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Hippocampal volumetric data are widely used in research but are rarely examined in clinical populations in regard to aiding diagnosis or correlating with objective memory test scores.To replicate and expand on the few prior clinical examinations of the utility of hippocampal volumetric data. We evaluated MRI volumetric data to determine (a) the degree of hippocampal loss across diagnostic groups compared with a cognitively intact group, (b) if total or lateralized hippocampal volumes predict diagnostic group membership, and (c) how total and lateralized volumes correlate with memory tests.We retrospectively examined hippocampal volumetric data and memory test scores for 294 individuals referred to a memory clinic.Individuals with mild cognitive impairment or Alzheimer disease had smaller hippocampal volumes compared with cognitively intact individuals. The raw and normalized total and lateralized hippocampal volumes were essentially equal for predicting diagnostic group membership, and notably low hippocampal volumes evidenced greater specificity than sensitivity. All of the volumetric data correlated with the memory test scores, with the total and left hippocampal volumes accounting for the slightly more variance in the diagnostic groups.The diagnostic groups exhibited hippocampal volume loss, which can be a potential biomarker for neurodegenerative disease in clinical practice. However, solely using hippocampal volumetric data to predict diagnostic group membership or memory test failure was not supported. While extreme hippocampal volume loss was rare in the cognitively intact group, the sensitivity of these volumetric data suggests a need for supplementation by other tools when making a diagnosis.

Autoimmune encephalopathy (AE) is an increasingly recognized cause of cognitive impairment. This study investigates the use of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to characterize treatment response of AE cognitive symptoms in ambulatory clinical practice.Retrospective evaluation of 29 consecutive patients treated for AE at the University of Cincinnati Memory Disorders Clinic. All patients underwent RBANS before treatment and 4-5 weeks after treatment. The Reliable Change index and clinically meaningful improvement method were used to determine if changes in RBANS performance were clinically significant.Clinically meaningful improvement was seen in 20 out of 29 (69 %) subjects on one or more RBANS domains and in 13 patients (45 %) for the global RBANS index. Measured improvement on one or more cognitive domain scores showed excellent agreement with clinical impression of change.The RBANS provided an efficient and effective means to document cognitive outcomes and treatment response in AE. The brief administration time, availability of normative data, and alternate versions make the RBANS useful in clinical practice and in clinical research related to AE.

Objective To investigate the relationship between aspirin and subclinical cerebrovascular heath, we evaluated the effect of chronic aspirin use on white matter lesions (WML) volume among women. Methods Chronic aspirin use was assessed in 1365 women who participated in the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Differences in WML volumes between aspirin users and nonusers were assessed with linear mixed models. A number of secondary analyses were performed, including lobe-specific analyses, subgroup analyses based on participants' overall risk of cerebrovascular disease, and a dose–response relationship analysis. Results The mean age of the women at magnetic resonance imaging examination was 77.6 years. Sixty-one percent of participants were chronic aspirin users. After adjusting for demographic variables and comorbidities, chronic aspirin use was nonsignificantly associated with 4.8% (95% CI: −6.8%, 17.9%) larger WML volumes. These null findings were confirmed in secondary and sensitivity analyses, including an active comparator evaluation where aspirin users were compared to users of nonaspirin nonsteroidal anti-inflammatory drugs or acetaminophen. Conclusions There was a nonsignificant difference in WML volumes between aspirin users and nonusers. Further, our results suggest that chronic aspirin use may not have a clinically significant effect on WML volumes in women.

