Heather Katzen

reasons for Seeking Genetic Susceptibility Testing Among First-degree Relatives of People With Alzheimer Disease

&NA; Advances in genetic research have provided a basis for susceptibility testing for Alzheimer disease (AD). Prior surveys have examined attitudes toward genetic testing for AD in hypothetical scenarios, but it is unclear what reasons would motivate people to seek testing in real‐life situations. This study presents data from the first randomized trial to evaluate genetic susceptibility testing for asymptomatic adult children of people with AD. We examined (1) reasons endorsed as motivations for seeking testing, (2) demographic characteristics associated with these reasons, and (3) how these reasons related to the eventual decision to pursue testing. Eligible participants were 206 adult children of people with AD (mean age 53 years; 72% female; 93% white), 77.7% of whom (n = 160) went on to seek testing. Participants endorsed numerous reasons for seeking susceptibility testing (mean 7.2), encompassing a range of motivations. The most commonly endorsed reasons were as follows: (1) to contribute to research (93.9%), (2) to arrange personal affairs (87.4%), and (3) the hope that effective treatment will be developed (86.8%). Women strongly endorsed more reasons for seeking testing than men (p < 0.05). The best predictor of actual pursuit of testing was strong endorsement of the need to prepare family members for AD (odds ratio = 3.3, p < 0.01). Findings suggest that genetic susceptibility testing is of interest to individuals at risk for AD for a variety of reasons, even in the relative absence of available treatments.

Side and type of motor symptom influence cognition in Parkinson's disease

It is well known that many patients with Parkinsons disease experience neuropsychological decline. However, the nature and extent of mental status change varies widely, with some patients showing mild or no cognitive impairments and others exhibiting frank dementia. Research has shown that several clinical disease parameters may differentially correlate with patterns of neuropsychological dysfunction. The present study examined side and type of motor symptom at disease onset and their relationship to cognition in idiopathic Parkinsons disease (PD). We identified 58 patients who initially presented with one of the following symptom profiles: right‐side tremor onset (RSO‐T; n = 15), right‐side bradykinesia/rigidity onset (n = 12), left‐side tremor onset (n = 19), and left‐side bradykinesia/rigidity onset (n = 12). There were no differences between groups in disease duration, overall mental status, education, or depression severity. We administered a battery of neuropsychological measures to the four PD subgroups and a group of matched control subjects (n = 40). MANCOVAs controlling for age revealed patients with RSO‐T performed significantly better than the other three PD subgroups across the entire neuropsychological battery. Further, the RSO‐T subgroup performed comparably to controls. In contrast, the other three PD subgroups showed widespread cognitive deficits. These findings suggest an intricate relationship between motor symptom and side of disease onset and it is the combination of these factors that may influence the disease course and extent of cognitive deterioration. Furthermore, patients who develop tremor on the right side of their body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function.

Motor neuron involvement in multisystem proteinopathy: Implications for ALS

Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND). Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families. Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25–52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion: Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD.

Features of gait most responsive to tap test in normal pressure hydrocephalus

OBJECTIVE To identify components of gait associated with a positive tap test (TT) in patients with idiopathic normal pressure hydrocephalus (iNPH). PATIENTS AND METHODS Thirty-three patients with iNPH underwent clinical evaluation pre- and post-TT and were classified as responders (Rs) or non-responders (NRs). Elements of gait were assessed with a formal standardized Gait Scale and compared between groups. RESULTS Analysis of pre/post-TT group differences revealed an interaction for Total Gait Score and Walking Score, with improvements in responders only. Total Gait Scores improved by 29% in the Rs and 4.85% in the NRs. Rs showed significant post-TT improvements on a timed 10m walk, turning, and balance. Tandem walking, turning, truck balance and start stop hesitation showed trends toward improvement. CONCLUSIONS The classic features of gait often used in determining diagnosis of NPH (wide based stride, reduced foot-floor clearance, and small steps) were not helpful in identifying responders to the TT. Walking speed, steps for turning, and tendency towards falling were most likely to improve post-TT. These straightforward measures can readily be adapted into clinical practice to assist in determination of shunt candidacy.

Genetic susceptibility testing versus family history- based risk assessment: Impact on perceived risk of Alzheimer disease

Purpose: We examined how an Alzheimer disease (AD) family history assessment as compared to a risk assessment incorporating the absence of a disease-associated susceptibility allele affected risk perception among adult children with a family history of AD.Methods: The REVEAL study is a clinical trial in which adult children of patients with AD were randomized to receive a risk assessment based upon family history alone or family history plus apolipoprotein E (APOE) disclosure. In this analysis, two subsets of women were identified, each of whom received identical 29% lifetime risk estimates of developing AD. One group received a risk estimate that incorporated APOE ε4-negative genetic test results (Genotype Group, n = 30), whereas the other received a risk estimate based on family history and gender (Family History Group, n = 36). Six weeks after risk disclosure, we surveyed participants regarding the impact of the risk assessment on their perceptions of AD risk.Results: 73% of the Genotype Group judged their risk to be lower compared to 25% of the Family History Group (P < 0.0001). 67% of the Genotype Group reported lower anxiety about AD, versus 26% of the Family History Group (P < 0.01). 80% of the Genotype Group indicated that the risk information had a positive impact, versus 36% of the Family History Group (P < 0.001). The Genotype Group was less likely to believe that they would develop AD (13% vs. 36%, P < 0.05) and was more likely to report that the risk assessment removed uncertainty about their chances of developing AD (63% vs. 9%, P < 0.0001).Conclusions: These data suggest that risk estimates incorporating negative genetic test results affect perceptions of disease susceptibility more strongly than identical estimates based on family history alone.

