Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

Fluorodeoxyglucose positron emission tomography in Richardson's syndrome and progressive supranuclear palsy-parkinsonism.

BACKGROUND: We hypothesized that postural instability and cognitive decline in patients with Richardson's syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism. METHODS: Eleven patients with Richardson's syndrome, 8 patients with progressive supranuclear palsy-parkinsonism, 12 with Parkinson's disease, and 10 controls underwent clinical assessment and fluorodeoxyglucose positron emission tomography (PET). RESULTS: Richardson's syndrome patients showed pronounced thalamic hypometabolism, and patients with progressive supranuclear palsy-parkinsonism pronounced putaminal hypometabolism, compared to all other investigated groups. The putamen/thalamus uptake ratio differentiated progressive supranuclear palsy-parkinsonism from Richardson's syndrome (area under the curve 5 0.86) and from Parkinson's disease (area under the curve 5 0.80) with acceptable accuracy. Frontal hypometabolism was predominantly found in Richardson's syndrome patients. CONCLUSIONS: Richardson's syndrome, progressive supranuclear palsy-parkinsonism and Parkinson's disease showed different metabolic patterns in fluorodeoxyglucose PET.

Clinical and psychometric distinction of frontotemporal and Alzheimer dementias.

BACKGROUND: A proportion of patients who meet the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations criteria for Alzheimer disease (AD) have frontotemporal lobar degeneration (FTLD) confirmed at autopsy, with or without concomitant AD. Thus, the clinical phenotypes of the 2 disorders may overlap. OBJECTIVE: To identify clinical and psychometric indicators that distinguish AD from FTLD at initial presentation. DESIGN: Longitudinal study of memory and aging. SETTING: Alzheimer's Disease Research Center, Washington University School of Medicine. PARTICIPANTS: Forty-eight clinically well-characterized cases of autopsy-confirmed FTLD (27 with psychometric testing results) were compared with 27 autopsy-confirmed AD cases. RESULTS: Behavioral abnormalities, particularly impulsivity (P<.001), disinhibition (P<.001), social withdrawal (P = .01), and progressive nonfluent aphasia, distinguished individuals with FTLD from those with AD. The individuals with FTLD performed better than those with AD on a visual test of episodic memory (P = .01), but worse on word fluency (P = .02) (performance correlated with aphasic features). Other cognitive and clinical features, including executive dysfunction and memory impairment, were comparable between the FTLD and AD groups. Concomitant histopathological AD was present in 11 of the 48 individuals with FTLD. CONCLUSIONS: Clinical and cognitive features of FTLD may overlap with AD, although behavioral and language difficulties distinguish those with FTLD. Memory loss in those with FTLD may in part reflect word-finding difficulties stemming from language dysfunction. Compounding the overlap of FTLD and AD clinical phenotypes is the presence of histopathological AD in almost one fourth of individuals with FTLD.

Als and Ftd: Insights into the disease mechanisms and therapeutic targets.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectively called TDP-43 proteinopathy. Recent discoveries in genetics (e.g. C9orf72 hexanucleotide expansion) and the subsequent neuropathological characterization have revealed remarkable overlap between ALS and FTLD-TDP indicating common pathways in pathogenesis. For ALS, an anti-glutamate agent riluzole may be offered to slow disease progression (Level A), and a promising molecule, arimoclomol, is currently in clinical trials. Other compounds, however, are being trailed and some have shown encouraging results. As new therapeutic approaches continue to emerge by targeting SOD1, TDP-43, or GRN, we present some advances that are being made in our understanding of the molecular mechanisms of these diseases, which together with gene and stem cell therapies may translate into new treatment options.

Molecular basis of ALS and FTD: implications for translational studies.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options.

Long-term outcome of deep brain stimulation in fragile X-associated tremor/ataxia syndrome.

INTRODUCTION: Fragile X-associated tremor/ataxia syndrome (FXTAS) presents as complex movement disorder including tremor and cerebellar ataxia. The efficacy and safety of deep brain stimulation of the nucleus ventralis intermedius of the thalamus in atypical tremor syndromes like FXTAS remains to be determined. METHODS: Here, we report the long-term outcome of three male genetically confirmed FXTAS patients treated with bilateral neurostimulation of the nucleus ventralis intermedius for up to four years. RESULTS: All patients demonstrated sustained improvement of both tremor and ataxia - the latter included improvement of intention tremor and axial tremor. Kinematic gait analyses further demonstrated a regularization of the gait cycle. Initial improvements of hand functional disability were not sustained and reached the preoperative level of impairment within one to two years from surgery. CONCLUSION: Our data on patients with a genetic cause of tremor show favorable outcome and may contribute to improved patient stratification for neurostimulation therapy in the future.

Immunological aspects and anti-amyloid strategy for Alzheimer's dementia.

