Carol Persad

Distinguishing Between Depression and Dementia in Older Persons: Neuropsychological and Neuropathological Correlates

Dementia and depression are frequently comorbid among older adult patients. Depression is related to cognitive decrement and can even represent the first signs of a neurodegenerative process. It can be difficult to distinguish depressed patients exhibiting the first signs of dementia from those whose cognition will improve with treatment. In this article, studies from the neuropsychological literature are reviewed that aid in accurate diagnosis and prognosis. Furthermore, the relationship between depression and dementia is explored by examining potential neurobiological mechanisms that may potentiate both syndromes in the context of the ongoing debate on depression as a prodrome and/or a risk factor for dementia. This article is concluded with suggestions for clinicians when deciding who to refer for neuropsychological assessment and with ideas for further research that might promote a better understanding of the complex association between depression and dementia during old age. (J Geriatr Psychiatry Neurol 2007;20:189-198)

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing

We compared the relative utility of neuropsychological testing and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) in differentiating Alzheimers disease (AD) from dementia with Lewy bodies (DLB). We studied 25 patients with AD, 20 with DLB, and 19 normal elderly controls. There was no difference between patient groups for MMSE, confrontational naming, or verbal learning. The DLB group was significantly more impaired than the AD group for verbal fluency, and the AD group was significantly more impaired than the DLB group for verbal delayed recall. The DLB group had greater difficulty than the AD group on a visual discrimination task that does not require motor functioning, but the difference did not reach significance. Family ratings of motor functioning suggested significantly greater impairment in DLB patients than in AD patients. PET studies revealed significantly lower local cerebral metabolic rates for glucose (lCMRglc) for visual cortex (Brodmann areas 17, 18, and 19) in the DLB than the AD group, but no differences for other regions commonly affected in AD, including posterior cingulate, superior parietal lobe, lateral temporal lobe, and the prefrontal region. Motor ratings were significantly correlated with lCMRglc in all areas of cerebral cortex, including Brodmann areas 17, 18, and 19. The results demonstrate a similar profile of cerebral hypometabolism in the two patient groups except in the visual cortex, where the DLB group shows markedly lower lCMRglc than the AD group. Neuropsychological testing also differentiates the groups, and family ratings of motor functioning are as robust as PET in these later stages of the disorders.

Measuring mild cognitive impairment in patients with Parkinson's disease.

We examined the frequency of Parkinson disease with mild cognitive impairment (PD‐MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD‐MCI using the new criteria for PD‐MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinsons disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD‐MCI when impaired performance was based on comparisons with normative scores. Forty‐two patients (93%) had multi‐domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinsons Disease‐Cognition. The Mini‐Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD‐MCI, and 103 (94%) had multi‐domain MCI. We observed dramatic differences in the proportion of patients who had PD‐MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease

We used positron emission tomography (PET) with (+)‐[11C]dihydrotetrabenazine ([+]‐[11C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimers disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)‐[11C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology. Ann Neurol 2004

Reliability of Repeated Cognitive Assessment of Dementia Using a Brief Computerized Battery

Objective: The aim of this study was to evaluate the short-term stability and reliability of a brief computerized cognitive battery in established dementia types. Method: Patients were administered the computerized battery twice with administrations approximately 2 hours apart, with intervening conventional neuropsychological tests. Patients were classified clinically, via consensus conference, as healthy controls (n = 23), mild cognitive impairment (n = 20), Alzheimer’s disease (n = 52), dementia with Lewy Bodies ([DLB], n = 10), or frontotemporal dementia (n = 9). Results: Minimal practice effects were evident across Cog-State test administrations. Small magnitude improvements were seen across all groups on a working memory task, and healthy controls showed a mild practice effect on the accuracy of associative learning. Conclusions: In established dementia, administration of the CogState tasks appears sensitive to cognitive impairment in dementia. Repeat administration also provided acceptable stability and test-retest reliability with minimal practice effects at short test-retest intervals despite intervening cognitive challenges.

