Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies.

Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases.

A scoping review of the unique landscape and challenges associated with dementia in the Western Pacific region.

Unlabelled: Dementia is a leading public health crisis that is projected to affect 152.8 million individuals by 2050, over half of whom will be living in the Western Pacific region. To determine the challenges and opportunities for capacity building in the region, this scoping review searched databases.

Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.

Background: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD).

Objective: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD.

Results: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical).

Survival in sporadic ALS is associated with lower p62 burden in the spinal cord.

The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease.

Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.

Aims: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown.

Methods: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)].

Results: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not.

Coexisting Lewy body disease and clinical parkinsonism in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) inclusions in motor and non-motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity.

A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes.

This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank.

TDP-43 levels in the brain tissue of ALS cases with and without or gene expansions.

Objective: To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the or genes.

Methods: The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the or genes and sporadic disease and 10 controls.

Results: Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate expansions.

Von Economo Neurons in Behavioral Variant Frontotemporal Dementia with Underlying Alzheimer's Disease.

The selective loss of von Economo neurons has been linked to the behavioral deficits in behavioral variant frontotemporal dementia (bvFTD) but whether these neurons are affected in bvFTD patients with underlying Alzheimer's disease (AD) has yet to be established. The present study assesses the von Economo neurons in pathological AD cases clinically diagnosed with either AD or bvFTD. Our results demonstrate no significant loss of von Economo neurons in all pathological AD cases, irrespective of clinical diagnosis or co-existing Lewy body pathology.

Coexisting Lewy body disease and clinical parkinsonism in frontotemporal lobar degeneration.

Objective: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features.

Methods: All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined.

The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability.

Objective: To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort.

Methods: A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score ≤3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy.

Distinct TDP-43 inclusion morphologies in frontotemporal lobar degeneration with and without amyotrophic lateral sclerosis.

The identification of the TAR DNA-binding protein 43 (TDP-43) as the ubiquitinated cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) confirmed that these two diseases share similar mechanisms, likely to be linked to the abnormal hyperphosphorylation, ubiquitination and cleavage of pathological TDP-43. Importantly however, a quantitative analysis of TDP-43 inclusions in predilection cortical regions of FTLD, FTLD-ALS and ALS cases has not been undertaken. The present study set out to assess this and demonstrates that distinct TDP-43 inclusion morphologies exist in the anterior cingulate cortex, but not the motor cortex of FTLD and FTLD-ALS.

Assessment of amyloid β in pathologically confirmed frontotemporal dementia syndromes.

Introduction: The diagnostic utility of in vivo amyloid β (Aβ) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Aβ in pathologically confirmed FTD syndromes.

Methods: Aβ was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of C-Pittsburgh compound B (PiB)-positron emission tomography imaging was assessed in a subset of FTD cases ( = 15).

Results: Aβ was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age.

Cerebellar atrophy in neurodegeneration-a meta-analysis.

Introduction: The cerebellum has strong cortical and subcortical connectivity, but is rarely taken into account for clinical diagnosis in many neurodegenerative conditions, particularly in the absence of clinical ataxia. The current meta-analysis aims to assess patterns of cerebellar grey matter atrophy in seven neurodegenerative conditions (Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (MSP)).

Methods: We carried out a systematic search in PubMed (any date: 14 July 2016) and a hand search of references from pertinent articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion.

Background: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion.

ALS/FTLD: experimental models and reality.

Amyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural variant, in which neuronal inclusions containing either TDP-43 or 3-repeat tau are most prevalent. Although the genetic mutations associated with these diseases have allowed various experimental models to be developed, the initial genetic forms identified remain the most common models employed to date.

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.

The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study.

Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions.

Objective: Despite evidence suggesting that the cerebellum may be targeted in amyotrophic lateral sclerosis (ALS), particularly in cases with repeat expansions in the ATXN2 and C9ORF72 genes, the integrity of cerebellar neurons has yet to be examined. The present study undertakes a histopathological analysis to assess the impact of these repeat expansions on cerebellar neurons and determine whether similar cerebellar pathology occurs in sporadic disease.

Methods: Purkinje and granule cells were quantified in the vermis and lateral cerebellar hemispheres of ALS cases with repeat expansions in the ATXN2 and C9ORF72 genes, sporadic disease, and sporadic progressive muscular atrophy with only lower motor neuron degeneration.

TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes.

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination.

Terra incognita-cerebellar contributions to neuropsychiatric and cognitive dysfunction in behavioral variant frontotemporal dementia.

Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioral variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function, and motivation and the degree of gray matter degeneration in cerebellar lobules V-VII.