Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.

Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein assembly in neurodegeneration. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases.

Progressive verbal apraxia of reading.

We identified a syndrome characterized by a relatively isolated progressive impairment of reading words that the patient was able to understand and repeat but without other components of speech apraxia. This cluster of symptoms fits a new syndrome designated Progressive Verbal Apraxia of Reading. A right-handed man (AB) came with a 2.

Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.

Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor.

Loss and microglia phagocytosis of synaptic proteins in frontotemporal lobar degeneration with TDP-43 proteinopathy.

Cortical synaptic loss has emerged as an early abnormality in Alzheimer's disease (AD) with a strong relationship to cognitive performance. However, the status of synapses in frontotemporal lobar degeneration (FTLD) has received meager experimental attention. The purpose of this study was to investigate changes in cortical synaptic proteins in FTLD with tar DNA binding protein-43 (TDP-43) proteinopathy.

Neural mechanisms of sentence production: a volumetric study of primary progressive aphasia.

Studies on the neural bases of sentence production have yielded mixed results, partly due to differences in tasks and participant types. In this study, 101 individuals with primary progressive aphasia (PPA) were evaluated using a test that required spoken production following an auditory prime (Northwestern Assessment of Verbs and Sentences-Sentence Production Priming Test, NAVS-SPPT), and one that required building a sentence by ordering word cards (Northwestern Anagram Test, NAT). Voxel-Based Morphometry revealed that gray matter (GM) volume in left inferior/middle frontal gyri (L IFG/MFG) was associated with sentence production accuracy on both tasks, more so for complex sentences, whereas, GM volume in left posterior temporal regions was exclusively associated with NAVS-SPPT performance and predicted by performance on a Digit Span Forward (DSF) task.

The production of adjectives in narratives by individuals with primary progressive aphasia.

Adjectives (e.g., ) are an important part of language, but have been little studied in individuals with impaired language.

Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA-binding Protein 43.

Objective: Age-related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA-binding protein 43 (TDP-43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP-43 and tau, along the well-charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non-amnestic dementia due to TDP-43 proteinopathy associated with frontotemporal lobar degeneration (FTLD-TDP).

Shades of gray in human white matter.

Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological function are mainly derived from animal models. Here, we investigated 15 whole-brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD).

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy.

Frontotemporal Degeneration with Transactive Response DNA-Binding Protein Type C at the Anterior Temporal Lobe.

The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions.

Evaluating the association between genetically proxied ACE inhibition and dementias.

Introduction: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown.

Methods: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach.

Results: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.

The eyes speak when the mouth cannot: Using eye movements to interpret omissions in primary progressive aphasia.

Though it may seem simple, object naming is a complex multistage process that can be impaired by lesions at various sites of the language network. Individuals with neurodegenerative disorders of language, known as primary progressive aphasias (PPA), have difficulty with naming objects, and instead frequently say "I don't know" or fail to give a vocal response at all, known as an omission. Whereas other types of naming errors (paraphasias) give clues as to which aspects of the language network have been compromised, the mechanisms underlying omissions remain largely unknown.

Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.

Background And Objectives: Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA.

Differential vulnerability of the dentate gyrus to tauopathies in dementias.

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles-3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group.

Stimulation of distinct parietal locations differentiates frontal versus hippocampal network involvement in memory formation.

Adjacent regions of parietal cortex are thought to affiliate with distinct large-scale networks and thereby make different contributions to memory formation. We directly tested this putative functional segregation within parietal cortex by perturbing activity of anterior versus posterior parietal areas. We applied noninvasive theta-burst transcranial magnetic stimulation to these locations immediately before a semantic encoding task, and subsequently tested recollection memory.

Temporopolar regions of the human brain.

Following prolonged neglect during the formative decades of behavioural neurology, the temporopolar region has become a site of vibrant research on the neurobiology of cognition and conduct. This turnaround can be attributed to increasing recognition of neurodegenerative diseases that target temporopolar regions for peak destruction. The resultant syndromes include behavioural dementia, associative agnosia, semantic forms of primary progressive aphasia and semantic dementia.

Integrity of Neuronal Size in the Entorhinal Cortex Is a Biological Substrate of Exceptional Cognitive Aging.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers ("Normal Elderly"), and individuals with amnestic mild cognitive impairment.