Alzheimer's dementia (AD) is the most common form of dementia among the elderly, accounting for at least two-thirds of all dementia cases. It represents a costly burden, since its global prevalence is estimated at 24 million cases. Amyloid beta or Aß plaques and neurofibrillary tangles define AD pathologically but do not fully explain it, because dementia may also be caused by inflammation resulting in neuronal, axonal synaptic loss and dysfunction. An important component of AD pathophysiology are amyloid plaques surrounded by activated microglia, cytokines, and complement components, suggesting inflammation. In the diagnosis of AD, cerebrospinal fluid markers, especially in vivo amyloid measurements, contribute to an accurate assessment of AD pathology and differential diagnosis. Aß levels are a very good marker for the presence of amyloid deposits in the brain, while total tau and phosphorylated tau are useful for the detection of neurodegeneration. The implementation of anti-amyloid therapy and other disease-modifying interventions may have immense clinical impact if initiated at an early or presymptomatic stage of AD, before significant brain damage occurs. This paper briefly reviews the abovementioned topics and provides recommendations for future studies.

Molecular basis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration with unclear etiology and no effective treatment to date. ALS is, however, increasingly recognized as a multisystem disorder associated with impaired cognition. The overlap between ALS and dementia at clinical, genetic and neuropathologic levels indicates a spectrum of clinical phenotypes that may include features of frontotemporal lobar degeneration (FTLD). Most cases of ALS are sporadic (SALS), but approximately 10% of all ALS cases are familial ALS (FALS). Mutations in the Cu/Zn superoxide dismutase-1 gene (SOD-1) occur in about 20% of FALS cases. Mutations in the TAR DNA-binding protein 43 gene (TARDBP or TDP-43) may occur in 3-4% of FALS cases, and less frequently, in FTLD. Recently, mutations in the fused in sarcoma/translation in liposarcoma gene (FUS/TLS) were identified as causing about 4-5% of FALS, SALS, and FTLD cases, but not SOD-1 ALS cases, indicating a pathogenic role of FUS, together with TDP-43, in possibly all types of ALS, except for SOD-1 linked ALS. TDP-43 and FUS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. Thus, TARDBP and FUS/TLS mutations define a novel class of neurodegenerative diseases called TDP-43- and FUS-proteinopathies, in which both misfolded proteins are novel targets for the development of therapeutics in this spectrum of diseases. However, SOD-1 linked ALS may have a pathogenic pathway distinct from other types of ALS.

Frontotemporal dementias: update on recent developments in molecular genetics and neuropathology.

Frontotemporal dementias (FTD) are the second most common type of presenile dementias, considered to be clinically and pathologically different from Alzheimer's dementia (AD). FTD differs clinically from AD because memory loss is rarely an early symptom. Instead, FTD is usually denoted by behavioural and language difficulties, and may co-occur with motor neuron disease (MND). Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) is the most common underlying pathology with and without MND. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD-U with or without MND, demonstrating that abnormal TDP-43 alone is sufficient to cause neurodegeneration. FTLD is a genetically complex disorder. A proportion of cases of FTLD-U have various pathogenic mutations in the progranulin (GRN) gene. Other FTLD-U entities with TDP-43 proteinopathy include FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with MND linked to chromosome 9p. In contrast, chromosome 3-linked dementia, a FTLD-U with chromatic modifying protein 2B (CHMP2B) mutation, has TDP-43 negative inclusions. Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. These recent discoveries will contribute to an accurate diagnosis, and facilitate the development of diagnosis and therapy.

Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.

HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.

OBJECTIVE: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques. METHODS: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred. RESULTS: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide. INTERPRETATION: HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.

Visual evoked potentials in multiple sclerosis patients treated with interferon beta-1a.

AIM: To study pattern-reversal visual evoked potentials (VEP) in patients with relapsing-remitting multiple sclerosis on interferon beta-1a treatment. METHODS: In a randomized, prospective, non-blinded, placebo-uncontrolled study, VEP were studied in 9 patients (18 eyes) with relapsing-remitting multiple sclerosis treated with interferon. Three of them have had an episode of unilateral optic neuritis. VEP were first recorded before interferon treatment and then followed up for 12 months, at 3-month intervals, in the time when patients were receiving interferon, 11 microg twice weekly. All patients did not appear regularly at 3-months intervals follow-up, except for 6-month follow-up. P100 latency and P100 amplitude in responses to full field, right and left half-field stimulation were evaluated. RESULTS: For the group of 18 eyes, there was no statistically significant difference in P100 latency and P100 amplitude before and after 6 months of treatment. In individual cases P100 latency was delayed in 3 eyes of 3 patients with a history of optic neuritis before treatment. At follow-up, P100 latency remained delayed in 3 eyes with a history of optic neuritis. Further, in 3 eyes of two patients who have had normal P100 latency before treatment, P100 latency became delayed. Overall, P100 latency was at follow-up delayed in 6 eyes of 5 patients. CONCLUSION: Interferon beta-1a therapy (22 microg per week) administered for 12 months during 1998/99 in Croatia showed no statistically significant VEP changes in the group of relapsing-remitting multiple sclerosis patients. However, VEP may reveal evidence for asymptomatic deterioration.