The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
Alzheimer's disease; tauopathy; acetylation; post-translational modification; tau
The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania’s Alzheimer’s Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly 206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study.
Age of onset; dementia; haplotype; presenilin
Research suggests that expectancy may modulate the response to medical interventions, including acupuncture. However, the paucity of validated tools to measure expectancy limits rigorous evaluation. We sought to validate a previously developed Acupuncture Expectancy Scale (AES) as an instrument to measure patients’ expected responses to acupuncture.
Participants were patients with stage I to III cancers seen in outpatient medical and radiation oncology clinics. They were drawn from three study cohorts that included 404 participants. We examined the reliability, validity and responsiveness of AES.
The scores of AES had internal consistency (Cronbach’s α coefficient) of 0.95 and test-retest reliability of 0.62 over four weeks without acupuncture treatment. Those who had previously used acupuncture had higher AES compared to those who were acupuncture naïve (12.4 vs. 9.5, p=0.002). AES was higher in those who reported willingness to participate in an acupuncture trial compared to those who did not want to participate in an acupuncture trial (11.5 vs. 8.1, p<0.001). Those patients who enrolled in a pilot trial of acupuncture had higher AES score than the general outpatient population (13.0 vs. 9.8, p=0.02), and expectancy increased during the course of acupuncture treatment (13.0 to 16.5, p<0.017).
The AES is reliable and valid, and scores appear to increase during or after prior therapy. Incorporation of AES in clinical trials and outcome studies can evaluate the role of expectancy on acupuncture outcomes.
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson’s disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time.
dopamine agonists; impulse control disorder; Parkinson’s disease
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
Gaucher disease (GD) carrier screening is controversial in the medical community. The goal of this study was to explore prenatal healthcare providers’ current GD carrier screening practices.
Prenatal healthcare providers were invited by email to complete an electronic-based survey.
A total of 1454 prenatal healthcare providers, including 209 genetic counselors, 450 midwives, and 795 physicians, completed the study. The majority of genetic counselors (n=208/209, >99%), physicians (n=415/450, 92%), and midwives (n=634/795, 80%) currently offer Jewish ancestry disease carrier screening to couples in whom one or both partners are Jewish. Of providers who offer Jewish ancestry disease screening, the majority of genetic counselors (n=199/208, 96%) and physicians (n=352/415, 85%) always or sometimes offer GD screening whereas the majority of midwives (n=357/634, 56%) never offer GD screening.
This study presents the first report of prenatal healthcare providers’ GD carrier screening practices in North America. Our results indicate that GD carrier screening is being offered at a high rate within the scope of Jewish ancestry-based carrier screening. This may highlight a need to move away from the debate as to whether GD carrier screening should be offered and, instead, focus on how best to provide GD carrier screening services.
Gaucher disease; prenatal healthcare providers; carrier screening; practices; survey
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
Despite cancer patients' extensive use of complementary and alternative medicine (CAM), validated instruments to measure attitudes, and beliefs predictive of CAM use are lacking. We aimed at developing and validating an instrument, attitudes and beliefs about CAM (ABCAM). The 15-item instrument was developed using the theory of planned behavior (TPB) as a framework. The literature review, qualitative interviews, expert content review, and cognitive interviews were used to develop the instrument, which was then administered to 317 outpatient oncology patients. The ABCAM was best represented as a 3-factor structure: expected benefits, perceived barriers, and subjective norms related to CAM use by cancer patients. These domains had Eigenvalues of 4.79, 2.37, and 1.43, and together explained over 57.2% of the variance. The 4-item expected benefits, 7-item perceived barriers, and 4-item subjective norms domain scores, each had an acceptable internal consistency (Cronbach's alpha) of 0.91, 0.76, and 0.75, respectively. As expected, CAM users had higher expected benefits, lower perceived barriers, and more positive subjective norms (all P < 0.001) than those who did not use CAM. Our study provides the initial evidence that the ABCAM instrument produced reliable and valid scores that measured attitudes and beliefs related to CAM use among cancer patients.
Most people with Parkinson's disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD.
A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, i.e. proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.
Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p<0.001); many of the other 10 analytes co-varied with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an eightfold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.
Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
Epidermal growth factor; EGF; Parkinson's Disease; Parkinson's Disease with Dementia; Biomarker; Plasma
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.
We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.
We found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.
Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.
Alzheimer's disease; Normal pressure hydrocephalus; Ventriculoperitoneal shunting; Tau; Amyloid beta 1-42; Cerebrospinal fluid
The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer’s disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.
