Search

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10 −8 ). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2 , TMEM59 , miR-4781 , and LDLRAD1 . Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

To better define the genotype-phenotype correlations between the type of GBA (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD).We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder GBA mutations, and conducted a meta-analysis of risk and AAO according to GBA genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results.Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe GBA mutation carriers, respectively. The observed frequency of severe GBA mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, p0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild GBA mutation carriers and 9.92 and 21.29 for severe GBA mutation carriers (p1 × 10(-6) for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild GBA mutation carriers, respectively (p = 4.3 × 10(-5)).These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.

The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease–related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.

Objective: To investigate the incidence of and risk factors for cognitive impairment in a large, well-defined clinical trial cohort of patients with early Parkinson disease (PD). Methods: The Mini-Mental State Examination (MMSE) was administered periodically over a median follow-up period of 6.5 years to participants in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial and its extension studies. Cognitive impairment was defined as scoring 2 standard deviations below age- and education-adjusted MMSE norms. Results: Cumulative incidence of cognitive impairment in the 740 participants with clinically confirmed PD (baseline age 61.0 ± 9.6 years, Hoehn-Yahr stage 1–2.5) was 2.4% (95% confidence interval: 1.2%–3.5%) at 2 years and 5.8% (3.7%–7.7%) at 5 years. Subjects who developed cognitive impairment (n = 46) showed significant progressive decline on neuropsychological tests measuring verbal learning and memory, visuospatial working memory, visuomotor speed, and attention, while the performance of the nonimpaired subjects (n = 694) stayed stable. Cognitive impairment was associated with older age, hallucinations, male gender, increased symmetry of parkinsonism, increased severity of motor impairment (except for tremor), speech and swallowing impairments, dexterity loss, and presence of gastroenterologic/urologic disorders at baseline. Conclusions: The relatively low incidence of cognitive impairment in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study may reflect recruitment bias inherent to clinical trial volunteers (e.g., younger age) or limitations of the Mini-Mental State Examination–based criterion. Besides confirming known risk factors for cognitive impairment, we identified potentially novel predictors such as bulbar dysfunction and gastroenterologic/urologic disorders (suggestive of autonomic dysfunction) early in the course of the disease.

To examine caloric intake, dietary composition, and body mass index (BMI) in participants in the Prospective Huntington At Risk Observational Study (PHAROS).Caloric intake and macronutrient composition were measured using the National Cancer Institute Food Frequency Questionnaire (FFQ) in 652 participants at risk for Huntington disease (HD) who did not meet clinical criteria for HD. Logistic regression was used to examine the relationship between macronutrients, BMI, caloric intake, and genetic status (CAG37 vs CAGor =37), adjusting for age, gender, and education. Linear regression was used to determine the relationship between caloric intake, BMI, and CAG repeat length.A total of 435 participants with CAG37 and 217 with CAGor =37 completed the FFQ. Individuals in the CAGor =37 group had a twofold odds of being represented in the second, third, or fourth quartile of caloric intake compared to the lowest quartile adjusted for age, gender, education, and BMI. This relationship was attenuated in the highest quartile when additionally adjusted for total motor score. In subjects with CAGor =37, higher caloric intake, but not BMI, was associated with both higher CAG repeat length (adjusted regression coefficient = 0.26, p = 0.032) and 5-year probability of onset of HD (adjusted regression coefficient = 0.024; p = 0.013). Adjusted analyses showed no differences in macronutrient composition between groups.Increased caloric intake may be necessary to maintain body mass index in clinically unaffected individuals with CAG repeat lengthor =37. This may be related to increased energy expenditure due to subtle motor impairment or a hypermetabolic state.

Objective: Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD. Methods: We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations. Results: We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at ≤45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at ≤45 years, p = 0.06). Conclusions: Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Objective: To evaluate the frequency of glucocerebrosidase ( GBA ) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study. Methods: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO Results: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p p 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) ( p GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, Rec NciI , and a novel mutation, P175P. Conclusions: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset. GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.

Background: Cognitive impairment continues to be a significant neurologic complication of HIV infection and has been associated with oxidative stress-induced neuronal injury. Selegiline is an MAO-B inhibitor with antioxidant and neurotrophic properties. This rationale has led to the design and implementation of this Selegiline Transdermal System (STS) study with the primary aims of assessing safety and tolerability of STS as well as improvement in cognitive performance. Methods: HIV-1 infected individuals with impaired cognitive functioning were enrolled in this placebo-controlled, three-arm study of STS across 17 sites. Cognitive impairment was determined using a standard battery of neuropsychological tests. Subjects were randomized to receive STS 3 mg/24 hours, STS 6 mg/24 hours, or matching placebo patches daily. The primary efficacy endpoint was defined as the change in neuropsychological composite Z-score (NPZ-6) from baseline to week 24. Measures of safety included frequencies of adverse experiences and abnormal results on laboratory tests. Results: A total of 128 subjects (88% men, 51% white) were enrolled, median age 45 years. Most subjects (62%) had mild to moderate AIDS dementia complex. The 24-week NPZ-6 median (interquartile range) changes were 0.22 (−0.28, 0.55) for the selegiline 3 mg/24 hours arm, 0.21 (−0.18, 0.62) for the selegiline 6 mg/24 hours arm, and 0.28 (−0.16, 0.64) for the placebo arm (a positive score indicates improvement from baseline) ( p = 0.914). Severe laboratory abnormalities were few and occurred in similar proportion among the three treatment arms. Conclusion: Selegiline was safe and well tolerated by HIV-infected individuals with cognitive impairment and mild to moderate immune suppression; however, no cognitive or functional improvement was observed in this phase II study.

