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1.  Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease 
Objective
To investigate how acetylcholinesterase inhibitor (ChEI) treatment impacts brain function in Parkinson’s disease (PD).
Methods
Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after three months of ChEI treatment and were compared to 15 age and sex matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low frequency fluctuations.
Results
At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (e.g., caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (e.g., lateral prefrontal cortex), and episodic memory (e.g., precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased post-treatment compared to baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention.
Conclusions
PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared to controls, and rivastigmine is associated with performance-related normalization in left frontal cortex function.
doi:10.1002/mds.25575
PMCID: PMC4001926  PMID: 23847120
acetylcholine (D02.092.211.111); magnetic resonance imaging functional (E01.370.350.825.500); attention (F02.830.104.214); Acetylcholinesterase Inhibitors (D27.505.519.389.275) executive control (F02.463.217)
2.  Cognition, glucose metabolism and amyloid burden in Alzheimer’s disease 
Neurobiology of aging  2010;33(2):215-225.
We investigated relationships between glucose metabolism, amyloid load and measures of cognitive and functional impairment in Alzheimer’s disease (AD). Patients meeting criteria for probable AD underwent [11C]PIB and [18F]FDG PET imaging and were assessed on a set of clinical measures. PIB Distribution volume ratios and FDG scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.
doi:10.1016/j.neurobiolaging.2010.03.011
PMCID: PMC2920373  PMID: 20417582
amyloid plaques; amyloidosis; Alzheimer’s disease; glucose metabolism; Pittsburgh compound-B; Fluorodeoxyglucose; dementia severity; cognition
3.  C-Reactive Protein is Related to Memory and Medial Temporal Brain Volume in Older Adults 
Brain, behavior, and immunity  2011;26(1):103-108.
Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community dwelling older adults with detectable (n = 76) and undetectable (n= 65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.
doi:10.1016/j.bbi.2011.07.240
PMCID: PMC3221922  PMID: 21843630
inflammation; memory; aging; cognition; temporal lobe; c-reactive protein; cytokines
4.  Cognitive Processing Speed in Older Adults: Relationship with White Matter Integrity 
PLoS ONE  2012;7(11):e50425.
Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55–87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.
doi:10.1371/journal.pone.0050425
PMCID: PMC3503892  PMID: 23185621
5.  Dementia = (MC)2: A Four-Item Screening Test for Mild Cognitive Impairment and Dementia 
To develop a practical informant-based screening tool that reliably identifies patients with mild cognitive impairment (MCI) and dementia, we analyzed data from a sample of patients and normal controls seen in a memory clinic. All subjects were evaluated with the Clinical Dementia Rating scale (CDR). Individual CDR responses were dichotomized and entered into a forward stepwise multivariable logistic regression model. Four independent predictors of MCI and dementia thus identified were combined into a prediction rule that was validated in a separate cohort drawn from the same clinic. Using a cut point of 2 or more positive responses to the four questions, the final prediction rule had sensitivity of 95% (95% CI 92 – 97%) for MCI or dementia, and a specificity of 91% (95% CI 86 – 95%). When applied to the validation cohort, the sensitivity for MCI or dementia was 96% (95% CI 94 – 98%), and the specificity was 96% (95% CI 92 – 98%). Using both cohorts, the positive likelihood ratio for MCI or dementia was 15.6 (95% CI 14.0 – 17.3) and the negative likelihood ratio 0.05 (95% CI 0.04 – 0.07). This tool has the potential to identify patients who warrant further cognitive evaluation in busy outpatient or emergency department settings.
doi:10.1097/WAD.0b013e31820bd36e
PMCID: PMC3156889  PMID: 21566510
Dementia; Mild Cognitive Impairment; Screening; Diagnosis
6.  MILD COGNITIVE IMPAIRMENT, DEMENTIA AND SUBTYPES AMONG OLDEST OLD WOMEN 
Archives of neurology  2011;68(5):631-636.
Objective
To determine the prevalence of mild cognitive impairment (MCI), dementia and subtypes among oldest old women.
Design
Prospective cohort study
Setting
Women, Cognitive Impairment Study of Exceptional Aging
Participants
1299 oldest old (≥ 85 years) women
Main Outcome Measures
All women completed a neuropsychological test battery. Those who screened positive for possible cognitive impairment (n=634) were further assessed for a diagnosis of dementia, MCI, or normal by an expert panel. Remaining women were considered cognitively normal. Dementia and MCI subtypes were determined using standard criteria.
Results
The women had a mean age of 88.2 years and 27.0% were ≥90 years; 231 women (17.8%) were diagnosed with dementia and 301 (23.2%) with MCI for a combined cognitive impairment prevalence of 41.0%. Clinical features consistent with Alzheimer’s disease and mixed dementia were most common, each accounting for 40% of dementia cases. Amnestic multiple domain and non-amnestic single domain were the most common MCI types, accounting for 33.9% and 28.9% of cases respectively. Cognitive impairment was more frequent among women ≥90 years compared to those 85–89 years (dementia 28.2% vs. 13.9%, p<0.0001, and MCI 24.5% v. 22.7%, p=0.02) and more common among women with less education, history of stroke, and prevalent depression.