The demonstrated benefits of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for cardiovascular and cerebrovascular disease are well established in the medical literature, and this class of medications is among those most commonly prescribed in the USA. In 2012, the US Food and Drug Administration issued updated recommendations regarding statin medications, and the panel's comments regarding memory impairment fostered clinical confusion (in part because of the lay media's amplification). Cognitive data from several large epidemiological studies have not reliably demonstrated a robust association between incident cognitive impairment and statin use, with some studies reporting a protective effect, some reporting an increased risk and others finding no association. Although several interventional studies have evaluated statins as a possible adjunctive treatment for Alzheimer's disease, none have clearly demonstrated a benefit. A small number of case series have reported infrequent memory difficulties associated with statin use. In these series, the patients' cognitive symptoms resolved after statin discontinuation. The existing medical literature does not suggest that cognitive considerations should play a major role in medical decision making to prescribe statins for the large majority of patients. As with any medication prescribed for older adults, careful clinical monitoring for side effects should be exercised. If a patient is suspected of having idiosyncratic memory impairment associated with use of a statin medication, the drug can be discontinued. The patient should then be followed with careful clinical observation for 1-3 months for resolution of the cognitive symptoms.

To characterize a cohort of individuals who have experienced rapidly progressive dementia with onset before age 45.Very little data regarding the clinical features or clinical spectrum of rapidly progressive young-onset dementia (RP-YOD) is available, primarily consisting of case reports or small series.A search of the Mayo Clinic medical record was employed to identify patients who had onset before age 45 of rapidly progressive dementia. All available medical records, laboratory data, neuroimaging studies, and pathologic data were reviewed.Twenty-two patients met the predefined inclusion and exclusion criteria. Behavioral and affective disorders, cerebellar dysfunction, and visual and/or oculomotor dysfunction were common early clinical features within the cohort, as were clinical features often associated with Creutzfeldt-Jakob disease. Diagnostic testing identified an etiology in most patients.Presentations of RP-YOD result from a variety of etiologies and significant overlap in clinical features is observed. Clinical features often associated with Creutzfeldt-Jakob disease seem to be common within the entire cohort of RP-YOD patients. Diagnostic studies aided in establishing a diagnosis in most patients, however 5 had uncertain diagnoses despite exhaustive evaluation.

Background: The rarity of young-onset dementia (YOD), the broad differential diagnosis and unusual clinical presentations present unique challenges to correctly recognize the condition and establish an accurate diagnosis. Limited data exist regarding clinical features associated with dementia prior to the age of 45. Methods: We retrospectively assessed cognitive and noncognitive neurological characteristics of 235 patients who presented for evaluation of YOD to investigate the clinical characteristics of YOD compared to later-onset dementias and to identify clinical features associated with specific etiologies that may aid in the evaluation of YOD. Results: Multiple cognitive domains were affected in most patients, and no significant differences in affected domains existed between groups. Early psychiatric and behavioral features occurred at very high frequencies. Nearly 80% of this YOD cohort had additional noncognitive symptoms or signs as a feature of their disease. Chorea was strongly associated with Huntington disease. Parkinsonism was not seen in patients having an autoimmune/inflammatory etiology. Conclusions: The rarity of YOD and the high frequency of early psychiatric features led to frequent misdiagnosis early in the clinical course. The high frequency of noncognitive symptoms and signs may aid clinicians in distinguishing patients requiring a more extensive evaluation for YOD.

Complimentary and alternative medicine has an extensive worldwide history and is commonly used by older patients. A number of different alternative medicines are used by patients having Alzheimer disease. It is both desirable and expected for clinicians to be acquainted with these medications.This paper discusses the available clinical trial evidence regarding 8 agents commonly used by people having Alzheimer disease. We provide an overview of the history and basic scientific evidence available for each agent, followed by a critical analysis of the evidence available from clinical trials, including the number of participants, trial duration, and specific outcomes evaluated.Although many of these compounds have been associated with interesting basic science, none has shown clear clinical benefit to date. Data available for some, such as Ginkgo biloba, curcumin, and huperzine A, suggest that further evaluation is warranted. Familiarity with this literature will allow clinicians to provide meaningful recommendations to patients who wish to use these agents.