Objective: To characterize deficits in nonverbal recognition memory and functional brain changes associated with these deficits in Alzheimer disease (AD). Methods: Using O-15 PET, we studied 11 patients with AD and 17 cognitively intact elders during the combined encoding and re- trieval periods of a nonverbal recognition task. Both task conditions involved recognition of line draw- ings of abstract shapes. In both conditions, subjects were first presented a list of shapes as study items, and then a list as test items, containing items from the study list and foils. In the titrated demand condition, the shape study list size (SLS) was adjusted prior to imaging so that each subject performed at approximately 75% recognition accuracy; difficulty during PET scanning in this condi- tion was approximately matched across subjects. A control task was used in which SLS 1 shape. Results: During performance of the titrated demand condition, SLS averaged 4.55 (1.86) shapes for patients with AD and 7.53 (4.81) for healthy elderly subjects (p 0.031). However, both groups of subjects were closely matched on performance in the titrated demand condition during PET scanning with 72.17% (7.98%) correct for patients with AD and 72.25% (7.03%) for elders (p 0.979). PET results demonstrated that patients with AD showed greater mean differences between the ti- trated demand condition and control in areas including the left fusiform and inferior frontal regions (Brodmann areas 19 and 45). Conclusions: Relative fusiform and inferior frontal differences may re- flect the Alzheimer disease (AD) patients' compensatory engagement of alternate brain regions. The strategy used by patients with AD is likely to be a general mechanism of compensation, rather than task-specific. NEUROLOGY 2007;69:32-41

Objective: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. Methods: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Results: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington9s Disease Rating Scale. When a movement disorder specialist initially had a global impression of “soft signs” present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Conclusions: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.

To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD).We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in theor =50 age at onset (AAO) category.The LRRK2 G2019S mutation was present in 28 cases with PD (5.6%) and two controls (0.6%) (chi(2) = 13.25; p0.01; odds ratio 9.18, 95% CI: 2.17 to 38.8). The mutations L1114L, I1122V, R1441C, and Y1699C were not identified. The frequency of the LRRK2 G2019S mutation was 4.9% in 245 cases with AAOor =50 years vs 6.2% in 259 cases with AAO50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p0.01). Age-specific penetrance to age 80 was 24% and was similar in Jewish and non-Jewish cases.The G2019S mutation is a risk factor in both early- and late-onset Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

Background: Mild parkinsonian signs (MPS) are associated with prevalent and incident dementia but it is not known whether they are associated with mild cognitive impairment (MCI). Objective: To determine whether MPS and specific MPS (changes in axial function, rigidity, tremor) are associated with MCI in nondemented community-dwelling older people in northern Manhattan, NY. Methods: Participants underwent neurologic assessment, including a modified motor portion of the Unified Parkinson Disease Rating Scale. MCI was diagnosed in nondemented participants who had cognitive impairment based on neuropsychological testing and no functional impairment. Participants with MCI were classified as having MCI with memory impairment (MCI+M) vs MCI without memory impairment (MCI-M). Results: MCI was present in 608 (27.3%) of 2,230 participants, including 255 participants with MCI+M and 353 with MCI-M; 1,622 participants did not have MCI. MPS were present in 369 (16.5%) of 2,230 participants. In a univariate logistic regression model, odds of MCI+M (vs no MCI) were 51% higher in participants with MPS compared to those with no MPS (OR = 1.51, 95% CI = 1.09 to 2.09, p = 0.01). Multivariate models yielded similar results (OR = 1.45, 95% CI = 1.03 to 2.05, p = 0.03). Rigidity was present in a higher proportion of participants with MCI+M compared to participants without MCI. Conclusions: Mild parkinsonian signs, especially rigidity, are associated with amnestic mild cognitive impairment. Mild parkinsonian signs and mild cognitive impairment may share similar pathogeneses. Whether this involves Alzheimer-type pathology, Lewy bodies, or vascular changes in the basal ganglia or basal ganglia circuitry deserves further investigation in postmortem studies.

To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-associated dementia (HIVD) in a cohort with advanced HIV infection.A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/muL, or300/microL but with cognitive impairment, underwent semiannual neurologic, cognitive, functional, and laboratory assessments. HIVD and minor cognitive motor disorder (MCMD) were defined using American Academy of Neurology criteria. The cumulative incidence of HIVD was estimated using Kaplan-Meier curves. Cox proportional hazards regression models were used to examine the associations between biologic variables and time to HIVD, adjusting for age, sex, years of education, duration of HIV infection, type of antiretroviral use, premorbid IQ score, and presence of MCMD.After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log10) were associated with time to HIVD; log10 levels of plasma TNFalpha (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be associated with time to HIVD.The lack of association between baseline plasma and CSF HIV RNA levels and incident dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-associated dementia.