Early menopausal hormone use influences brain regions used for visual working memory.

Objective:The cognitive benefit of postmenopausal hormone use is controversial; however, timing of treatment close to menopause may increase the likelihood of preserving cognitive function. We examined the effects of early-initiation hormone use on visual working memory, hypothesizing that long-term hormone use is associated with greater brain activation during visual working memory. Methods:This was a cross-sectional comparison of long-term early hormone users-current (n = 13) and past (n = 24; 2.1 ± 1.0 years off hormones)-with never users (n = 18), using a visual memory task and functional magnetic resonance imaging (MRI). We evaluated 55 women older than 60 years at the University of Michigans General Clinical Research Center. Hormone users had completed at least 10 continuous years of conjugated equine estrogens with or without medroxyprogesterone acetate, begun within 2 years of menopause. Women were excluded for illness, medication, intermittent estrogen use, phytoestrogen use, recent smoking, and MRI contraindications. The primary outcome was functional MRI-detected brain activity during the visual memory task. Results:Compared with never users, both groups of hormone users had increased activation in the frontal and parietal cortices, insula, hippocampus, and cingulate; combined hormone users also had increased activation in the putamen and raphe (corrected P < 0.05 or uncorrected P < 0.001 with a priori hypothesis). Across the entire sample, the medial temporal cortex (P < 0.0001 right; P < 0.018 left) and right hippocampus (P < 0.0001) positively correlated with task performance. Conclusions:Hormone use was associated with increased brain activation during the visual memory task, in regions used for visual working memory. A positive correlation between activation and task performance suggests that early-initiation, long-term postmenopausal hormone use may benefit visual working memory.

Hormonal Environment Affects Cognition Independent of Age during the Menopause Transition

CONTEXT Cognitive decline is prevalent in aging populations, and cognitive complaints are common during menopause. However, the extent of hormonal influence is unclear, particularly when considered independent of the aging process. OBJECTIVE We sought to determine differences in cognitive function attributable to menopause, hypothesizing that differences would be associated with reproductive rather than chronological age. DESIGN AND SETTING In this cross-sectional study at a university hospital, we combined neuropsychological measures with functional magnetic resonance imaging to comprehensively assess cognitive function. PARTICIPANTS Sixty-seven menopausal women, aged 42-61 yr, recruited from a population-based menopause study, grouped into menopause stages based on hormonal and cycle criteria (premenopause, perimenopause, and postmenopause), participated in the study. MAIN OUTCOME MEASURES Neuropsychological and functional magnetic resonance imaging measures of verbal, visual, and executive cognitive function. RESULTS We found age-independent menopause effects on verbal function. Menopause groups differed in phonemic verbal fluency (F = 3.58, P < 0.019) and regional brain activation (inferior frontal cortex: corrected P < 0.000 right, P < 0.036 left; left prefrontal cortex: P < 0.012); left temporal pole: P < 0.001). Verbal measures correlated with estradiol and FSH (phonemic fluency: R = 0.249, P < 0.047 estradiol, R = -0.275, P < 0.029 FSH; semantic fluency: R = 0.318, P < 0.011 estradiol, R = -0.321, P < 0.010 FSH; right inferior frontal cortex: R = 0.364, P < 0.008 FSH; left inferior frontal cortex: R = -0.431, P < 0.001 estradiol, left prefrontal cortex: R = 0.279, P < 0.045 FSH; left temporal pole: R = -0.310, P < 0.024 estradiol, R = 0.451, P < 0.001 FSH; left parahippocampal gyrus: R = -0.278, P < 0.044 estradiol; left parietal cortex: R = -0.326, P < 0.017 estradiol). CONCLUSIONS Results suggest that verbal fluency mechanisms are vulnerable during the menopausal transition. Targeted intervention may preserve function of this critical cognitive domain.