Conclusions
In this large sample of oldest old women, approximately 40% had clinically adjudicated cognitive impairment. Subtypes of dementia and MCI were similar to younger populations. Our results suggest that women in the fastest growing demographic, the oldest old, should be carefully screened for cognitive disorders, especially high risk groups.
doi:10.1001/archneurol.2011.82
PMCID: PMC3108074  PMID: 21555638
7.  Sporadic Corticobasal Syndrome due to FTLD-TDP 
Acta neuropathologica  2009;119(3):365-374.
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
doi:10.1007/s00401-009-0605-1
PMCID: PMC2832091  PMID: 19876635
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
8.  Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden 
Brain  2010;133(2):512-528.
Patients with early age-of-onset Alzheimer’s disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer’s disease are associated with differences in the distribution and burden of fibrillar amyloid-β. Patients meeting criteria for probable Alzheimer’s disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 ± 5.9 years) and late-onset (n = 18, 72.0 ± 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [18F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer’s disease patient groups showed increased [11C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [11C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo–parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [11C]-labelled Pittsburgh compound-B and [18F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β was associated with greater posterior cortical hypometabolism in early-onset Alzheimer’s disease. Our data are consistent with a model in which both early amyloid-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer’s disease in young patients.
doi:10.1093/brain/awp326
PMCID: PMC2858015  PMID: 20080878
Alzheimer’s disease; age of onset; amyloid-β; [18F]-labelled fluorodeoxyglucose; [11C]-labelled Pittsburgh compound-B
9.  Heterogeneous patterns of tissue injury in NARP syndrome 
Journal of Neurology  2010;258(3):440-448.
Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual–spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-010-5775-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00415-010-5775-1
PMCID: PMC3068520  PMID: 20953793
Mitochondrial disorders; Neuroophthalmology; Neuropsychology; Cerebellar disease; Neuropathy
10.  Cognitive and Neuropsychiatric Profile of the Synucleinopathies: Parkinson's Disease, Dementia with Lewy Bodies and Multiple System Atrophy 
Parkinson's Disease (PD), multiple system atrophy (MSA) and dementia with Lewy Bodies (DLB) share α-synuclein immunoreactivity 1. These “synucleinopathies” have overlapping signs and symptoms, but less is known about similarities and differences in their cognitive and neuropsychiatric profiles. We compared the cognitive and neuropsychiatric profiles of individuals with PD, MSA and DLB. Overall, the DLB group showed the most cognitive impairment, the MSA group demonstrated milder impairment and the PD group was the least cognitively impaired. The DLB and MSA groups showed worse executive function and visuospatial skills than PD, while DLB showed impaired memory relative to both PD and MSA. On the neuropsychiatric screening, all groups endorsed depression and anxiety; the DLB group alone endorsed delusions and disinhibition. Consistent with their greater level of cognitive and neuropsychiatric impairment, the DLB group showed the greatest amount of functional impairment on a measure of instrumental ADLs (FAQ). We found that MSA subjects had cognitive difficulties that fell between the mild deficits of the PD group and the more severe deficits of the DLB group. PD, MSA and DLB groups have similar neuropsychiatric profiles of increased depression and anxiety. Similar underlying α-synuclein pathology may contribute to these shared features.
doi:10.1097/WAD.0b013e3181b5065d
PMCID: PMC2886667  PMID: 19935145
Parkinson's Disease; Dementia with Lewy Bodies; multiple system atrophy; dementia; alpha-synuclein
11.  Cognitive Control, Goal Maintenance, and Prefrontal Function in Healthy Aging 
Cognitive control impairments in healthy older adults may partly reflect disturbances in the ability to actively maintain goal-relevant information, a function that depends on the engagement of lateral prefrontal cortex (PFC). In 2 functional magnetic resonance imaging studies, healthy young and older adults performed versions of a task in which contextual cues provide goal-relevant information used to bias processing of subsequent ambiguous probes. In Study 1, a blocked design and manipulation of the cue--probe delay interval revealed a generalized pattern of enhanced task-related brain activity in older adults but combined with a specific delay-related reduction of activity in lateral PFC regions. In Study 2, a combined blocked/event-related design revealed enhanced sustained (i.e., across-trial) activity but a reduction in transient trial-related activation in lateral PFC among older adults. Further analyses of within-trial activity dynamics indicated that, within these and other lateral PFC regions, older adults showed reduced activation during the cue and delay period but increased activation at the time of the probe, particularly on high-interference trials. These results are consistent with the hypothesis that age-related impairments in goal maintenance abilities cause a compensatory shift in older adults from a proactive (seen in young adults) to a reactive cognitive control strategy.
doi:10.1093/cercor/bhm135
PMCID: PMC2904686  PMID: 17804479
compensation; event-related; executive function; inhibition; working memory

Results 1-11 (11)