Dylan Harwood

Frontal Lobe Hypometabolism and Impaired Insight in Alzheimer Disease

OBJECTIVE The authors examined the relationship between impaired insight regarding cognitive and functional deficits and frontal cortex hypometabolism in 41 patients with Alzheimer disease (AD). METHODS Regional cerebral glucose metabolism was determined with (18F)fluorodeoxyglucose and positron emission tomography. Level of insight was measured with the clinician-rated Neurobehavioral Rating Scale, and severity of global cognitive impairment was determined with the Mini-Mental State Exam. RESULTS Inaccurate insight was correlated with glucose metabolic rate in the right lateral frontal cortex (Brodmann areas 6 and 45, and the lateral aspect of Brodmann areas 8 and 9) after controlling for global cognitive dysfunction. CONCLUSIONS The findings from this study help to further elucidate the neurobiological mechanisms underlying impaired insight in AD, indicating a link between this important clinical phenomenon and dysmetabolism in a focal region of the right prefrontal cortex.

The neural correlates of naming and fluency deficits in Alzheimer’s disease: an FDG-PET study

To examine the neural processes associated with language deficits in Alzheimers disease (AD), and in particular to elucidate the correlates of confrontation naming and word retrieval impairments.

The role of cognitive impairment and caregiver support in diabetes management of older outpatients.

Objectives: To examine the role of cognitive impairment and caregiver support in diabetes care adherence and glycemic control. Methods: Fifty-one veteran male outpatients (27 with caregivers) aged 60 years and older with type 2 diabetes were evaluated for cognitive impairment with the Cognitive Abilities Screening Instrument. Patients or caregivers completed diabetes self-care and depression scales. Medical morbidity information and HbA1c plasma levels at baseline and 1 year later were obtained from electronic medical records. Results: Greater cognitive impairment (F = 5.1, p < .05), and presence of a caregiver (F = 5.3, p < .05), were independently associated with worse diabetes care adherence (adjusting for age, education, medical comorbidity, and depression). In addition, Mean HbA1c levels were worse in the cognitively impaired group with caregivers relative to the three other groups (F = 4.10, p < .05, η2 =.09). One year later, mean HbA1c levels rose from 7.7 to 8.2% in the cognitively impaired group with caregivers. Conclusion: Cognitive impairment is associated with worse diabetes care management. Surprisingly, the presence of a caregiver is not protective. Further research is necessary to examine the healthcare needs of cognitively impaired, diabetic patients and their caregivers.

Cerebral metabolism, cognition, and functional abilities in Alzheimer disease.

Patients with Alzheimer disease (AD) exhibit profound difficulties in completing instrumental activities of daily living (IADLs), such as managing finances, organizing medications, and food preparation. It is unclear which brain areas underlie IADL deficits in AD. To address this question, we used voxel-based analysis to correlate the performance of IADLs with resting cerebral metabolism as measured during [18F] fluorodeoxyglucose–positron emission tomography (FDG-PET) imaging in 44 patients with AD. Poorer ability to complete IADLs was associated with hypometabolism in right-sided cortical regions, including the parietal lobe, posterior temporal cortex, dorsolateral prefrontal cortex, and frontal pole. Follow-up path analyses examining anatomically defined regions of interest (ROI) demonstrated that the association between metabolism and IADLs was mediated by global cognition in frontal ROIs, and partially mediated by global cognition in the parietal ROI. Findings suggest that hypometabolism of right sided brain regions involved in executive functioning, visuospatial processing, attention, and working memory underlie functional impairments in patients with AD.

Executive deficits and regional brain metabolism in Alzheimer's disease.

Executive deficits are common in patients with Alzheimers disease (AD), contribute prominently to clinical disability, and may be associated with frontal lobe pathology. This study examined regional brain hypometabolism associated with executive dysfunction in patients with AD.

Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

OBJECTIVE Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This studys goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. METHODS In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. (18)F-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. RESULTS Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. CONCLUSION Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

Association between cerebral metabolism and Rey–Osterrieth Complex Figure Test performance in Alzheimer's disease

The copy condition of the Rey–Osterrieth Complex Figure (ROCF) is sensitive to Alzheimers disease (AD) pathology, but its neural correlates remain unclear. We used fluorodeoxyglucose positron emission tomography (FDG–PET) to elucidate this association in 77 patients with probable AD. We observed a correlation between ROCF and metabolic rate of bilateral temporal–parietal cortex and occipital lobe, and right frontal lobe. Global and local elements of the ROCF correlated with metabolic rate of these same regions. The copy approach correlated with right lateral temporal cortex. The ROCF appears reflective of posterior temporal–parietal cortex functioning, highlighting the role of visuospatial processing in constructional abilities in AD.

Effect of Memantine Treatment on Regional Cortical Metabolism in Alzheimer's Disease

OBJECTIVES Cortical systems involved in the response to medication treatment for Alzheimers disease (AD) are poorly understood. Preclinical studies have demonstrated the effect of memantine on neuroreceptors and cell physiology, although the impact of treatment on cortical activity in vivo is not known. DESIGN F-fluorodeoxyglucose positron emission tomography (PET) imaging and clinical assessment before and after open-label memantine treatment. PARTICIPANTS/SETTING Seventeen outpatients with probable AD on stable cholinesterase inhibitor medication. INTERVENTION Memantine up to 10 mg twice daily for 10 weeks. MEASUREMENTS Voxel-based analyses of change in cortical metabolic activity; Mattis Dementia Rating Scale (DRS), and Neurobehavioral Rating Scale (NRS). RESULTS : Mean age was 81 years; mean Mini-Mental State Examination score was 19.4. Compared with baseline, metabolic activity was significantly higher after 10 weeks memantine treatment in two cortical regions bilaterally: the inferior temporal gyrus (BA 20) and the angular gyrus/supramarginal gyrus (BA 39, 40). There was no significant relationship between change in DRS score and change in cortical metabolism, although change in NRS score was associated with the extent of metabolic change in the right parietal and temporal cortex. CONCLUSION Metabolic activity in bilateral inferior parietal and temporal cortex increases during 10 weeks of memantine treatment in patients with AD. PET imaging can reveal functional effects of medications on neural activity and may help to define critical mechanisms involved in drug treatment.

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging

OBJECTIVE To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms. METHODS Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4β2* nicotinic cholinergic receptor binding using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used. RESULTS 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: rs = -0.55, p = 0.008; right: rs = -0.50, p = 0.02; N = 22) and hippocampus (left: rs = -0.65, p = 0.001; right: rs = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: rs = -0.50, p = 0.01; right: rs = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score. CONCLUSION Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.

18F-Fluorodeoxyglucose Positron Emission Tomography Cortical Metabolic Activity Associated with Distinct Agitation Behaviors in Alzheimer Disease

OBJECTIVE This study aimed to investigate the neurobiologic correlates of two distinct clusters of agitation symptoms to identify the unique biologic substrates underlying agitated behaviors. METHODS Eighty-eight outpatients with mild to moderate Alzheimer disease (AD) were recruited from the VA Greater Los Angeles Healthcare System Geropsychiatry Outpatient Program. A cross-sectional investigation was conducted of the relationship between cerebral glucose metabolism measured via 18F-fluorodeoxyglucose positron emission tomography and agitated symptoms from the Neuropsychiatric Inventory (NPI) in patients with AD. Two empirically derived clusters of agitation symptoms were investigated: an Agitation factor comprising agitation/aggression and irritability/lability items of the NPI, and a Behavioral Dyscontrol factor comprising elation/euphoria, disinhibition, aberrant motor behavior, sleep, and appetite items of the NPI. Mean cerebral metabolism for patients who scored positively on each of the two factors was compared with mean cerebral metabolism for those who did not. RESULTS Patients with AD who scored positively on the Agitation factor showed reduced glucose metabolism of the right temporal, right frontal, and bilateral cingulate cortex. In contrast, the Behavioral Dyscontrol factor did not show specific neurobiologic correlates. CONCLUSION Symptoms encompassed within the Agitation factor have distinct neurobiologic underpinnings. The precipitants, course, and outcomes related to these symptoms may be unique from other neuropsychiatric symptoms characteristic of AD. Special attention to treatment of agitated behaviors involving anger, aggressiveness, hostility, and irritability/emotional lability is warranted, because they appear to reflect a clinically relevant symptom cluster with unique underlying neurobiologic correlates.