Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and ...remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.
The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, ...and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD‐TAU) and the TDP‐43 proteinopathy of FTLD‐TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD‐TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.
This Review is part of the special issue “Cholinergic Mechanisms” and summarizes the relevance to basal forebrain cholinergic neurons (BFCN) of neuropathologic markers associated with dementias. Available evidence points to early and substantial degeneration of the BFCN in Alzheimer’s disease and diffuse Lewy body disease. BFCN are resilient to the neurodegenerative effect of some tauopathies in frontotemporal lobar degeneration (FTLD), such as that is corticobasal degeneration, and they are apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick’s disease. These findings have important implications for selective neuronal vulnerability and cholinergic based therapies in dementias.
Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the ...aged human substantia nigra contain very high levels of mtDNA deletions. Molecules with deletions are largely clonal within each neuron; that is, they originate from a single deleted mtDNA molecule that has expanded clonally. The fraction of mtDNA deletions is significantly higher in cytochrome c oxidase (COX)-deficient neurons than in COX-positive neurons, suggesting that mtDNA deletions may be directly responsible for impaired cellular respiration.
Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes ...from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14
+
cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.
The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of ...SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ɛ4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.
Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration ...(FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.
Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and ...activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.
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•Pathological tau (pTau) primes NF-κB and IL-1β signaling in human primary microglia•Suppressing pTau reduces inflammasome activation in tauopathy mice•Myeloid-cell restricted deletion of ASC improves cognitive function in hTau mice•pTau co-exists with elevated IL-1β and ASC in human tauopathy brains and CSF
Jiang et al. show pathological tau primes and activates interleukin-1β in microglia via MyD88-, NLRP3-, and ASC-dependent pathways. Suppressing tau, MyD88, or ASC reduces tau pathology and inflammasome activation and improves cognitive function in the hTau mice. Tau burden co-exists with elevated IL-1β and ASC in human tauopathy brains.
Apical dendrites of Betz cells are important sites for the integration of cortical input, however their health has not been fully assessed in ALS patients. We investigated the primary motor cortices ...isolated from post-mortem normal control subjects, patients with familial ALS (fALS), sporadic ALS (sALS), ALS with frontotemporal dementia (FTD-ALS), and Alzheimer's disease (AD), and found profound apical dendrite degeneration of Betz cells in both fALS and sALS, as well as FTD-ALS patients. In contrast, Betz cells of AD patients and normal controls retain cellular integrity in the motor cortex, and CA1 pyramidal neurons show abnormalities predominantly within their soma, rather than the apical dendrite. In line with extensive vacuolation and cytoarchitectural disintegration, the numbers of synapses were also significantly reduced only in ALS patients. Our findings indicate apical dendrite degeneration as a novel cellular pathology that distinguishes ALS and further support the importance of cortical dysfunction for disease pathology.
The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, ...neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.
Dendritic spines are highly dynamic and changes in their density, size, and shape underlie structural synaptic plasticity in cognition and memory. Fine membranous protrusions of spines, termed ...dendritic spinules, can contact neighboring neurons or glial cells and are positively regulated by neuronal activity. Spinules are thinner than filopodia, variable in length, and often emerge from large mushroom spines. Due to their nanoscale, spinules have frequently been overlooked in diffraction-limited microscopy datasets. Until recently, our knowledge of spinules has been interpreted largely from single snapshots in time captured by electron microscopy. We summarize herein the current knowledge about the molecular mechanisms of spinule formation. Additionally, we discuss possible spinule functions in structural synaptic plasticity in the context of development, adulthood, aging, and psychiatric disorders. The literature collectively implicates spinules as a mode of structural synaptic plasticity and suggests the existence of morphologically and functionally distinct spinule subsets. A recent time-lapse, enhanced resolution imaging study demonstrated that the majority of spinules are small, short-lived, and dynamic, potentially exploring their environment or mediating retrograde signaling and membrane remodeling
trans-endocytosis. A subset of activity-enhanced, elongated, long-lived spinules is associated with complex PSDs, and preferentially contacts adjacent axonal boutons not presynaptic to the spine head. Hence, long-lived spinules can form secondary synapses with the potential to alter synaptic connectivity. Published studies further suggest that decreased spinules are associated with impaired synaptic plasticity and intellectual disability, while increased spinules are linked to hyperexcitability and neurodegenerative diseases. In summary, the literature indicates that spinules mediate structural synaptic plasticity and perturbations in spinules can contribute to synaptic dysfunction and psychiatric disease. Additional studies would be beneficial to further delineate the molecular mechanisms of spinule formation and determine the exact role of spinules in development, adulthood, aging, and psychiatric disorders.
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