Alzheimer’s disease; Frontotemporal lobar dementia; Frontotemporal dementia; FTD; Philadelphia Brief Assessment of the Cognition; PBAC; Neuropsychological assessment; Philadelphia (repeatable) Verbal Learning Test
The most common genetic contributor to late-onset Parkinson disease (PD) is the LRRK2 gene. In order to effectively integrate LRRK2 genetic testing into clinical practice, a strategy tailored to the PD population must be developed. We assessed 168 individuals with PD for baseline knowledge of genetics, perceived risk, and interest and opinions regarding genetic counseling and testing. Most participants felt that they were familiar with general genetics terms but overall knowledge levels were low, with an average score of 55%. The majority of participants thought it was likely they inherited a PD gene (72%), believed genetic testing for PD would be useful (86%), and were interested in genetic testing (59%) and genetic counseling (56%). However, only a few participants had heard of any genetic tests for PD (29%) or LRRK2 (10%). There appears to be a significant level of interest in genetics and genetic testing within the PD population, but a considerable deficit in genetics knowledge and an over-estimation of risk. Genetic education and counseling tools to address these needs were developed to provide patients with the ability to make informed and knowledgeable genetic testing decisions.
Parkinson disease; Genetic testing; Genetic knowledge; Attitudes; Perceived risk
AD patients' early and progressive cognitive impairments hinder their capacity to provide informed consent. Unfortunately, the limited research on techniques to improve capacity has shown mixed results. Therefore, we tested whether a memory and organizational aid improves AD patient performance on measures of capacity and competency to give informed consent.
Design, Setting, and Participants
AD patients randomly assigned to standard consent, or standard plus a memory and organizational aid.
Memory and organizational aid summarized at a 6th grade reading level the content of information mandated under the Common Rule's informed consent disclosure requirements.
Three psychiatrists without access to patient data independently reviewed MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) interview transcripts to judge whether the patient was capable of providing informed consent. The agreement of at least two of three experts defined a participant as capable of providing informed consent. Secondary outcomes are MacCAT-CR measures of understanding, appreciation and reasoning, and comparison to cognitively normal older adult norms.
AD intervention and control groups were similar in terms of age, education, and cognitive status. The intervention group was more likely to be judged competent than control group and had higher scores on MacCAT-CR measure of understanding. The intervention had no effect on measures of appreciation or reasoning.
A consent process that addresses an AD patients' deficits in memory and attention can improve capacity to give informed consent for early phase AD research. The results also validate the MacCAT-CR as an instrument to measure capacity, especially the understanding subscale.
Alzheimer's disease; informed consent; capacity; research ethics
Olfactory deficits appear early in the course of Parkinson’s disease (PD) but their prognostic significance is not known. The goal of this study was to determine whether the severity of olfactory impairment is associated with subsequent risk of developing complications of PD. One hundred patients with PD self-administered the University of Pennsylvania Smell Identification Test (UPSIT). Testing was done, on average, 3.6 years from the time of initial diagnosis. The incidence of neuropsychiatric features of PD, including cognitive decline and visual hallucinations, was ascertained through chart review after an average of 6.8 years of follow-up. Incidence of motor outcomes including falls and dyskinesias was also obtained. There was a significant trend for increased risk of neuropsychiatric complications across declining quartiles of olfactory test scores. In addition, subjects in the lowest quartile of olfactory performance had a significantly higher adjusted risk of hallucinations (HR = 4.70, 95% CI 1.64, 13.42) and cognitive decline (HR = 3.10, 95% CI 1.05, 9.21) than those in the reference quartile. There was no association between olfactory dysfunction and dyskinesias, and a very modest association with risk of falls. These findings suggest that severity of olfactory impairment early in the disease course may be a useful marker for the risk of neuropsychiatric complications of PD.
Parkinson’s disease; olfaction; dementia; visual hallucinations
It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD). These comparative studies rely on powerful database tools to quickly generate data sets which match diverse and complementary criteria set by the studies.
In this paper, we present a novel Integrated NeuroDegenerative Disease (INDD) database developed at the University of Pennsylvania (Penn) through a consortium of Penn investigators. Since these investigators work on AD, PD, ALS and FTLD, this allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used Microsoft SQL Server as the platform with built-in “backwards” functionality to provide Access as a front-end client to interface with the database. We used PHP hypertext Preprocessor to create the “front end” web interface and then integrated individual neurodegenerative disease databases using a master lookup table. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database.
We compare the results of a biomarker study using the INDD database to those using an alternative approach by querying individual database separately.
We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies across several neurodegenerative diseases.
Database; Neurodegenerative Disease; Microsoft SQL; Relational Neurodegenerative Disease Database
To compare presentation of Alzheimer disease (AD) at the time of initial evaluation at a university specialty clinic across three ethnoracial groups in order to understand similarities and differences in the demographic, clinical, cognitive, psychiatric, and biologic features.