Objective: To determine the inter-rater reliability of a modification of the Memorial Sloan-Kettering (MSK) Staging for HIV-associated cognitive impairment. Methods: Data were abstracted on neurologic, neuropsychological, and functional status on 100 individuals participating at four sites in the Northeast AIDS Dementia (NEAD) Consortium cohort study, a longitudinal study of predictors of cognitive impairment in HIV-infected individuals. Neuropsychological performance was defined 1) based on the neuropsychologist’s global impression and 2) solely based on neuropsychological test scores. Raters at each site used the abstracted data to assign an MSK stage to each subject blind to any identifying information. Inter-rater reliability was assessed using kappa statistics. Agreement between computer-generated ratings and site-generated ratings was also assessed. Results: Kappa statistics for pair-wise agreement among the sites regarding MSK stage ranged from 0.70–0.91, representing good to excellent agreement between sites. Agreement between computer-generated ratings and site-generated ratings was in the good to excellent range (0.62–0.79). Conclusions: The authors have modified the MSK rating scale and developed a reliable instrument that can be used in multicenter studies. This instrument will be useful in staging HIV-dementia in future longitudinal studies and will be valuable in increasing accuracy of clinicopathologic studies.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z -scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day ( p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

Objective: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects.Methods: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported.Results: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan–Meier estimate of the 1-year incidence of SDSP was 36%.Conclusion: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Background: Early onset PD has been associated with different mutations in the Parkin gene, including exon deletions and duplications.Methods: The authors performed an extensive mutational analysis on 50 probands with onset of PD at younger than 50 years of age. Thirteen probands were ascertained from a registry of familial PD and 37 probands by age at onset at younger than 50 years, blind to family history. Mutational analysis was undertaken on the probands and available family members and included conventional techniques (single strand conformation polymorphism analysis and sequencing) and a newly developed method of quantitative duplex PCR to detect alterations of gene dosage (exon deletions and duplications) in Parkin.Results: Using this new technique, the authors detected eight alterations of gene dosage in the probands, whereas 12 mutations were found by conventional methods among the probands and another different mutation in an affected family member. In total, the authors identified compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no Parkin mutation in 74% of the 50 probands. We expanded the occurrence of Parkin mutations to another ethnic group (African-American).Conclusion: The authors systematically screened all 12 Parkin exons by quantitative PCR and conventional methods in 50 probands. Eight mutations were newly reported, 2 of which are localized in exon 1, and 38% of the mutations were gene dosage alterations. These results underline the need to screen all exons and to undertake gene dosage studies. Furthermore, this study reveals a frequency of heterozygous mutation carriers that may signify a unique mode of inheritance and expression of the Parkin gene.

Objective: To assess HIV-1 RNA levels and the relationship between HIV-1 reverse transcriptase (RT) genotype from plasma and cerebrospinal fluid (CSF) during treatment with abacavir (Ziagen, ABC) or placebo in combination with stable background therapy (SBG) in subjects with AIDS dementia complex (ADC) (study CNA3001). Design: One-hundred and five HIV-1 infected adults with ADC were randomized to receive either ABC (600 mg twice daily) or ABC-matched placebo (twice daily) in addition to SBG for 12 weeks. Methods: Plasma and CSF were collected for population sequencing at baseline and week 12 (CSF optional). Sequences were analyzed for mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI). Results: Sixty out of sixty-seven subjects with baseline plasma HIV-RT sequence data harbored virus with ≥ 1 NRTI-associated mutations; 50 out of 67 had the M184V mutation. At week 12, more subjects in the ABC group had plasma HIV-1 RNA ≤ 400 copies/ml than the SBG group (46% versus 13%, P= 0.002). Non-response to ABC was associated with multiple baseline zidovudine (ZDV)/stavudine (d4T)-associated mutations. Baseline RT mutation patterns differed in 14 out of 21 (67%) paired samples from plasma and CSF. Four subjects experienced > 1 log 10 copies/ml reductions in CSF HIV-1 RNA, two in the absence of reductions in plasma HIV-1 RNA and two with undetectable plasma HIV-1 RNA at baseline. Conclusions: Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations. HIV-1 RNA responses and RT genotype appear to be discordant between CSF and plasma in some subjects.

Cognitive and functional outcomes are of primary interest in the design of efficacy trials in HIV-associated cognitive impairment. In a longitudinal cohort study, weak associations were found between measures of cognitive performance and commonly used measures of daily functioning (mostly self-report measures) in HIV-infected individuals. Modifications of current functional scales or new functional instruments are needed to assess the clinical relevance of cognitive changes in clinical trials of HIV-associated cognitive impairment.

To determine whether the pathologic mechanisms of AD alter the brain networks subserving performance of a verbal recognition task.Functional imaging studies comparing task-related activation in AD patients and controls generally have not used network analysis and have not controlled for task difficulty.H2 15O PET was used to measure regional cerebral blood flow in 14 patients and 11 healthy elders during the performance of a serial verbal recognition task under two conditions: low demand, with study list size (SLS) equal to one; and titrated demand, with SLS adjusted so that each subject recognized words at 75% accuracy. The Scaled Subprofile Model was used to identify networks of regionally covarying activity across these task conditions.In the elders, higher SLS was associated with the recruitment of a network of brain areas involving left anterior cingulate and anterior insula (R2 = 0.94; p0.0001). Three patients also expressed this network. In the remaining patients, higher SLS was associated with the recruitment of an alternate network consisting of left posterior temporal cortex, calcarine cortex, posterior cingulate, and the vermis (R2 = 0.81, p0.001). Expression of this network was unrelated to SLS in the elders and more intact AD patients.The patients' use of the alternate network may indicate compensation for processing deficits. The transition from the normal to the alternate network may indicate a point where brain disease has irreversibly altered brain function and thus may have important implications for therapeutic intervention.