A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease

BackgroundHallucinations occur in 20–40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinsons disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings.MethodsThe UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons.Results and DiscussionSeventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles.ConclusionUsing the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.

Cognitive decline affects subject attrition in longitudinal research

We evaluated prospectively 210 patients with idiopathic Parkinson’s disease (PD) to determine whether cognitive deterioration and disease disability affect subject drop out. Subjects who refused to return for follow-up testing had a greater degree of bradykinesia and overall disability, more advanced disease, fewer years of education and greater depressive symptomatology. However, discriminant analysis indicated that performance on the neuropsychological measures, rather than PD severity, significantly predicted whether patients return for follow-up testing. Our findings indicate that cognitive impairment uniquely contributes to subject attrition, which may distort dementia estimates in PD.

Recall of disclosed apolipoprotein E genotype and lifetime risk estimate for Alzheimer's disease: the REVEAL Study.

Purpose: To determine whether individuals recall their apolipoprotein E genotype and numeric lifetime risk estimates after undergoing a risk assessment for Alzheimers disease.Methods: One-hundred and four participants underwent Alzheimers disease risk assessment that included disclosure of apolipoprotein E genotype and a numeric lifetime risk estimate.Results: At six weeks and one year post-disclosure, 59% and 48% of participants, respectively, recalled their lifetime risk estimate, and 69% and 63% recalled their apolipoprotein E genotype. Participants were more likely to remember their genotype than numeric lifetime risk estimate at one year (P < 0.05). Apolipoprotein E ɛ4-positive participants had better recall of their genotype at both time points (P < 0.05). Participants were more likely to recall whether they carried the “risk-enhancing form of apolipoprotein E” than their specific genotype (P < 0.05).Conclusions: These data suggest that apolipoprotein E genotype, especially the presence of an ɛ4 allele, is more memorable than a numeric risk estimate for Alzheimers disease. Participants recalled genotype information in a more simplified, binary form. Health professionals testing for complex disorders such as Alzheimers disease must find an appropriate balance between communicating risk in an understandable format and addressing the probabilistic nature of the information.

Postshunt Cognitive and Functional Improvement in Idiopathic Normal Pressure Hydrocephalus

BACKGROUND: Improvement in gait after shunt placement has been well documented in idiopathic normal pressure hydrocephalus (iNPH); however, controversy remains regarding the extent and pattern of postsurgical cognitive changes. Conflicting findings may be explained by variability in both test selection and follow-up intervals across studies. Furthermore, most investigations lack a control group, making it difficult to disentangle practice effects from a true treatment effect. OBJECTIVE: To examine postshunt changes in a sample of well-characterized iNPH participants compared with a group of age- and education-matched healthy control subjects. METHODS: We identified 12 participants with iNPH undergoing shunt placement and 9 control participants. All participants were evaluated with comprehensive neuropsychological testing and standardized gait assessment at baseline and were followed up for 6 months. RESULTS: Repeated-measures analysis of variance revealed a significant group- (iNPH and control) by-time (baseline and 6 months) interaction for Trailmaking Test B: (P < .003) and Symbol Digit Modalities (P < .02), with greater improvement in iNPH participants relative to control subjects. In addition, the iNPH group showed greater improvement in gait (P < .001) and caregivers reported improved activities of daily living (P < .01) and reduced caregiver distress (P < .01). CONCLUSION: This study demonstrates improvements in mental tracking speed and sustained attention 6 months after shunt placement in iNPH. The present investigation is the first study to use a controlled design to show that cognitive improvement in iNPH is independent of practice effects. Furthermore, these findings indicate functional and quality-of-life improvements for both the shunt responder and their caregiver.

Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH.

Objective: To assess the effects of low-dose acetazolamide treatment on volumetric MRI markers and clinical outcome in idiopathic normal-pressure hydrocephalus (iNPH). Methods: We analyzed MRI and gait measures from 8 patients with iNPH with serial MRIs from an institutional review board–approved imaging protocol who had been treated off-label with low-dose acetazolamide (125–375 mg/day). MRI studies included fluid-attenuated inversion recovery and 3D T1-weighted high-resolution imaging. Automated analyses were employed to quantify each patients ventricular, global white matter hyperintensities (WMH), and periventricular WMH (PVH) volumes prior to and throughout treatment. Clinical outcome was based on gait changes assessed quantitatively using the Boon scale. Results: Five of 8 patients responded positively to treatment, with median gait improvement of 4 points on the Boon scale. A significant decrease in PVH volume (−6.1 ± 1.9 mL, p = 0.002) was seen in these patients following treatment. One patients gait was unchanged and 2 patients demonstrated worsened gait and were referred for shunt surgery. No reduction in PVH volume was detected in the latter 2 patients. Nonperiventricular WMH and lateral ventricle volumes remained largely unchanged in all patients. Conclusions: These preliminary findings provide new evidence that low-dose acetazolamide can reduce PVH and may improve gait in iNPH. PVH volume, reflecting transependymal CSF, is shown to be a potential MRI indicator of pharmacologic intervention effectiveness. Further studies of pharmacologic treatment of iNPH are needed and may be enhanced by incorporating quantitative MRI outcomes. Classification of evidence: This study provides Class IV evidence that low-dose acetazolamide reverses PVH volume and, in some cases, improves gait in iNPH.