A total of 1,341 self-identified African American, Latino (primarily of Caribbean origin), and white non-Hispanic (“WNH”) subjects were recruited from primary care sites or by referral by primary care physicians.
Demographic variables and age of onset of AD, as well as cognitive, functional, and mood impairments at the time of initial presentation and frequencies of apolipoprotein E genotypes, were compared across groups.
Differences among ethnoracial groups were found for nearly all variables of interest. In particular, the largely immigrant Puerto Rican Latino group had an earlier age of onset of AD, more cognitive impairment, and greater severity of cognitive impairment at the time of initial evaluation in the setting of low average education and socioeconomic status. There was more depression in the Latinos compared with African Americans and WNHs. Greater severity of symptoms was not accounted for by a difference in lag time between onset of symptoms and initial evaluation. The apolipoprotein E-4 genotype was not associated with AD in the Latino cohort.
Minority groups in Philadelphia, especially Latinos, exhibit a more severe profile of AD at the time of presentation than WNHs. Important potential confounds need to be considered and future research comparing immigrant and nonimmigrant Latino groups will be necessary to elucidate the highly significant differences reported.
Alzheimer disease; APOE; dementia; ethnoracial differences
Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (epoD), is brain-penetrant and we subsequently evaluated whether epoD can compensate for tau loss-of-function in PS19 tau Tg mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month old male PS19 mice with low doses of epoD once-weekly for a 3-month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, epoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.
Tau; Microtubule; Blood-brain barrier; Alzheimer's disease; Learning and Memory; Transgenic
Major psychiatric diseases such as schizophrenia and mood disorders have not been linked to a specific pathology, but their clinical features overlap with some aspects of the behavioral variant of frontotemporal lobar degeneration. Although the significance of pathological 43-kDa (transactivation response) DNA-binding protein (TDP-43) for frontotemporal lobar degeneration was appreciated only recently, the prevalence of TDP-43 pathology in patients with severe mental illness vs controls has not been systematically addressed.
To examine patients with chronic psychiatric diseases, mainlyschizophrenia, for evidence of neurodegenerative TDP-43 pathology in comparison with controls.
Prospective longitudinal clinical evaluation and retrospective medical record review, immunohistochemical identification of pathological TDP-43 in the central nervous system, and genotyping for gene alterations known to cause TDP-43 proteinopathies including the TDP-43 (TARDBP) and progranulin (GRN) genes.
University health system.
One hundred fifty-one subjects including 91 patients with severe mental illness (mainly schizophrenia) and 60 controls.
Main Outcome Measures
Clinical medical record review, neuronal and glial TDP-43 pathology, and TARDP and GRN genotyping status.
Significant TDP-43 pathology in the amygdala/periamygdaloid region or the hippocampus/transentorhinal cortex was absent in both groups in subjects younger than 65 years but present in elderly subjects (29% [25 of 86] of the psychiatric patients and 29% [10 of 34] of control subjects). Twenty-three percent (8 of 35) of the positive cases showed significant TDP-43 pathology in extended brain scans. There were no evident differences between the 2 groups in the frequency, degree, or morphological pattern of TDP-43 pathology. The latter included (1) subpial and subependymal, (2) focal, or (3) diffuse lesions in deep brain parenchyma and (4) perivascular pathology. A new GRN variant of unknown significance (c.620T>C, p.Met207Thr) was found in 1 patient with schizophrenia with TDP-43 pathology. No known TARDBP mutations or other variants were found in any of the subjects studied herein.
The similar findings of TDP-43 pathology in elderly patients with severe mental illness and controls suggest common age-dependent TDP-43 changes in limbic brain areas that may signify that these regions are affected early in the course of a cerebral TDP-43 multisystem proteinopathy. Finally, our data provide an age-related baseline for the development of whole-brain pathological TDP-43 evolution schemata.
The problem of Alzheimer’s disease (AD) exemplifies the challenges of dealing with a broad range of aging related chronic disorders that require long-term, labor-intensive and expensive care. As the “baby-boom” generation ages and brain diseases become more prevalent, the need to confront the pending health care crisis is more urgent than ever before. Indeed, there is now a critical need to expand significantly the national effort to solve the problem of AD with special focus on prevention.
The “Prevent Alzheimer’s Disease 2020” (PAD 2020) initiative aims to create a new paradigm for planning and supporting the organization of worldwide cooperative research networks to develop new technologies for early detection and treatments of aging related memory and motor impairments. PAD 2020 is developing an implementation plan to justify: a) increasing the federal budget for research; b) developing novel national resources to discover new interventions for memory and motor disorders; c) creating innovative and streamlined decision-making processes for selecting and supporting new ideas.