Objective: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTls), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. Design: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. Setting: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites Patients: Adult HIV-infected patients (n = 1313) with CD4 counts < 50 × 10 6 cells/l. Interventions: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. Main outcome measures: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. Results: Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. Conclusions: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

In the era of genetic research for neurodegenerative diseases, less attention has been paid to epidemiologists' search for potential environmental risk factors for Parkinson disease (PD). Epidemiologic evidence suggests that cigarette smoking is associated with about 50% lower risk of PD1 and exposure to certain pesticides such as rotenone and paraquat is associated with doubled risk.2 Recent studies also suggest that higher concentration of serum urate, an endogenous antioxidant, is associated with a lower risk of PD.3 Compared with these observations, another epidemiologic finding has been largely neglected. Several prospective studies,4–7 including the Honolulu-Asia Aging Study (HAAS),6 have reported that higher consumption of dairy products, or milk alone, was associated with higher risk for PD. The authors thank Dr. Freya Kamel for suggestions on the editorial.

Several case reports have suggested an association between human T-cell lymphotropic virus type II (HTLV-II) infection and chronic neurologic disease. We performed serial neurologic examinations in injection-drug users (IDU), a group known to be at increased risk for HTLV-II infection. At baseline, those infected with HTLV-II alone, human immunodeficiency virus (HIV) alone, or both were significantly more likely to have neurologic disability than uninfected subjects. Longitudinally, HTLV-II infection was independently associated with the development of global neurologic disability and neuropathy, suggesting that HTLV-II causes neurologic disease.NEUROLOGY 1996;46: 1556-1560

Article abstract—We attempted to characterize the changes in cognition associated with the earliest, or preclinical, stages of Alzheimer's disease (AD) by administering a comprehensive neuropsychological test battery to a group of initially nondemented older adults participating in a prospective epidemiologic study of dementia. Using Cox regression analyses, we examined the associations between baseline neuropsychological test scores and subsequent development of AD. Results confirmed preliminary findings that baseline scores on the Boston Naming Test, Immediate Recall on the Selective Reminding Test, and the Similarities subtest of the Wechsler Adult Intelligence Scale-Revised were significantly and independently associated with later diagnosis of AD. Analyses controlled for the effects of age, education, sex, and language of test administration. These results lend support to the notion of a preclinical phase of AD and indicate that this very early stage of AD is characterized by poor word-finding ability, abstract reasoning, and memory.

Results of therapeutic trials with physostigmine in the treatment of Alzheimer disease (AD) have been inconsistent and controversy persists concerning safety and efficacy. In a double-blind, placebo-controlled, crossover study, patients received 6 weeks of oral physostigmine (OP) and placebo in random order. Twenty-nine patients with AD received as much as 16 mg/day of OP and were assessed with neuropsychological and functional measures. No significant cardiac side effects were noted, though other systemic adverse effects were noted, requiring dose reduction in four patients. There was a slight but significant improvement (12%) in performance on the selective reminding test with physostigmine and the memory performance was correlated with dosage. This improvement compares favorably with the 15% decrease in scores seen in an untreated comparison cohort followed for an equivalent time period. There was a trend toward an improvement in communication and a reduction in memory complaint. These results suggest that oral physostigmine is safe and may improve memory in AD.

The "Predictors Study" is a prospective cohort study of the natural history of Alzheimer disease (AD), the aim of which is to identify milestones in disease progression and to develop a model to predict disease course in individual patients. The empirical background to this study is based on previous reports that the presence of extrapyramidal signs (EPS), myoclonus, and psychosis in AD may signify greater disease severity at any given stage and a more rapid course of the disease over time. The present analyses were conducted to determine whether these independent "predictor" variables were associated with greater disease severity at baseline within a new cohort of 224 mild AD patients recruited from three different medical centers (in New York, Baltimore, and Boston). Measures of disease severity were provided by the modified Mini-Mental State Examination (mMMSE) and the Blessed Dementia Rating Scale (BDRS), which measures functional capacity. Independent variables were EPS, delusions, and slowing of the posterior dominant EEG rhythm. The frequency of myoclonus and hallucinations was too low to permit adequate statistical assessment of their effects at this time. EPS and EEG slowing were associated with low mMMSE scores, whereas delusions were primarily associated with impaired functional capacity. These effects were independent of the influence of age and disease duration. These results indicate that the effects of these independent variables can be detected at mild stages of AD and that these effects can be generalized across different geographical regions.