It is increasingly evident that early identification of cognitive impairment in older adults presents opportunities for interventions that aim to mitigate the impact of cognitive symptoms on daily function and that attempt to delay (or ultimately prevent) progression from mild cognitive impairment (MCI) to dementia. To date, no intervention has proven protective in ultimately preventing conversion to dementia. However, several lifestyle, dietary, and pharmacologic interventions have suggested symptomatic benefit for those having MCI. A number of diet and lifestyle recommendations have been associated with decreased risk of dementia both in cognitively intact older adults and in those having mild cognitive impairment. Thus, these recommendations may be appropriate for both people presenting with subjective cognitive concerns and for those having objective evidence of memory problems. It remains less certain whether adopting these lifestyle habits in later life confers the benefits seen in epidemiological cohorts (where people have likely practiced them for many years). Discussion of starting on a cholinesterase inhibitor is appropriate for those having MCI, particularly those in whom the MCI is thought to have a vascular etiology or to represent the prodromal stage of a neurodegenerative disease. Recent meta-analyses exploring the use of cholinesterase inhibitors in patients having MCI have concluded that there is no evidence to support this practice. Although meta-analytic techniques seemingly strengthen the confidence in a recommendation via the incorporation of a large number of subjects analyzed, the technique is not capable of overcoming any inherent weaknesses of the individual studies included in the analysis. It is arguable whether studies in MCI may have employed endpoints poorly adapted to investigating effect of cholinesterase inhibitors. Most studies have used cognitive screening examinations, all of which stretch their detection ability to identify subjects with MCI, let alone discriminate subtle differences between them. Some have used conversion from MCI to dementia as an endpoint, which may not be the best measure for a symptomatic treatment. Further, once conversion to dementia has occurred, a cholinesterase inhibitor would be started in most (if not all) clinical settings, a reality not well reflected in most study designs. Additionally, several large studies have not permitted subject stratification by APOE carrier status, another important defect in assessing outcome. In clinical practice, our center typically does recommend cholinesterase inhibitors for patients having MCI. Despite the modest effect size, many patients do wish to start on treatment. It appears that this is a generally accepted practice and experience, as most clinical trials for prodromal Alzheimer's disease specify that participants should be taking a cholinesterase inhibitor.

His speech is severely impaired and he cannot swallow liquids or solids. The leg lesions have been present for several years and are painless. What is the likely diagnosis?

Objective— To perform a pilot study to examine a range of cognitive flexibility tasks early in cocaine withdrawal. Background— Previous neuropsychological investigations of cocaine withdrawal have conflicted regarding whether impaired cognitive flexibility occurs. However, most studies have examined patients later in withdrawal. Anxiety and yohimbine-induced panic are greatest early in withdrawal, and both anxiety and increased noradrenergic tone can impair cognitive flexibility. Method— Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence–matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention. Results— As predicted, impairments were found on the cognitive flexibility tasks. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention. Conclusions— We propose that the cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic networks. Further research will explore the effects of pharmacologic manipulation of the noradrenergic system on cognition in acute withdrawal. Recently, propranolol has been shown to benefit patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response.

In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors. We performed a cross-sectional analysis of 7199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score. Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values p p JINS, 2014, 20, 1–12)

Spinal cord compression may be associated with a fusiform cord lesion on T2-weighted magnetic resonance imaging (MRI) images, leading to confusion with transverse myelitis and delaying effective surgical treatment.We describe 5 patients referred for evaluation of suspected neuromyelitis optica in whom the final diagnosis was symptomatic cervical spinal stenosis. The patients had gradually progressive myelopathy, with symptoms progressing over an average of 34.4 weeks. Although cervical spinal cord MRI identified long T2 hyperintense lesions, gadolinium enhancement was localized to the level of maximum spinal cord compression, in contrast to the much more extensive distribution of gadolinium enhancement characteristic of myelitis. Compressive myelopathy symptoms responded poorly to corticosteroids, but responded well to surgical decompression.Cervical cord compression due to spinal stenosis may lead to long intramedullary fusiform T2 hyperintensity on MRI, mimicking inflammatory myelopathy, but the diagnoses can be accurately distinguished by a combination of clinical and radiologic characteristics.