Since 1978, the National Institute on Aging (NIA/NIH) established an extensive national network of AD research facilities at academic institutions including: AD Centers (ADCs), Consortium to Establish a Registry for AD (CERAD), AD Cooperative Study (ADCS), AD Drug Discovery Program, National Alzheimer’s Coordinating Center (NACC), National Cell Repository for AD (NCRAD), and AD Neuroimaging Initiative (ADNI). However, despite the success of these program and their critical contributions, they are no longer adequate to meet the challenges presented by AD.
PAD2020 is designed to address these changes by improving the efficiency and effectiveness of these programs. For example, the ADCs (P30s and P50s) can be enhanced by converting some into Comprehensive AD Centers (CADCs) to support not only research, but also by being demonstration projects on care/ treatment, clinical trials, and education as well as by seamlessly integrating multi-site collaborative studies (ADCS, ADNI, Patient Registries, Clinical Data Banks, etc.) into a cohesive structure that further enhances the original mission of the NIA ADCs.
Regional CADCs offer greater efficiency and cost savings while serving as coordinating hubs of existing ADCs thereby offering greater economies of scale and programmatic integration. The CADCs also broaden the scope of ADC activities to include research on interventions, diagnosis, imaging, prevention trials, and other longitudinal studies that require long-term support. Thus, CADCs can address the urgent need to identify subjects at high risk of AD for prevention trials and very early in the course of AD for clinical trials of disease modification. The enhanced CADCs will allow more flexibility among ADCs by supporting collaborative linkages with other institutions, and drawing upon a wider expertise from different locations.
This perspective paper describes the University of Pennsylvania (Penn) CADC Model as an illustrative example of how an existing ADC can be converted into a CADC by better utilization of Penn academic resources to address the wide range of problems concerning AD. The intent of this position paper is to stimulate thinking and foster the development of other or alternative models for a systems approach to the study of dementia and movement disorders.
To measure clinically relevant change in Alzheimer's disease (AD) using a family member completed dementia severity rating scale (DSRS) questionnaire.
Measuring rate of change provides important clinical information. Most neuropsychological scores change nonlinearly, complicating their use as a predictor of change throughout the illness.
DSRS and Mini Mental State (MMS) scores were prospectively collected on 702 patients with AD from first evaluation until they became too impaired to return to clinic.
DSRS score increased an average of 4.48 points per year (95% CI 4.14 - 4.82) throughout the entire range of severity. In contrast, the MMS declined an average of 2.15 points per year (95% CI 1.85-2.46) during the first two years, accelerated to 3.83 points per year (95% CI 3.28-4.38) during the subsequent three years and then slowed to an annual decline of 1.63 points during the last two years (95% CI 0.21-3.05). A younger age of symptom onset was associated with an increased rate of DSRS change (p=0.03).
The DSRS provides a clinical measure of functional impairment in AD that increases about 4.48 points per year from the earliest symptomatic stage until patients become too severely impaired to return to clinic.
Dementia severity rating scale; Alzheimer's disease; Rate of decline
To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology.
The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer’s disease (n=128) and with FTLD (n= 108) including patients with a social comportment/ dysexecutive (SOC/ EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/ EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.
Frontotemporal lobar dementia; longitudinal analysis; neuropsychological assessment; episodic memory; semantic memory; Pick’s disease
Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer’s disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in ‘animal’ fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.
frontotemporal dementia; Alzheimer’s disease; longitudinal assessment
Alzheimer’s disease (AD) patients have been reported to have shorter telomeres in peripheral blood leukocytes (PBLs) than age-matched control subjects. However, it is unclear if PBL telomere length reflects brain telomere length, which might play a more direct role in AD pathogenesis. We examined the correlation between PBL and cerebellum telomere length in AD patients, and compared telomere lengths in cerebella from individuals with AD versus age-matched control subjects.
Mean telomere lengths were measured using quantitative telomere polymerase chain reaction of genomic DNA prepared from matched PBL and cerebellum samples from 29 individuals with pathologically confirmed sporadic AD. Telomere length was also measured in cerebellum samples of 30 AD patients versus 22 unaffected age-matched control subjects.
The PBL and cerebellum telomere lengths were directly correlated in individuals with AD (r = 0.42, P = 0.023). Nonetheless, cerebellum telomere lengths were not significantly different in AD patients and age-matched control subjects.
Reduced PBL telomere length in AD might not reflect reduced telomere length in bulk brain tissue, but may be a marker of changes in a subset of brain tissues or other tissues that affect the pathogenesis of AD.
Alzheimer’s disease; Telomere; Cerebellum; Aging