Estrogen was the hormone of the 1990s, empowering postmenopausal women against the future ravages of osteoporosis, cardiovascular disease, and perhaps AD. Three large primary prevention trials in AD will provide information in several years on the efficacy of estrogen replacement therapy (ERT) in preventing or delaying the onset of AD. In this issue of Neurology , Wang et al.1 present the third large double-blind, placebo-controlled trial of estrogen in women with AD published this year. All three studies1-3 found no role for conjugated equine estrogens (CEE) in the treatment of postmenopausal women with AD (table). View this table: Table 1. Characteristics of the studies Laboratory evidence suggests that estrogen may increase cholinergic transmission, has neurotrophic effects,4 and has antiamyloidogenic properties.5 This has made estrogen an attractive candidate for both prevention and treatment of AD. A meta-analysis of 10 studies, including …

Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.

Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimer's disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's disease, we studied 1124 elderly women who were initially free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community.Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1-5 years).Overall, 156 (12.5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimer's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5.8%] oestrogen users vs 158/968 [16.3%] nonusers; 0.40 [95% Cl 0.22-0.85], p0.01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer's disease.Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women.

The term “neurodegenerative” implies a period of normal development preceding cell death. Determining when decline begins and the selective vulnerability of specific brain regions to the degenerative cascade is key to development of disease-modifying therapies. Huntington disease (HD), an autosomal dominant disease with little contribution from modifier genes, and complete penetrance in individuals with CAG repeat length ≥40 in the Huntington ( Htt ) gene, permits the identification of an at-risk population for whom the probability of age at diagnosis can be modeled based on CAG repeat length and age. What if Huntington disease is both a neurodevelopmental disorder and a neurodegenerative disease? The possibility that mutant Htt ( mHtt ) might result in fundamental embryonic developmental abnormalities that correlate with the patterns of …

Objective: To compare the cognitive performance carriers and non-carriers of parkin mutations with long disease duration. Background We and others have reported that early-onset Parkinson disease (EOPD) individuals who are parkin mutation carriers have similar neuropsychological performance to non-carriers; however, it is unknown whether the risk for cognitive impairment among carriers and non-carriers remains similar as the disease advances. Design/Methods: We recruited 1103 individuals through the CORE-PD study through 16 centers, of which 155 probands underwent detailed neuropsychological testing. Carriers of LRRK2 and GBA mutation were excluded. Participants were divided by disease duration (range 1-47 years) median split. Neuropsychological performance among participants with longer duration (>14years) was examined. Neuropsychological domains included psychomotor speed, attention, memory, visuospatial function, and executive function. Domain scores were compared for parkin heterozygotes (n=9), compound heterozygotes/homozygotes combined (n=17) and non-carriers (n=22). Linear regression models were applied to assess the association between parkin mutation status (independent variable) and domain scores (dependent), adjusted for age, education and age at onset (AAO). Models were repeated to compare: 1.) homozygotes/compound heterozygotes to non-carriers excluding heterozygotes, and 2.) all mutation carriers to non-carriers. Results: Parkin mutation status was associated with younger age (heterozyogtes=53.4years, homozygotes/compound heterozygotes=53.3years, non-carriers=61.4years, p=0.012) and younger AAO (heterozygotes=30.4, homozygotes/compound heterozygotes=27.4, non-carrier=40.2 p parkin homozygotes/compound heterozygotes mutation status was associated with better performance after adjustment for age, AAO and education for memory (p=0.029) and attention (p=0.004). When all parkin carriers were compared with non-carriers the differences were noted in the executive domain (p=0.013) as well as memory and attention. Conclusions: EOPD individuals with long disease duration who are parkin mutation carriers perform better on tests of memory, attention and executive functioning than non-carriers. Supported by: NS36630, ULI RR024156 (Karen Marder). Disclosure: Dr. Caccappolo has nothing to disclose. Dr. Alcalay has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the NIH, Michael J. Fox Parkinson Disease Foundation, CHDI, and the Huntington9s Disease Society of America. Dr. Tang has nothing to disclose. Dr. Rosado has nothing to disclose. Dr. Mejia-Santana has nothing to disclose. Dr. Ruiz has nothing to disclose. Dr. Orbe-Reilly has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Verbitsky has nothing to disclose. Dr. Kisselev has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Colcher has nothing to disclose. Dr. Comella has received personal compensation for activities with Ipsen, Merz Pharma, Allergan, Inc., and NuPathe. Dr. Comella has received research support from Ipsen, Merz Pharma, Allergan, Inc., the National Institutes of Health, and the Dystonia Study Group. Dr. Siderowf has received personal compensation for activities with Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. Dr. Siderowf has received research support from the NINDS, the Department of Health of the Commonwealth of Pennsylvania, and Avid Radiopharmaceuticals. Dr. Jennings has received personal compensation for activities with Lundbeck Research USA as a speaker. Dr. Nance has received research support from Medivation, Santhera, Juvantia, Neurosearch Sweden, Pfizer Inc, Neuraltus, Impax, and Schwarz Biosciences. Dr. Bressman has received license fee payments from Beth Israel/Mount Sinai/Athena. Dr. Scott has nothing to disclose. Dr. Tanner has received personal compensation for activities with Impax Pharmaceuticals, Allergan, Inc. & Genentech, Inc. as a consultant. Dr. Tanner has received research support from Michael J. Fox Foundation, Department of Defense, Parkinson9s Disease Foundation, Parkinson9s Institute, Unity Walk and Brin Foundation. Dr. Mickel has nothing to disclose. Dr. Waters has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Intec Pharma, Merz Pharma, Oxford Biomedica, RJG Foundation, IMPAX Pharmaceuticals, and Lundbeck as a consultant. Dr. Fahn has received personal compensation in an editorial capacity for Elsevier and Springer. Dr. Cote has nothing to disclose. Dr. Frucht has received personal compensation for activities with UCB Pharma. Dr. Ford has received personal compensation for activities with Novartis and Medtronic, Inc. Dr. Rezak has received personal compensation for activities with Medtronic, Teva, Novartis, Allergan, Smih-Klein, Boehringer-Ingleheim, and UBC as a speaker. Dr. Friedman has received personal compensation for activities with Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Genzyme Corporation, Adix, Roche Diagnostics Corporation. Dr. Friedman has received research support from Teva Neuroscience, Merck & Co., Inc., EMD Serono, Schering-Plough Corporation, National Institutes of Health, Michael J. Fox Foundation, GE Healthcare and Acadia. Dr. Marsh has nothing to disclose. Dr. Hiner has received personal compensation for activities with Teva Neuroscience. Dr. Payami has nothing to disclose. Dr. Molho has received personal compensation for activities with Allergan, Teva, Merz, Ipsen, and Boehringer Ingelheim. Dr. Molho has received research support from Teva, Allergan, Merz, IPsen, Parkinson9s Study Group, and Huntington9s Study Group. Dr. Ottman has received personal compensation for activities with Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Clark has nothing to disclose.

