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1.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
2.  Atherosclerosis Risk Factors in American Indians With Alzheimer Disease 
Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.
doi:10.1097/WAD.0b013e318169d701
PMCID: PMC3176329  PMID: 18580594
atherosclerosis; hypertension; diabetes; homocysteine; Alzheimer disease
3.  Brain MRI, Apoliprotein E Genotype, and Plasma Homocysteine in American Indian Alzheimer Disease Patients and Indian Controls 
Current Alzheimer research  2009;6(1):52-58.
We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61–89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5–13 years in the AD group and 12–16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 μmol/L vs. 9.8 μmol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eε4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).
PMCID: PMC2752625  PMID: 19199875
Alzheimer disease; American Indian; white matter hyperintensities; homocysteine; apolipoprotein E
4.  TDP-43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a Midwest-Southwest Consortium for FTLD study 
TDP-43 is a major component of the inclusions in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We studied TDP-43-pathology in the hippocampus and frontal cortex of autopsy brains with FTLD-U (n=68), dementia lacking distinctive histopathology (n=4), other neurodegenerative diseases (n=23), and controls (n=12). A marked enhancement of TDP-43-positive dystrophic neurites (DN) was obtained by using a sensitive immunohistochemistry protocol. Two previously unrecognized patterns of pathology were observed: frequent long DN in the CA1 region and frequent dot-like DN in the neocortical layer II, which were seen in 39% and 15% of the FTLD-U cases, respectively. Four FTLD-U cases showed no TDP-43 pathology and were reclassified as FTLD-U, non-TDP-43 proteinopathy. Frequent long DN, but not dot-like DN, were significantly associated with progranulin mutations. Three of the DLDH cases were reclassified as FTLD-U. Of the cases with other neurodegenerative diseases, 43% showed TDP-43-pathology in the hippocampus but only 4% in the frontal cortex. No TDP-43-pathology was seen in controls. These results indicate that the sensitivity of the TDP-43 immunohistochemistry method affects both the quantity of the pathology and the types of pathology that can be detected. Involvement of both the hippocampus and frontal cortex may be a diagnostically important feature in FTLD-U.
doi:10.1097/NEN.0b013e31816a12a6
PMCID: PMC2635119  PMID: 18379440
Frontotemporal lobar degeneration with ubiquitinated inclusions; frontotemporal lobar degeneration with motor neuron disease; dementia lacking distinctive histopathology; progranulin; TAR DNA-binding protein 43; dystrophic neurites; autopsy; immunohistochemistry

Results 1-4 (4)