Objective: Low scores on tests of learning, memory, and executive function have been associated with subclinical cerebrovascular pathology in the absence of stroke. In a population-based, stroke-free cohort, we hypothesized that lower performance in these cognitive domains would predict incident stroke. Methods: From 2003-2007, REGARDS enrolled black and white adults aged ≥45 throughout the U.S. Participants are followed by phone twice a year for stroke events and biennially for longitudinal cognitive assessments. Word list learning and recall tasks are used to measure learning and memory, and semantic and letter fluency tasks to measure executive function. Included participants were stroke-free at enrollment and remained so prior to their cognitive assessments. We assessed incident stroke risk through September 1, 2012 using standard survival analyses adjusted for age, education, race, and geographic region. Results: Sample sizes up to 20,422 varied by cognitive task, and follow-up time ranged up to 7 years. Adjusted hazard ratios (95% CI) for stroke associated with the lowest versus highest quintiles of pre-stroke cognitive scores were 1.90 (1.24, 2.93) for learning, 2.23 (1.45, 3.42) for memory, and 1.69 (1.10, 2.61) and 1.98 (1.12, 3.52) for executive function as assessed by semantic and letter fluency, respectively (Figure). Conclusions: In a stroke-free, population-based cohort, lower baseline function in each cognitive domain was associated with increased risk of incident stroke. Low scores may signal the progression and severity of stroke risk factors.

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72 . For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin ( GRN : p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau ( MAPT : p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Objective: The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Methods: The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually. Results: Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants. Conclusions: Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.

Introduction: ApoE genotype affects cholesterol metabolism, and carriers of the e4 allele have increased risk of heart disease, stroke, Alzheimer’s disease, vascular dementia, Mild Cognitive Impairment, and cognitive decline. Studies have yielded mixed results on the independent and interactive effects of e4 carrier status, demographics, and health variables on risk of cognitive decline. Methods: Drawing from a stratified random subsample of REGARDS study participants, we performed ApoE genotyping on 424 incident cognitive decline cases and 554 cohort members without cognitive decline. Participants with normal baseline cognitive status, no baseline stroke history, and sufficient longitudinal cognitive data were eligible. Incident cognitive decline was defined as a score > 1.5 SD below age-, education-, race- and sex-adjusted expected score on > 2 of 3 cognitive tests (memory, learning, executive function) at most recent assessment. Results: ApoE e4 carrier status interacted with age to determine odds of incident cognitive decline. In sample-weighted and fully adjusted regression models, greater risk for cognitive decline was seen in e4 carriers above but not below age 65 (Table). Stroke Belt residence, lower income, abstaining from alcohol, smoking, diabetes, heart disease, and incident stroke were independent predictors of decline after accounting for e4 carrier status and other model variables (p values < .05) (data not shown). Discussion: Drawing from a national cohort of black and white adults and controlling for key demographics in defining cases of substantive cognitive decline, risk for decline was higher for older ApoE e4 carriers. Risk of decline was also higher for residents of the Stroke Belt and those with low income, smoking, alcohol abstinence, CVD, or incident stroke, even after accounting for e4 and other possible confounders. Results highlight the interplay of genetics and environment in determining cognitive decline risk.