Objective: We describe all Juvenile Parkinson9s Disease (JPD) probands who were recruited through the CORE-PD study. Background JPD is exceptionally rare, seldom reported, and defined as disease age at onset (AAO) Design/Methods: Eleven hundred and three individuals with early-onset PD (defined as AAO SNCA , PRKN , PINK1 , DJ1 , LRRK2 and GBA . Results: Twenty probands (1.8%) reported AAO PRKN carriers, two were PRKN heterozygotes, two carried heterozygous GBA mutations (one L444P and one N370S) and one carried the LRRK2 G2019S mutation. Only four (20%) reported a family history of PD in a first degree relative, all of whom carried PRKN mutations (two compound heterozygotes and two heterozygotes). Of these four probands, two had a family history of JPD in siblings (one heterozygote with AAO=16 and one compound heterozygote with AAO=12), each with a similar genotype to proband. None of the 66 PRKN mutation carriers with disease onset>20 had a sibling with JPD. Conclusions: JPD is extremely rare among EOPD. While identifiable genetic risk factors are common, first degree family history of PD is present in a minority. Supported by: Funded by NIH NS36630, UL1 RR024156 (K.S.M.), NS050487, NS060113 (L.N.C.), the Parkinson9s Disease Foundation (K.S.M., S.F., and L.N.C.), P50 NS039764 (W.K.S) and NS36960 (H.P). RNA is a Brookdale Foundation Leadership in Aging Fellow. Disclosure: Dr. Alcalay has nothing to disclose. Dr. Rosado has nothing to disclose. Dr. Mejia-Santana has nothing to disclose. Dr. Orbe-Reilly has nothing to disclose. Dr. Caccappolo has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Ruiz has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Verbitsky has nothing to disclose. Dr. Kisselev has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Comella has received personal compensation for activities with Ipsen, Merz Pharma, Allergan, Inc., and NuPathe. Dr. Comella has received research support from Ipsen, Merz Pharma, Allergan, Inc., the National Institutes of Health, and the Dystonia Study Group. Dr. Colcher has nothing to disclose. Dr. Jennings has received personal compensation for activities with Lundbeck Research USA as a speaker. Dr. Nance has received research support from Medivation, Santhera, Juvantia, Neurosearch Sweden, Pfizer Inc, Neuraltus, Impax, and Schwarz Biosciences. Dr. Bressman has received license fee payments from Beth Israel/Mount Sinai/Athena. Dr. Scott has nothing to disclose. Dr. Tanner has received personal compensation for activities with Impax Pharmaceuticals, Allergan, Inc. & Genentech, Inc. as a consultant. Dr. Tanner has received research support from Michael J. Fox Foundation, Department of Defense, Parkinson9s Disease Foundation, Parkinson9s Institute, Unity Walk and Brin Foundation. Dr. Andrews has nothing to disclose. Dr. Waters has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Intec Pharma, Merz Pharma, Oxford Biomedica, RJG Foundation, IMPAX Pharmaceuticals, and Lundbeck as a consultant. Dr. Fahn has received personal compensation in an editorial capacity for Elsevier and Springer. Dr. Cote has nothing to disclose. Dr. Frucht has received personal compensation for activities with UCB Pharma. Dr. Ford has received personal compensation for activities with Novartis and Medtronic, Inc. Dr. Rezak has received personal compensation for activities with Medtronic, Teva, Novartis, Allergan, Smih-Klein, Boehringer-Ingleheim, and UBC as a speaker. Dr. Novak has nothing to disclose. Dr. Friedman has received personal compensation for activities with Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Genzyme Corporation, Adix, Roche Diagnostics Corporation. Dr. Friedman has received research support from Teva Neuroscience, Merck & Co., Inc., EMD Serono, Schering-Plough Corporation, National Institutes of Health, Michael J. Fox Foundation, GE Healthcare and Acadia. Dr. Pfeiffer has received personal compensation for activities with UCB Pharmaceuticals, Teva Neurosciences, Novartis, Glaxo-Smith-Kline, and Boehringer Ingelheim.Dr. Pfeiffer has received personal compensation in an editorial capacity for Parkinsonism and Related Disorders.Dr. Pfeiffer has received (royalty or license fee or contractual rights) payments from Butterworth Heinemann, Elsevier, CRC Press, Taylor & Francis, and Humana Press.Dr. Pfeiffer has received research support from Boehringer Ingelheim, UCB Pharmaceuticals, and Schwarz Biosciences. Dr. Marsh has received research support from Eli Lilly & Company, Forest Pharmaceuticals, Acadia, Ovation, and National Institutes of Health. Dr. Hiner has received personal compensation for activities with Teva Neuroscience. Dr. Siderowf has received personal compensation for activities with Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. Dr. Siderowf has received research support from the NINDS, the Department of Health of the Commonwealth of Pennsylvania, and Avid Radiopharmaceuticals. Dr. Payami has nothing to disclose. Dr. Molho has received personal compensation for activities with Allergan, Teva, Merz, Ipsen, and Boehringer Ingelheim. Dr. Molho has received research support from Teva, Allergan, Merz, IPsen, Parkinson9s Study Group, and Huntington9s Study Group. Dr. Nutt has received personal compensation for activities with XenPort, Impax Laboratories, Neurogen, Synosia, Neuroderm, Merck, Lily/Medtronic, Elan Pharmaceuticals, Lundbeck, Merz Pharmaceuticals, Synagile, and the National Parkinson Foundation. Dr. Nutt has received research support from Merck. Dr. Factor has received personal compensation for activities with Merz and Ipsen as a consultant. Dr. Factor has received personal compensation in an editorial capacity for Current Neurology and Neuroscience. Dr. Factor has received research support from Ceregene, Teva Neuroscience, Ipsen, and EMD Serono. Dr. Ottman has received personal compensation for activities with Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Clark has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the NIH, Michael J. Fox Parkinson Disease Foundation, CHDI, and the Huntington9s Disease Society of America.

