, and greater caregiver distress than the TAD group. Thus, the EAD subgroup is characterized by executive dysfunction, neuropsychiatric symptoms, and functional disability in excess of that seen in TAD. Whether our EAD subgroup represents an actual frontal variant of Alzheimer's disease awaits replication in a larger sample including neuroimaging and pathological confirmation, as well as longitudinal assessment of cognition and neuropsychiatric symptoms.     

White matter hyperintensities at critical crossroads for executive function and verbal abilities in small vessel disease

The presence of white matter lesions in patients with cerebral small vessel disease (SVD) is among the main causes of cognitive decline. We investigated the relation between white matter hyperintensity (WMH) locations and executive and language abilities in 442 SVD patients without dementia with varying burden of WMH. We used Stroop Word Reading, Stroop Color Naming, Stroop Color‐Word Naming, and Category Fluency as language measures with varying degrees of executive demands. The Symbol Digit Modalities Test (SDMT) was used as a control task, as it measures processing speed without requiring language use or verbal output. A voxel‐based lesion–symptom mapping (VLSM) approach was used, corrected for age, sex, education, and lesion volume. VLSM analyses revealed statistically significant clusters for tests requiring language use, but not for SDMT. Worse scores on all tests were associated with WMH in forceps minor, thalamic radiations and caudate nuclei. In conclusion, an association was found between WMH in a core frontostriatal network and executive‐verbal abilities in SVD, independent of lesion volume and processing speed. This circuitry underlying executive‐language functioning might be of potential clinical importance for elderly with SVD. More detailed language testing is required in future research to elucidate the nature of language production difficulties in SVD.     

Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease

The authors retrospectively explored the behavioral and functional imaging profile of Alzheimer's disease (AD) patients who respond to cholinesterase inhibitor therapy by using the Neuropsychiatric Inventory (NPI) and baseline [99mTc]HMPAO SPECT. Thirty AD patients were divided into three groups (Responders, Nonresponders, and Unchanged) based on their behavioral response to donepezil. Responders had significantly (P < or = 0.01) more pretreatment irritability, disinhibition (P < or = 0.05), and euphoria (P = 0.05) than Nonresponders and significantly lower lateral orbital frontal (P < 0.00001) and dorsolateral frontal (P < or = 0.0005) perfusion bilaterally. A pretreatment orbitofrontal syndrome may predict behavioral response to cholinesterase inhibitor therapy in AD.     

Motor sequencing in Parkinson's disease: relationship to executive function and motor rigidity

Parkinson's disease (PD) is a movement disorder that also affects central cognitive processing; however, the extent to which high-order cognitive processes disrupted by PD affect complex motor function is incompletely explicated. The present analysis provides an examination of the relative contributions of simple motor versus complex cognitive functions involving sequencing, problem solving, and overall cognitive status to complex motor movements involving sequencing and temporal ordering in PD. Motor sequencing performance was videotaped for quantitative scoring. Compared with an age-matched control group, the PD group was impaired on motor agility and motor sequencing tasks in addition to cognitive sequencing and set shifting tasks. Neither current cognitive functioning, age, disease duration, nor overall intellectual abilities accounted for the relationships between motor sequencing and cognitive sequencing abilities in PD. By contrast, both sequencing and nonsequencing executive functions predicted motor sequencing performance as well as or better than motor rigidity or overall cognitive status. These relationships were strongest for the most challenging motor sequencing task, fist-edge-palm, and did not apply to the least challenging task, which required simple alternations of hand movements. Unlike PD, controls showed correlations between motor sequencing tests and executive functioning only tapping nonsequencing abilities. Thus, despite the predominant motor feature of PD, executive functions, as assessed by sequencing and set formation, predicted motor sequencing performance as well as or better than simple motor performance. The results further suggest that the more complex the motor sequencing task, the more susceptible it is to influence from generalized cognitive sequencing ability.     

Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease.

A higher prevalence of dementia in individuals with fewer years of education has suggested that education may protect against Alzheimer's disease (AD). We tested whether individuals with more years of education have a more advanced AD before it is clinically evident. As a measure of pathophysiological severity, we quantified regional cerebral blood flow (rCBF), by the 133Xenon inhalation technique; a specific pattern of flow reduction in the parietotemporal cortex corresponds to AD pathology. In 3 groups of patients with probable AD, matched for clinical measures of dementia severity but with varying levels of education, whole-cortex mean flows were comparable. However, the parietotemporal perfusion deficit was significantly greater in the group with the highest level of education, indicating that AD was more advanced in this group. We conclude that education or its covariates or both may provide a reserve that compensates for the neuropathological changes of AD and delays the onset of its clinical manifestations.     

White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease

BACKGROUND AND OBJECTIVE: Methodological variability in the assessment of white matter hyperintensities (WMH) in dementia may explain inconsistent reports of its prevalence and impact on cognition. We used a method of brain MRI segmentation for quantifying both tissue and WMH volumes in Alzheimer's disease (AD) and examined the association between WMH and structural and cognitive variables. METHODS: A consecutive series of 81 patients meeting NINCDS-ADRDA criteria for probable AD was studied. Nineteen healthy volunteers of comparable age served as the control group. Patients had a complete neurological and neuropsychological evaluation, and a three dimensional MRI was obtained. Images were segmented into grey matter, white matter, and cerebrospinal fluid. WMH were edited on segmented images, and lobar assignments were based on Talairach coordinates. RESULTS: Mild and moderate to severe AD patients had significantly more WMH than controls (p<0.05). WMH preferentially involved the frontal lobes (70%), were inversely correlated with grey matter cortical volume (R(2) = 0.23, p<0.001), and were significantly associated with vascular risk factors and with a worse performance on memory tasks. CONCLUSION: Objective measurements of tissue volumes in AD demonstrated that WMH are significantly related to cortical atrophy and neuropsychological impairment.     

SPECT in Alzheimer's disease: features associated with bilateral parietotemporal hypoperfusion

OBJECTIVE: To investigate why bilateral parietotemporal hypoperfusion, the typical SPECT pattern of Alzheimer's disease (AD), occurs in some but not in all patients with probable AD. METHODS: We reviewed the SPECT scans of 220 patients presenting with cognitive impairment. Among them, 104 patients fulfilled NINCDS-ADRDA criteria for probable AD, 48 (32 women) with early onset (before age of 65) and 56 (40 women) with late onset of the symptoms. Dementia severity was assessed by the Mini-Mental State Examination. The SPECT scans were classified by visual inspection blind to clinical diagnoses. RESULTS: Bilateral parietotemporal hypoperfusion was more frequent in patients with severe AD, in those with early onset of the symptoms, and in men. Duration of symptoms, type of gamma-camera or radiopharmaceutical agent used were not associated with this SPECT pattern. CONCLUSION: These findings may be useful in the clinical setting and point to heterogeneity of AD according to age at onset.