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Key Points Primary progressive aphasia (PPA) is a clinical syndrome caused by selective neurodegeneration of the language-dominant cerebral hemisphere, thus affecting the language network The language disorder manifest in patients with PPA can take the form of agrammatic, logopenic or semantic aphasia, depending on the anatomical distribution of cortical atrophy PPA can be caused by several types of neuropathology, including Alzheimer disease and frontotemporal lobar degeneration; these diseases tend to be associated with specific variants of PPA Concepts relating to Wernicke's area and anterior temporal lobe function need to be revised on the basis of the relationships identified between the clinical characteristics and neuroanatomy of peak atrophy sites in PPA PPA susceptibility, aetiology and pathogenesis, and the asymmetry of cerebral atrophy in particular, are poorly understood and require further elucidation Effective PPA treatments are urgently needed; development of such treatments should be considered a research area of importance Primary progressive aphasia (PPA) is caused by asymmetric, selective neurodegeneration of cerebral areas involved in language. Agrammatic and semantic PPAs are typically manifestations of frontotemporal lobar degeneration, whereas the logopenic PPA is more often associated with Alzheimer disease pathology. Here, Mesulam et al . review the subclassification, clinical features and neuropathology of PPA, and discuss how increased knowledge of PPA has advanced our understanding of the neural substrates of the language network. 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.

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-β (Aβ), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Aβ earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Aβ clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Aβ clearance.

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.

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 via 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.

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.

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA-induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to Aβ42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of “SuperAgers”, humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to Aβ42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and Aβ42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration. Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.

A large body of evidence indicates that basal forebrain cholinergic neurons are selectively vulnerable to degeneration early in Alzheimer disease (AD). Recent studies, however, demonstrate reductions in cortical activity of the cholinergic enzyme choline acetyltransferase only in late stages of AD. To address this apparent contradiction, we compared abnormalities in magnocellular basal forebrain cholinergic neurons and their axons in nondemented young (<65 years; n = 6), nondemented old (>65 years; n = 7), pathologically mild (n = 5), and pathologically severe (n = 5) AD cases. Cholinergic axon abnormalities (i.e. thickened fibers and ballooned terminals) were evident in nondemented middle-aged cases, increased in nondemented old cases, and reduced in density in severe AD. This suggests that loss of cortical cholinergic axons in AD occurs preferentially in fibers with these abnormalities. Paired helical filament 1-immunoreactive pretangles and tangles were observed as early as the third decade prior to their appearance in entorhinal/perirhinal cortex; they were increased in mild and severe AD. These results indicate that basal forebrain cholinergic neuron abnormalities are present very early in aging and in the course of AD. Therefore, despite the morphologic alterations, choline acetyltransferase activity, but not necessarily normal neuron functions, may be preserved.

Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.

Abstract Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.