Compared with the knife-edge lobar atrophy that defines the gross pathology of frontotemporal dementia (FTD), the clinical picture of this disorder has less sharp contours.1,2⇓ Articles in this issue of Neurology consider the prevalence of FTD,3 clinical diagnostic criteria for FTD,4 and CSF biomarkers as diagnostic aids.5 Although FTD is uncommon in autopsy series from research centers or from community-based dementia studies,6 the counter-claim is that FTD is underrecognized clinically and accounts for at least 20% of presenile dementia.1 Epidemiologic studies of dementia typically survey people aged 65 and older and may exclude most cases of FTD. Ratnavalli et al.3 determined the prevalence of dementia with onset before age 65 in a geographically defined population. They contacted all primary care, specialty neurology, and psychiatry providers, examined district medical records, and personally evaluated as many patients with suspected FTD as possible, using a detailed clinical and radiologic assessment. They diagnosed FTD according to the consensus criteria of 1998,7 a modification of the earlier set of Manchester–Lund criteria.8 A small retrospective study showed that the consensus criteria had excellent sensitivity and specificity when applied by …

Objective: To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. Background: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. Methods: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. Results: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber’s hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. Conclusions: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.

The authors conducted a pilot randomized, double-blind, placebo-controlled clinical trial of the transdermal administration of selegiline in HIV+ patients to obtain preliminary data to assess its safety, tolerability, and impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few adverse events. Improvements favoring the selegiline group were suggested on single tests of verbal memory and motor/psychomotor performance, warranting a larger study.

Objective: To assess the safety and tolerability of lexipafant in HIV-associated cognitive impairment. Background: Cognitive impairment is the most common neurologic complication of advanced HIV-1 infection. There is evidence that a variety of inflammatory mediators, including platelet-activating factor (PAF), may contribute to neuronal injury. We hypothesized that lexipafant, a PAF antagonist, might improve cognitive dysfunction in HIV-infected people. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the safety and tolerability of lexipafant 500 mg/day. The primary outcome measure for tolerability was the ability to complete the study on the originally assigned dosage of medication. Thirty patients with cognitive impairment were enrolled. Results: Lexipafant was safe and well tolerated. Ninety-three percent in the placebo group and 88% in the lexipafant group completed the study at the originally assigned dosage. Trends toward improvement were seen in neuropsychological performance, especially verbal memory, in the lexipafant treatment group. Conclusions: This study shows that lexipafant, the first PAF antagonist used in HIV-associated cognitive impairment, is a safe and well tolerated compound. The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance.