Validity of a Brief Computerized Cognitive Screening Test in Dementia

Background: While preliminary evidence supports the criterion validity of the CogState computerized brief battery in mild cognitive impairment (MCI) and Alzheimer disease (AD), definitive validation studies examining a wider range of dementia-related disorders relative to conventional neuropsychological techniques are necessary. Methods: Participants satisfying clinical consensus criteria for dementia (AD, n = 37; frontotemporal dementia, n = 7; and dementia with Lewy bodies, n = 5), MCI (n = 16), and the healthy controls (n = 22) were administered a battery of brief neuropsychological and select computerized (CogState) cognitive tests. The battery, administered through the University of Michigan Alzheimer’s Disease Research Center, included measures of processing speed, attention, working memory, and learning. Results: CogState and standard neuropsychological task scores were significantly lower for dementia participants than that of the nondementia groups (P < .05), with a single CogState test distinguishing control from MCI participants, but minimal differentiation existing between dementias using the CogState. Correlations were modest between conventional and computerized test scores, covering matching domains and mostly reflecting the multidimensional nature of cognitive paradigms. Conclusions: Results support the clinical validity of this brief computerized screening battery when used in established dementias, but not to differentiate between various dementias, and suggest that the select CogState battery’s effectiveness in identifying MCI from controls was not as strong as identifying specific dementias.

Impact of Mild Cognitive Impairment on Health-Related Quality of Life in Parkinson's Disease

Background/Aims: To assess the impact of mild cognitive impairment (MCI) or cognitive decline on health-related quality of life (HR-QOL) in Parkinsons disease (PD). Methods: HR-QOL measured by the Parkinson Disease Quality of Life Questionnaire (PDQ-39), MCI according to Movement Disorder Society Task Force criteria and cognitive decline from premorbid baseline were assessed in non-demented PD patients at 6 movement disorder clinics. Results: Among 137 patients, after adjusting for education, gender, disease duration, and Movement Disorder Society Unified Parkinsons Disease Rating Scale total score, MCI was associated with worse scores within the PDQ-39 dimension of communication (p = 0.008). Subjects were divided into tertiles of cognitive decline from premorbid level. Scores in the dimension of stigma were worst in the second tertile of cognitive decline (p = 0.03). MCI was associated with worse social support scores in the second tertile of cognitive decline (p = 0.008). Conclusion: MCI and cognitive decline from premorbid baseline are associated with reduced HR-QOL in communication, stigma, and social support domains. The cognitive decline from premorbid baseline modifies the association between MCI and HR-QOL in PD and knowing both will allow a better appreciation of difficulties patients face in daily life.

Enhanced Neuroactivation during Verbal Memory Processing in Postmenopausal Women Receiving Short Term Hormone Therapy

OBJECTIVE To study the effects of hormone therapy on brain activation patterns during verbal memory in postmenopausal women. DESIGN A randomized, double-blind placebo-controlled cross-over study was performed. SETTING A tertiary care university medical center. PATIENT(S) Ten healthy postmenopausal women (age range 56-60 years) were recruited from the local community. INTERVENTION(S) Women were randomized to the order they received combined hormone therapy, 5 microg of ethinyl E(2) and 1 mg of norethindrone acetate, and placebo. Volunteers received hormone therapy or placebo for 4 weeks, followed by a 1-month washout period, and then received the other treatment for 4 weeks. A functional magnetic resonance imaging (fMRI) was performed at the end of each 4-week treatment using a verbal memory task. MAIN OUTCOME MEASURE(S) Brain activation patterns were compared between hormone therapy and placebo. RESULT(S) Hormone therapy was associated with increased activation in the left middle/superior frontal cortex (BA 6,9), medial frontal cortex and dorsal anterior cingulate (BA 24,32), posterior cingulate (BA 6), and left inferior parietal cortex (BA 40) during memory encoding. All regions were significant with correction for multiple comparisons. CONCLUSION(S) Hormone therapy increased neural activation in frontal and parietal areas in postmenopausal women during a verbal memory task.