Intrusion Errors and Progression of Cognitive Deficits in Older Adults with Mild Cognitive Impairment and PreMCI States.

INTRODUCTION: Among persons with amnestic mild cognitive impairment (aMCI), intrusion errors on subscales that measure proactive semantic interference (PSI) may be among the earliest behavioral markers of elevated Alzheimer's disease brain pathology. While there has been considerable cross-sectional work in the area, it is presently unknown whether semantic intrusion errors are predictive of progression of cognitive impairment in aMCI or PreMCI (not cognitively normal but not meeting full criteria for MCI). METHODS: This study examined the extent to which the percentage of semantic intrusion errors (PIE) based on total responses on a novel cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), could predict clinical/cognitive outcomes over an average 26-month period in older adults initially diagnosed with aMCI, PreMCI, and normal cognition. RESULTS: On the LASSI-L subscale sensitive to PSI, a PIE cut point of 44% intrusion errors distinguished between those at-risk individuals with PreMCI who progressed to MCI over time compared to individuals with PreMCI who reverted to normal on longitudinal follow-up. Importantly, PIE was able to accurately predict 83.3% of aMCI individuals who later progressed to dementia. DISCUSSION: These preliminary findings indicate that PIE on LASSI-L subscales that measure PSI may be a useful predictor of clinical progression overtime in at-risk older adults.

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load.

OBJECTIVE: To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. METHODS: Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures. RESULTS: LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain. CONCLUSION: Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study.

OBJECTIVE: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. METHODS: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. RESULTS: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. CONCLUSIONS: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology.

Anaplastic Lymphoma Kinase Positive Mesenteric Inflammatory Myofibroblastic Tumor in Adult Woman.

Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms containing spindle cells and inflammatory components that can be locally aggressive. They have unclear biological behavior and may recur after resection. A 31-year-old woman presented with three months of cough, fatigue, weight loss, abdominal pain, anemia, and elevated inflammatory markers. CT showed a large well-circumscribed enhancing mass in the right colic mesentery. The patient underwent a laparoscopic right colectomy. Pathologic review showed fascicular spindle cells with admixed chronic inflammatory cells. Cells stained diffusely positive for SMA and anaplastic lymphoma kinase (ALK), diagnostic of an IMT. Post-operatively, the patient reported symptom resolution and had normalization of lab values. She remains disease-free at 20 months. IMT is rare in adults, accounting for 0.7%-1.0% of lung tumors. Up to 30% of patients present with elevated inflammatory markers. On imaging, IMTs are soft tissue masses with variable enhancement and fibrosis, often suspected to be malignant neoplasms. Up to 80% of IMTs are driven by altered tyrosine kinase signaling and half of IMTs express ALK, which may be treated in unresectable/recurrent cases using ALK-inhibitors. IMT may recur in 10%-15% of patients. The roles of adjuvant treatments are unclear given the rarity and unpredictable biological behavior. Long-term follow-up with regular radiologic and laboratory surveillance is recommended given possible local recurrence. IMTs are best managed in a multidisciplinary setting given their unpredictable nature. Surgery is the mainstay of IMT treatment with long-term control expected in >80% of adult patients.

Utility of Plasma Neurofilament Light in the 1Florida Alzheimer's Disease Research Center (ADRC).

BACKGROUND: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. OBJECTIVE: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. METHODS: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. RESULTS: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. CONCLUSION: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

The significance of marked nuclear atypia in grade 1 cervical intraepithelial neoplasia.

Approximately 10% to 15% of cases of grade 1 cervical intraepithelial neoplasia are found to have progressed to a high-grade squamous intraepithelial lesion or higher at follow-up, and there are presently no reliable morphological predictors of this subset. It has recently been reported that cases of grade 1 cervical intraepithelial neoplasia that display marked nuclear atypia (defined as cases with at least 5 epithelial cells with nuclear enlargement of at least 5 times the size of an intermediate cell, and/or multinucleation of at least 5 nuclei.) have a substantially higher rate of high-grade squamous intraepithelial lesion on short-term follow-up and may, therefore, require more aggressive initial management. We report herein our experience with a cohort of such cases. After a review of consecutive cervical biopsies, 352 cases with grade 1 cervical intraepithelial neoplasia were classified into group 1 (grade 1 cervical intraepithelial neoplasia with marked atypia, n = 31) and group 2 (grade 1 cervical intraepithelial neoplasia without marked atypia, n = 321). The average follow-up rates for groups 1 and 2 were 93.55% (29/31) and 90.65% (291/321), respectively. Average follow-up durations were 14.3 and 17.9 months, respectively. The follow-up high-grade squamous intraepithelial lesion rate of the cases with marked atypia was 10.34%, as compared with 11.68% for cases without marked atypia. The follow-up interpretive frequency (in cytologic samples) of "low-grade squamous intraepithelial lesion" was significantly higher in group 1(19/29 versus 114/291, P = .009). However, no significant differences were identified between groups 1 and 2 regarding the interpretive frequencies of either high-grade squamous intraepithelial lesion (3/29 versus 34/291, P = 1) or "negative for intraepithelial lesion or malignancy" (6/29 versus 56/291, P = .8) in follow-up cytologic samples. In subsets of both groups in which high-risk human papillomavirus testing was performed in the Papanicolaou test sample that immediately preceded the index cervical biopsies, no significant differences in viral load were found. In conclusion, grade 1 cervical intraepithelial neoplasia with marked atypia does not have a higher follow-up high-grade squamous intraepithelial lesion rate than grade 1 cervical intraepithelial neoplasia without marked atypia in our patient population. Further studies are required to address the significance of marked atypia in grade 1 cervical intraepithelial neoplasia and whether patients with this finding should be managed differently.