Reply from the Authors: We thank Drs. Piccirilli, D'Alessandro, Finali, and Piccinin for their interest in our research and for their thoughtful comments. We concur that the degree of cognitive dysfunction and the pattern of neuropsychological strengths and weaknesses varies widely among patients with PD. …

We examined the pattern of cognitive impairment and rate of cognitive and functional decline as a function of age at symptom onset in 127 patients with probable Alzheimer's disease (AD). At baseline, early-onset (before age 65) and late-onset groups were mildly and comparably impaired on the modified Mini-Mental State Examination (mMMS) and the Blessed Dementia Rating Scale-Part 1 (BDRS). Repeated-measures analysis of variance revealed significantly more rapid decline in early-onset subjects over a 2-year follow-up period. Multivariate linear regression analyses indicated that age at symptom onset strongly predicted rate of decline on the mMMS and the BDRS, even after controlling for symptom duration, gender, family history of dementia, and baseline mMMS and BDRS scores. Early- and late-onset AD subjects also differed in terms of pattern of performance on the mMMS. Early-onset subjects scored significantly lower than late-onset subjects on attentional items of the mMMS at baseline and follow-up. Conversely, late-onset subjects scored significantly lower than early-onset subjects on memory and naming items at baseline, and the two groups were comparable on these tasks at follow-up. Results provide longitudinal evidence of more rapid cognitive and functional decline in subjects with early-onset AD and suggest that early-onset AD may be characterized by predominant impairment of attentional skills.

We investigated the relationship between extrapyramidal signs (EPS) and the cognitive function in 90 patients meeting NINCDS-ADRDA criteria for probable Alzheimer's disease (AD) by dividing them into those showing no evidence of EPS and those showing at least one EPS on the Unified Parkinson's Disease Rating Scale. Cognitive function was assessed by neuropsychological tests of verbal memory, orientation, abstract reasoning, language, and construction. Patients with EPS were significantly more impaired than patients without EPS on tests of short-term learning and memory, orientation, naming, verbal fluency, and construction, but not on tests of long-term memory, abstract reasoning, or verbal comprehension. These results could not be explained by any differences in age, education, or disease duration between the groups. Since this pattern of neuropsychological impairment resembles that of patients with Parkinson's disease and other EPS syndromes, we hypothesize that EPS are associated with neuropathologic and neuropsychological changes that are superimposed over the classic features of AD.

We obtained data from 111 gay men who entered a longitudinal study of the natural history of human immunodeficiency virus (HIV) without clinical evidence of acquired immunodeficiency syndrome (AIDS), and examined them regularly over a 36-month period. Using a Cox proportional-hazard regression model to compare cumulative risk of mortality in subjects with and without cognitive impairment and several putative risk factors present at baseline, we found that the mortality risk ratio (RR) associated with poor neuropsychologic test performance was significantly increased (RR = 2.9; 95% confidence interval [CI], 1.1 to 7.8), and increased further (RR = 4.1; 95% CI, 1.3 to 12.5) when adjusted for other factors associated with mortality (a history of a disturbance in movement or gait, CD4-lymphocyte and red blood-cell counts, and age). A significant increase in symptoms related to cognitive impairment and gait, a decline in neuropsychologic test performance, and declines in CD4-lymphocyte and red-cell counts occurred over the study period. A second model was constructed to adjust for changes in CD4-lymphocyte and red-cell counts, age, medical stage, and motor symptoms over the study period, but the mortality RR for poor neuropsychologic test performance at baseline changed very little (RR = 4.7; 95% CI, 1.5 to 14.9). We conclude that the presence of cognitive impairment, manifest by poor neuropsychologic test performance in both asymptomatic and symptomatic gay men with HIV infection, is associated with a significantly increased risk of death. This effect progresses in parallel with the immunologic and systemic effects of HIV.

We re-reviewed 257 patient records previously reviewed for an incidence study of dementia in Parkinson's disease (PD) to determine the frequency, date of death, and cause of death. We posited that if disease duration is shortened when dementia occurs, then dementia may be far more common than reflected in prevalence studies. There were 17 deaths among 65 demented patients and 28 deaths among 168 nondemented patients. When we matched a subset of the nondemented patients to the demented patients by age and disease duration distributions, the demented subjects had significantly more deaths (p less than 0.02), and survival among demented subjects was decreased (p less than 0.05). Dementia was a significant predictor of death in this sample. We conclude that dementia reduces survival in patients with PD. Incidence is a much better measure of dementia in PD than prevalence because shortened duration makes it less likely to detect dementia in prevalence surveys.

The proportion of patients with idiopathic Parkinson's disease (PD) who are considered demented ranges from 10% to 15%. Because dementia may affect survival in PD, the incidence rate of dementia, rather than proportion, would be a more accurate measure of disease frequency. We previously estimated the proportion of patients with PD and dementia to be 10.9% from the records of a cohort with the idiopathic form of PD in a major medical center. We reviewed the clinical records of this cohort after 4 years and 9 months to estimate the incidence rate of dementia. We identified 65 new cases of dementia from the 249 patient-records available. Using the number of person-years of follow-up for each case as the denominator, we estimated the overall incidence rate to be 69 per 1,000 person-years of observation. The mean age of this cohort was 71.4 years. The cumulative incidence of dementia increased with age. By 85 years of age, over 65% of the surviving members of the cohort were demented. The age-specific incidence rates for dementia in this cohort of PD were significantly greater than for a similarly aged cohort of healthy elderly people. The age-specific standard morbidity ratios indicated that, compared with people of similar ages, patients with PD have the highest increase in risk for dementia between ages 65 and 75.