Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease.

Alzheimer's disease (AD) has been genetically and pathologically associated with neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor involved in innate immunity. TREM2 rare protein coding genetic variants have been linked to AD. A soluble TREM2 (sTREM2) cleavage product is elevated in AD. It is unclear whether there is a relationship between elevated sTREM2 and markers of inflammation. The hypothesis of this investigation was that central and peripheral inflammation play a role in sTREM2 levels in AD. A consistent association of peripheral or central markers of inflammation and CSF sTREM2 levels was not found, suggesting a limited impact of general inflammation on sTREM2 levels. An association between peripheral sTREM2 levels and CSF sTREM2, as well as an association between CSF sTREM2 and a marker of blood brain barrier integrity, was observed in AD, suggesting a potential role of peripheral TREM2 in central TREM2 biology.

Association of cognitive domains with postural instability/gait disturbance in Parkinson's disease.

INTRODUCTION: Research suggests an association between global cognition and postural instability/gait disturbance (PIGD) in Parkinson disease (PD), but the relationship between specific cognitive domains and PIGD symptoms is not clear. This study examined the association of cognition (global and specific cognitive domains) with PIGD symptoms in a large, well-characterized sample of individuals with PD. METHODS: Cognitive function was measured with a detailed neuropsychological assessment, including global cognition, executive function, memory, visuospatial function, and language. PIGD symptoms were measured using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, Motor Examination subscale. Multiple linear regression analyses were performed to assess the relationship between cognition and PIGD symptoms with models adjusting for age, sex, education, enrollment site, disease duration, and motor symptom severity. RESULTS: The analysis included 783 participants, with mean (standard deviation) age of 67.3 (9.7) years and median (interquartile range) MDS-UPDRS Motor Subscale score of 26 (17, 35). Deficits in global cognition, executive function, memory, and phonemic fluency were associated with more severe PIGD symptoms. Deficits in executive function were associated with impairments in gait, freezing, and postural stability, while visuospatial impairments were associated only with more severe freezing, and poorer memory function was associated only with greater postural instability. DISCUSSION: While impairments in global cognition and aspects of executive functioning were associated with more severe PIGD symptoms, specific cognitive domains were differentially related to distinct PIGD components, suggesting the presence of multiple neural pathways contributing to associations between cognition and PIGD symptoms in persons with PD.

Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease / Estudios clínicos y moleculares revelan una mutación PSEN1 (L153V) en una familia peruana con enfermedad de Alzheimer de inicio temprano

Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family.

Las mutaciones del gen de presenilina 1 (PSEN1) se encuentran en el 30-70% de los casos de enfermedad de Alzheimer de inicio temprano (EAIP) familiar (inicio <60 años). La prevalencia de estas mutaciones es muy variable, incluidas las diferencias étnicas en todo el mundo. No se han descrito parientes peruanos con EA familiar (EAF). Se realizó una evaluación clínica estandarizada y una evaluación cognitiva en una familia peruana con EAIP grave. El curso clínico se caracterizó por un inicio muy temprano (antes de los 35 años), deterioro cognitivo progresivo con pérdida temprana de memoria, desorientación espacial y disfunción ejecutiva. Secuenciamos todos los exones de PSEN1 en el probando e identificamos un cambio de ADN c.475C>G que resultó en una mutación sin sentido p.L153V en el dominio transmembrana 2 del gen. Esta mutación también está presente en los tres hermanos afectados adicionales, pero no en un miembro de la familia no afectado, lo que es consistente con la segregación de esta mutación con la enfermedad. Este es el primer informe de una familia peruana afectada con EAIP asociada con una mutación PSEN1. Esta misma mutación se ha informado previamente en familias inglesas y francesas, pero una nueva variante muy cercana a la mutación y el análisis de marcadores informativos de ascendencia sugieren que la mutación podría ser de origen amerindio o africano en esta familia peruana.

Cerebrospinal fluid amyloid ß and tau in LRRK2 mutation carriers.

