Taxonomic Interference Associated with Phonemic Paraphasias in Agrammatic Primary Progressive Aphasia.

Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visual search task where they matched a stimulus noun to 1 of 16 object pictures as their eye movements were recorded. Participants were subsequently asked to name the same items. We measured taxonomic interference (ratio of time spent viewing related vs. unrelated foils) during the search task for each item. Target items that elicited a phonemic paraphasia during object naming elicited increased taxonomic interference during the search task in agrammatic but not logopenic PPA patients. These results could reflect either very subtle sub-clinical semantic distortions of word representations or partial degradation of specific phonological word forms in agrammatic PPA during both word-to-picture matching (input stage) and picture naming (output stage). The mechanism for phonemic paraphasias in logopenic patients seems to be different and to be operative at the pre-articulatory stage of phonological retrieval. Glucose metabolic imaging suggests that degeneration in the left posterior frontal lobe and left temporo-parietal junction, respectively, might underlie these different patterns of phonemic paraphasia.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

AIMS: Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. METHODS: Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. RESULTS: Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). CONCLUSIONS: White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.

Linking human brain local activity fluctuations to structural and functional network architectures.

Activity of cortical local neuronal populations fluctuates continuously, and a large proportion of these fluctuations are shared across populations of neurons. Here we seek organizational rules that link these two phenomena. Using neuronal activity, as identified by functional MRI (fMRI) and for a given voxel or brain region, we derive a single measure of full bandwidth brain-oxygenation-level-dependent (BOLD) fluctuations by calculating the slope, α, for the log-linear power spectrum. For the same voxel or region, we also measure the temporal coherence of its fluctuations to other voxels or regions, based on exceeding a given threshold, Θ, for zero lag correlation, establishing functional connectivity between pairs of neuronal populations. From resting state fMRI, we calculated whole-brain group-averaged maps for α and for functional connectivity. Both maps showed similar spatial organization, with a correlation coefficient of 0.75 between the two parameters across all brain voxels, as well as variability with hodology. A computational model replicated the main results, suggesting that synaptic low-pass filtering can account for these interrelationships. We also investigated the relationship between α and structural connectivity, as determined by diffusion tensor imaging-based tractography. We observe that the correlation between α and connectivity depends on attentional state; specifically, α correlated more highly to structural connectivity during rest than while attending to a task. Overall, these results provide global rules for the dynamics between frequency characteristics of local brain activity and the architecture of underlying brain networks.

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. In this study, we used a novel eye tracking approach to probe the cognitive mechanisms of omissions in the logopenic and semantic variants of PPA (PPA-L and PPA-S). For each participant, we identified pictures of common objects (e.g., animals, tools) that they could name aloud correctly, as well as pictures that elicited an omission. In a separate word-to-picture matching task, those pictures appeared as targets embedded among an array with 15 foils. Participants were given a verbal cue and tasked with pointing to the target, while eye movements were monitored. On trials with correctly-named targets, controls and both PPA groups ceased visual search soon after foveating the target. On omission trials, however, the PPA-S group failed to stop searching, and went on to view many foils "post-target". As further indication of impaired word knowledge, gaze of the PPA-S group was subject to excessive "taxonomic capture", such that they spent less time viewing the target and more time viewing related foils on omission trials. In contrast, viewing behavior of the PPA-L group was similar to controls on both correctly-named and omission trials. These results indicate that the mechanisms of omission in PPA differ by variant. In PPA-S, anterior temporal lobe degeneration causes taxonomic blurring, such that words from the same category can no longer be reliably distinguished. In PPA-L, word knowledge remains relatively intact, and omissions instead appear to be caused by downstream factors (e.g., lexical access, phonological encoding). These findings demonstrate that when words fail, eye movements can be particularly informative.

Alteration in connections between muscle and anterior horn motoneurons after peripheral nerve repair.

The connections between the spinal cord and lower leg muscles of the rat are significantly altered by repair of the intervening sciatric nerve. Muscles supplied by the peroneal branch of the sciatic are innervated by fewer motoneurons after sciatic repair. Many of these neurons originally innervated the peroneal muscles, and others formerly served the antagonistic tibial muscles. Perikarya in the size range of alpha motoneurons regained peripheral connections with greater frequency than those in the gamma range. There are thus postoperative defects in the extent and specificity of alpha reinnervation as well as in the degree of gamma control.