Longitudinal cytological follow-up of patients with a papanicolaou test interpretation of "atypical squamous cells of undetermined significance" that was followed by a negative reflex test for high-risk human papillomavirus types.

The 2001 consensus guidelines essentially equated the follow-up management of patients with a Papanicolaou (Pap) test interpretation of negative for intraepithelial lesion or malignancy and those with an interpretation of atypical squamous cells of undetermined significance (ASC-US) that was followed by a negative reflex test for high-risk human papillomavirus (HR HPV) types: follow-up cytology in 12 months. As several years have elapsed since these guidelines attained some measure of widespread implementation, we sought to determine whether, in routinely diagnosed cases, the full spectrum of follow-up cytological findings are indeed identical in these 2 groups. Clinical and pathological data of consecutive patients with a Pap test interpretation of ASC-US during a 6-week period (n = 587), in which reflex human papillomavirus testing was performed (n = 497) and in which HR HPV types were not detected (n = 300), were reviewed (study group). A randomly selected control group of 300 patients whose Pap tests were reported as negative (negative for intraepithelial lesion or malignancy) during the same period were similarly reviewed. The follow-up Pap tests were classified into the various Bethesda 2001 diagnostic categories, and both groups were compared. The average follow-up duration in the study and control groups was 26.03 and 25.9 months, respectively. When all of the follow-up Pap tests in each group (study, n = 555; control, n = 356) were used for the comparisons, patients in the study group were significantly more likely to have an abnormal follow-up Pap test result than the control group patients (24.9% vs 7.6%, P < 0.0001); this was primarily attributable to the more frequent repeat interpretations of ASC-US in the former group (20.5% vs 5.1%, P < 0.0001). The HR HPV detection rates in the follow-up ASC-US cases were not significantly different between the study and control groups. There were no significant differences between both groups regarding the diagnostic frequencies of low-grade squamous intraepithelial lesion and atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (HGSIL). No examples of HGSIL or invasive cancer were identified in the follow-up of either group. All comparisons of statistical significance retained their significance when only 1 follow-up Pap test per patient, the most severe interpretation, was used. Our findings suggest that some significant differences exist between these 2 groups, most notably the comparatively increased frequency of repeat ASC-US interpretations in the study group. However, the extraordinary rarity of the most clinically significant interpretations of HGSIL and carcinoma in this setting can be confirmed because no such cases were identified during the follow-up of either group.

Squamous dysplasia of the uterine cervix: tissue sampling-related diagnostic considerations in 600 consecutive biopsies.

Despite the technological advances in colposcopic techniques, there continues to be a 10% to 20% discordance rate between the colposcopic findings and the histological diagnoses on the resultant biopsies. One of the many factors to which this may be theoretically attributable is related to sampling error from the paraffin-embedded tissue block. In this study, we evaluated the clinical efficacy of routinely obtaining 6 sections in cervical biopsies, using the frequency with which dysplastic lesions would be missed with various levels of sectioning as the sole benchmark determinant of clinical efficacy. Our database was searched for all cervical biopsies in which a diagnosis of squamous dysplastic lesion was made for the period February 1, 2006 to April 28, 2006. All cases were processed in 6-level sectioning, which entails cutting and staining (hematoxylin-eosin) 6 consecutive sections from the paraffin block without preserving or discarding any intervening unstained sections. The first level at which a diagnosis of dysplastic lesion could be unequivocally made by a gynecologic pathologist was determined. Six hundred consecutive biopsies from 404 patients were reviewed. For the whole cohort, the average level at which a dysplastic lesion was unequivocally diagnosable was 1.9 (median, 1). Three hundred fifty-seven (59.5%), 97 (16.2%), 41 (6.8%), 55 (9.2%), 34 (5.7%), and 16 (2.6%) of the 600 lesions were diagnosable at levels 1, 2, 3, 4, 5, and 6, respectively. The cervical intraepithelial neoplasia (CIN) 2 and 3 (n = 89) was, on average, diagnosable at an earlier level (1.35) compared with CIN 1 (level, 2.025; P < 0.001 [n = 511]). Indeed, 79.8% of the CIN 2-3 cases were diagnosable at level 1, as compared with 56% of the CIN 1 cases (P < 0.001); 87, 38, 52, 32, and 16 cases of CIN 1 and 10, 3, 3, 2, and 0 cases of CIN 2-3 were diagnosable at levels 2, 3, 4, 5, and 6, respectively. Therefore, if sectioning were limited to 3 levels, 17.5% (105/600) of all dysplastic lesions would have been missed, including 19.6% (100/511) of CIN 1 and 5.6% (5/89) of CIN 2-3. Because not more than 3 levels are routinely evaluated in most laboratories, our findings suggest that sampling error is indeed at least 1 significant factor contributing to colposcopic/histological discrepancies. Using our clinical efficacy standard, when no pathologic findings are initially identified in a colposcopic-directed biopsy, at least 5 levels (a priori or in recuts) are required to ensure a 100% diagnostic accuracy for CIN 2-3.

Acculturation and drug use among dually diagnosed Hispanic adolescents.

With drug abuse among Hispanic youth on the rise, examining cultural factors such as acculturation may provide insight into understanding and addressing this problem. This study examined the relationship between acculturation and severity of drug use among a sample of severely impaired Hispanic adolescents referred for residential substance abuse treatment. As recent studies with clinical samples have found, it was hypothesized that lower levels of acculturation would be associated with higher levels of substance use. Results indicated that youth born outside the United States reported greater frequency of drug use at intake into treatment than those born in the United States, supporting the hypothesis.