OBJECTIVE: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid ß (Aß) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aß and tau as markers of early or presymptomatic PD. METHODS: CSF Aß42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement. RESULTS: Reduced CSF Aß42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aß42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau. CONCLUSIONS: The disposition of Aß and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.

Diagnosis and management of Parkinson's disease dementia.

Parkinson's disease (PD) has long been considered predominantly a motor disorder. However, its frequent association with dementia, which contributes significantly to the morbidity and mortality of the condition, is gaining increasing recognition. PD dementia (PDD) has a unique clinical profile and neuropathology, distinct from Alzheimer's disease (AD). Cholinergic deficits, a feature of both AD and PDD, underlie the rationale for cholinesterase inhibitor therapy in both conditions. In clinical practice, it is important that PDD should be recognised and appropriately treated. This review aims to outline the recently proposed clinical diagnostic criteria for PDD and to summarise the guidelines/recommendations published since 2006 on the use of cholinesterase inhibitors in the management of PDD. Although the cholinesterase inhibitor rivastigmine has recently been approved for the management of PDD, there remains a need for the development of novel therapies that can affect key mechanisms of the disease or prevent/delay patients with PD and mild cognitive impairment from progressing to PDD.

CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.

BACKGROUND: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Abeta(42) as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. METHODS: We determined the ratio of CSF tau/Abeta(42) (T/Abeta) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). RESULTS: We identified 16% of the control group with abnormally elevated CSF T/Abeta; all were 53 years or older. Using age-matched controls with normal CSF T/Abeta we showed that the high CSF T/Abeta subgroup of controls had significantly increased frequency of the epsilon4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. CONCLUSIONS: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

Neural transplantation in Huntington disease: long-term grafts in two patients.

OBJECTIVE: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. METHODS: Methods used were pathologic examination, histochemistry, and immunohistochemistry. RESULTS: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. CONCLUSIONS: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.

A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.

Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory changes.

In Alzheimer's disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC alpha2-adrenoreceptor (AR) binding site density, as determined by 3H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic alpha1-AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of alpha1-AR subtypes (alpha1A- and alpha1D-AR) and alpha2C-AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of alpha1A-AR mRNA. The expression of the alpha1A-AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of alpha1A-, alpha1D- and alpha2C-AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain.

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

Selective dendritic degeneration of medium spiny neurons in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of dementia and shows more severely impaired performance on tests of executive functions compared to Alzheimer disease. Here the authors demonstrate selective spinodendritic degeneration of medium spiny neurons in regions of the caudate nucleus that subserve executive functions and propose that this may underlie, at least in part, the heightened executive dysfunction observed in patients with DLB.

Rate of progression differs in frontotemporal dementia and Alzheimer disease.

OBJECTIVE: To compare survival and rates of cognitive and functional decline in patients with autopsy-confirmed frontotemporal dementia (FTD) and Alzheimer disease (AD) in a large multicenter study. BACKGROUND: Despite advances in the clinical characterization of FTD, little is known about its rate of progression. Characterizing survival and rate of decline in FTD is important because it can provide prognostic guidelines and benchmarks to use in the evaluation of disease-modifying drugs. METHODS: Seventy patients with FTD and 70 patients with AD who were followed by seven Alzheimer disease research centers until confirmation of diagnosis at autopsy were matched for overall age, education, and Mini-Mental State Examination (MMSE) score at initial evaluation. Survival and rates of cognitive and functional decline were compared. RESULTS: Patients with FTD had significantly shorter survival from initial evaluation to death than patients with AD (FTD = 4.2 years, AD = 6.0 years; log-rank test = 5.17, p < 0.05), and they declined significantly faster over one year on the MMSE (mean annual rate of change: -6.7 points for FTD vs -2.3 points for AD). A significantly greater proportion of patients with FTD were impaired in basic activities of daily living (ADLs) at initial evaluation, and lost the capacity for independent or minimally-assisted ADLs over the subsequent year. CONCLUSIONS: The results are consistent with shorter survival and faster rates of cognitive and functional decline in patients with frontotemporal dementia (FTD) compared to those with Alzheimer disease (AD). This suggests that FTD follows a more malignant disease course than AD once dementia is clinically recognized.

Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both.

OBJECTIVE: To examine the neuropsychological profile of dementia patients from a community-based autopsy sample of dementia, comparing Alzheimer disease (AD), Lewy body pathology (LBP) alone, and LBP with coexistent AD (AD/LBP). METHODS: The authors reviewed 135 subjects from a community-based study of dementia for whom autopsy and brain tissue was available. Diagnostic groups were determined according to standard neuropathologic methods and criteria, and the presence of LBs was determined using alpha-synuclein immunostaining. Neuropathologically defined diagnostic groups of AD, AD/LBP, and LBP were examined for differences on neuropsychological test performance at the time of initial study enrollment. RESULTS: There were 48 patients with AD alone, 65 with LB and AD pathology (AD/LBP), and 22 with LBP alone (LBP alone). There were no significant differences between groups demographically or on performance of enrollment Mini-Mental State Examination (MMSE) or Dementia Rating Scale (DRS). AD patients performed worse than the LBP patients on memory measures (Fuld Object Memory Evaluation Delayed Recall, Wechsler Memory Scale Logical Memory Immediate and Delayed Recall; p < 0.05) and a naming task (Consortium to Establish a Registry for Alzheimer's Disease Naming; p < 0.05). LBP patients were more impaired than AD patients on executive function (Trail Making Test Part B; p < 0.05) and attention tasks (Wechsler Adult Intelligence Scale-Revised Digit Span; p < 0.05). Decline in MMSE and DRS scores over time were greatest in the patients with AD/LBP. CONCLUSIONS: In a community-based sample of older, medically complicated patients with dementia, there are neuropsychological differences between dementia subtypes at the time of diagnosis. In particular, patients with Alzheimer disease (AD) alone and AD/Lewy body pathology (LBP) had more severe memory impairment than patients with LBP. LBP alone was associated with more severe executive dysfunction. Patients with AD/LBP had the most rapid rate of cognitive decline.

Genetic association between the APOE*4 allele and Lewy bodies in Alzheimer disease.

OBJECTIVE: To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD). METHODS: With use of alpha-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs. RESULTS: There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without an APOE*4 allele. CONCLUSION: The APOE*4 allele is associated with the presence of concomitant Lewy bodies in Alzheimer disease.

Beta-synuclein gene alterations in dementia with Lewy bodies.

OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.

Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques.

The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic-pituitary-adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Pro-opiomelanocortin in the anterior pituitary and corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function.

Alpha-synuclein in motor neuron disease: an immunohistologic study.

Alpha-synuclein (ASN) has been implicated in neurodegenerative disorders characterized by Lewy body inclusions such as Parkinson's disease and dementia with Lewy bodies. Lewy body-like inclusions have also been observed in spinal neurons of patients with amyotrophic lateral sclerosis (ALS) and reports suggest possible ASN abnormalities in ALS patients. We assessed ASN immunoreactivity in spinal and brain tissues of subjects who had died of progressive motor neuron disorders (MND). Clinical records of subjects with MND and a comparison group were reviewed to determine the diagnosis according to El-Escariol Criteria of ALS. Cervical, thoracic and lumbar cord sections were stained with an antibody to ASN. A blinded, semiquantitative review of sections from both groups included examination for evidence of spheroids, neuronal staining, cytoplasmic inclusions, anterior horn granules, white and gray matter glial staining, corticospinal tract axonal fiber and myelin changes. MND cases, including ALS and progressive muscular atrophy, displayed significantly increased ASN staining of spheroids ( P< or =0.001), and glial staining in gray and white matter ( P< or =0.05). Significant abnormal staining of corticospinal axon tract fibers and myelin was also observed ( P< or =0.05 and 0.01). Detection of possible ASN-positive neuronal inclusions did not differ between groups. Significant ASN abnormalities were observed in MND. These findings suggest a possible role for ASN in MND; however, the precise nature of this association is unclear.

Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study.

OBJECTIVE: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.