Introduction: Stroke and vascular risk factors are recognized as important markers of increased risk of cognitive impairment. Experience of stroke-like symptoms and/or transient ischemic attack (SS/TIA) are suspected to represent another independent marker of risk for cognitive impairment. Methods: We assessed these relationships in REGARDS, a national longitudinal cohort study following over 30,000 black and white participants aged 45 and older from the 48 contiguous states. Cognitive function is assessed by several scales, including the Six-Item Screener (SIS), conducted by telephone at baseline and annually during follow-up. After excluding those who were impaired at first assessment, 23,830 participants (mean baseline age 64.2) were stroke free at baseline and had at least two cognitive function assessments (11,096 with two to four, and 12,734 with more than four). Observation time was censored after a suspected stroke during follow-up (censoring 1439 assessments in 515 participants). SS/TIA were assessed using the Questionnaire for Verifying Stroke-Free Status. The association between report of SS/TIA and subsequent impairment was assessed using logistic regression, both univariately and after adjustment for a variety of risk factors. In addition, the role of the Framingham Stroke Risk (FSR) in these relationships was examined. Incident impairment was characterized as a score of 4 or fewer on the most recently assessed SIS. Models were fitted separately for white and black subjects to evaluate race-specific effects. Results: Among blacks, the presence of any incident SS/TIA was associated with 1.66 (95% CI: 1.45, 1.89) times the likelihood of impairment in an unadjusted model, compared to those with no SS/TIA, which was slightly attenuated to 1.41 (95% CI: 1.23, 1.62) in a model incorporating gender, income, region and education. Among whites, the unadjusted OR was 2.08 (95% CI: 1.81, 2.39), with an adjusted OR of 1.85 (95% CI: 1.61, 2.13). The association between SS/TIA differed by FSRF, with a stronger association between SS/TIA and impairment among those with lower FSR, both for blacks and whites. Discussion: In an initially stroke-free cohort and with censoring of incident stroke cases in the follow-up, report of SS/TIA was strongly related to increased risk of cognitive impairment. The stronger association between self-report of SS/TIA and incident cognitive impairment among those with lower FSR score suggests these symptoms may reflect risk factors for cognitive impairment not captured in the FSR. This effect was larger in whites, suggesting differential sensitivity or exposure to this risk.

The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Seizures have been recognized to occur in multiple sclerosis (MS) since early descriptions of the disease. Various studies have attempted to determine the incidence and prevalence of seizures in MS; although they differ in the reported prevalence, seizures do appear to be more common in MS cohorts than in the general population. The pathological underpinning of seizures in MS remains indeterminate. Cortical and subcortical demyelination and inflammation may explain the increased frequency of seizures in MS, although this hypothetical correlation remains to be proven. Management of seizures in MS is similar to the management of seizures in other patients. Consideration of the underlying neurological deficits related to MS may be necessary, and dosages of antiepileptic drugs should be adjusted if increased sensitivity to the adverse effects of these agents or interaction with other centrally acting medications is suspected. The prognosis of epilepsy in patients with MS remains uncertain, with some studies suggesting a more favourable prognosis than others.

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from I to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateratized topography of degeneration across all affected individuals. (C) 2007 Elsevier Inc. All rights reserved.

Onset of dementia before age 45 years presents a difficult clinical circumstance, having a broad differential diagnosis and numerous psychosocial implications for the patient and their family. Few data exist regarding the demographics characterizing this population or the etiologic diagnoses among those affected.To characterize the demographic characteristics and the etiologic causes of dementia with age at onset younger than 45 years.Observational, retrospective, single-cohort study.Multispecialty group academic medical center.We searched the Mayo Clinic Rochester electronic Medical Record Linkage System to identify individuals who were seen for evaluation of progressive cognitive decline between the ages of 17 and 45 years from January 1996 through December 2006. This search identified 235 individuals who met the established inclusion and exclusion criteria.All available clinical, laboratory, magnetic resonance imaging, and pathological data were reviewed.Causes varied, with neurodegenerative etiologies accounting for 31.1% of the cohort; Alzheimer disease was uncommon. Autoimmune or inflammatory causes accounted for 21.3%. At last follow-up, 44 patients (18.7%) had an unknown etiology, despite exhaustive evaluation. Cause varied with age, with inborn errors of metabolism being more common before age 30 years and with neurodegenerative etiologies being more common after age 35 years.Young-onset dementia (age at onset,45 years) includes a broad variety of etiologies, with few patients having a potentially treatable disorder. The etiologic spectrum and the relative percentages of patients within etiologic groups differed in important ways from existing reports of early-onset dementia (ie, age at onset,65 years).

Upregulated noradrenergic activity occurs early in cocaine withdrawal. Our previous work revealed impaired cognitive flexibility in acute cocaine withdrawal, a cognitive domain that appears to be modulated by noradrenergic activity. Therefore, we wished to determine the effect of beta-adrenergic antagonists on cognitive performance in acute cocaine withdrawal. Eleven subjects acutely withdrawing from cocaine were tested in this pilot study on tasks of cognitive flexibility as well as word fluency, attention, verbal memory, and spatial memory, off and on propranolol in a double-blinded manner. Propranolol significantly benefited certain aspects of cognitive flexibility in acute cocaine withdrawal, and improved some measures of verbal fluency and verbal recall. Cocaine withdrawal treatment is characterized by high failure rates. Further research is needed to determine the role this finding of a reversible cognitive impairment in cocaine withdrawal has in treatment.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis., Author Summary The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.

Summary Background The progranulin gene ( GRN ) is mutated in 5–10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. Methods We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene ( APOE ), and for haplotypes of the microtubule-associated protein tau gene ( MAPT ). Findings Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44–69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE ɛ4 allele. Interpretation Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

As our society ages, age-related diseases assume increasing prominence as both personal and public health concerns. Disorders of cognition are particularly important in both regards, and Alzheimer's disease is by far the most common cause of dementia of aging. In 2000, the prevalence of Alzheimer's disease in the United States was estimated to be 4.5 million individuals, and this number has been projected to increase to 14 million by 2050. Although not an inevitable consequence of aging, these numbers speak to the dramatic scope of its impact. This article focuses on Alzheimer's disease and the milder degrees of cognitive impairment that may precede the clinical diagnosis of probable Alzheimer's disease, such as mild cognitive impairment.

Objective: To validate the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute cognitive battery using other measures of cognitive function and measures of vascular risk. Background The recent NINDS-CSN Vascular Cognitive Impairment Harmonization Standards recommended a 5-minute neuropsychological battery as a brief screening instrument sensitive to deficits commonly seen in vascular cognitive impairment (VCI). Design/Methods: Cross-sectional study involving 7,199 stroke-free US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to October 2007. We examined effects of demographics on the NINDS-CSN 5-minute battery score at first assessment (in 2009 and later), and correlation of 5-minute battery scores with other cognitive tests and with measures of cerebrovascular risk. Results: Total scores on the NINDS-CSN 5-minute battery were highly related to age (Spearman9s ρ = -0.305, p Conclusions: The NINDS-CSN 5-minute battery is a brief, easily administered screening measure of cognition that is sensitive to increasing levels of cerebrovascular risk. The NINDS-CSN 5-minute battery offers a valid method of screening for cognitive correlates in VCI. Supported by: A cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke and grant T32 HL072757 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Service. Disclosure: Dr. Kennedy has nothing to disclose. Dr. Wadley has nothing to disclose. Dr. McClure has nothing to disclose. Dr. Unverzagt has received personal compensation for activities with Eli Lilly & Company as a consultant. Dr. Unverzagt has received research support from Posit Science Inc. Dr. Crowe has nothing to disclose. Dr. Kelley has received personal compensation for activities with Eli Lilly & Company as a consultant. Dr. Nyenhuis has received personal compensation for activities with Pfizer Inc and Eisai Inc., as a speaker. Dr. Kana has nothing to disclose. Dr. Marceaux has nothing to disclose. Dr. Tamura has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Howard has received personal compensation for activities with Bayer Healthcare and Abbott Labratories as a consultant. Dr. Howard has received research support from Amgen Inc. and Bayer Healthcare.

Inflammatory Diseases of the Central Nervous System Trevor Kilpatrick, Richard M. Ransohoff, Steven Wesselingh, 282 pp., Cambridge University Press, 2009, $110 This brief book succeeds in its ambitious aim, providing readers an overview of the role of the immune system in CNS disease. It reviews the extensive and exciting advances over the past 20 years, describing our current understanding of the complex relationship between the immune system, the nervous system, and the interactive role that environmental and host factors play in mediating that relationship. The book begins by reviewing the interactions between the immune and nervous systems. Topics include the role of systemic immune cells in providing innate and adaptive immune responses, followed by a discussion of the increasing appreciation of the complex role that microglia play in maintenance and protection of the …