Subicular input from temporal cortex in the rhesus monkey.

The subicular cortices of the primate hippocampal formation form a physical and connectional link between the cortex of the temporal lobe and the hippocampus. Their direct connections with all classes of cortex in the temporal lobe except primary sensory cortex underscore the pivotal role of these areas in the potential interplay between the hippocampal formation and the association cortices.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease.

Recent observations in our laboratory have indicated substantial and systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer disease (AD). Previous attempts to study the relationship between cortical cholinergic loss and the density of cortical pathological lesions have resulted in conflicting findings. Furthermore, most reports have correlated density of plaques and tangles with the residual level of cholinergic innervation rather than its loss. The purpose of the present study was to determine the relationship between loss of cholinergic axons and density of tangles and beta-amyloid (Abeta) deposits in various cortical areas of AD brains. Abeta deposits and tangles were observed throughout the cerebral cortex. Quantitative analysis revealed almost no correlation between loss of cholinergic fibers and the density of Abeta deposits. Qualitative observations revealed similar results when cored and neuritic plaques were considered separately. By contrast, cholinergic fiber loss displayed a significant correlation with the density of tangles (r = 0.52-0.79). However, in a few areas, such as the cingulate cortex, tangle density appeared to be unrelated to the loss of cholinergic fibers. These results indicate that cortical cholinergic denervation in AD is related to cytoskeletal pathology. However, the lack of a perfect relationship with cytoskeletal pathology implicates additional factors in the cholinergic pathology of AD.

Involutional and developmental implications of age-related neuronal changes: in search of an engram for wisdom.

The changes in neuronal size and number that occur with aging can be viewed from a developmental rather than an involutional perspective. According to this speculative vantage point, age-related neuronal attrition need not lead to intellectual decline and may, instead, represent a progressive fine-tuning of cerebral networks.

Neurofibrillary tangles have no obligatory predilection for acetylcholinesterase-rich neurons.

Parts of the brain that are prone to NFT formation normally contain many neurons that are intensely acetylcholinesterase (AChE)-positive. In this study, we used thioflavin-S immunofluorescence, AChE histochemistry, and AChE immunocytochemistry to investigate the possibility that intense AChE positivity may act as a perikaryal marker for the vulnerability to NFT formation. Our observations in entorhinal and motor cortices and in the subthalamic nucleus demonstrate major mismatches between the distribution of AChE-rich neurons in normal brains and the distribution of NFT in AD. There is therefore no obligatory relationship between intense AChE positivity in the premorbid period and subsequent vulnerability to tangle formation.

Acetylcholinesterase-rich pyramidal neurons in Alzheimer's disease.

The distribution of acetylcholinesterase (AChE)-rich pyramidal neurons was studied in the cortices of 7 Alzheimer's Disease (AD) patients and 4 normal-aged subjects. Both groups showed a characteristic distribution of these neurons with the highest density in motor and premotor areas, moderate density in association cortices, and low density in limbic-paralimbic areas. Three areas (Brodmann areas 6,22, and 24) were chosen for quantitative analysis. The number of pyramidal neurons that display an AChE-rich staining pattern was significantly reduced in AD patients. Nerve cell density was not significantly different in adjacent Nissl-stained sections. The density of AChE-rich (cholinergic) fibers was also decreased in all three cortical areas of the AD patients but was not correlated with the number of AChE-rich neurons. Loss of AChE-rich neurons was more pronounced in areas with high counts of tangles. These findings show that layer 3 and 5 pyramidal neurons in AD display a reduction of AChE activity. This phenomenon can not be attributed to the well known loss of cortical neurons or cholinergic innervation in AD.

The acute neurotoxicity and effects upon cholinergic axons of intracerebrally injected beta-amyloid in the rat brain.

The acute neurotoxicity and effects upon cholinergic axons of an intracerebrally injected synthetic peptide corresponding to the first 1-40 amino acids of beta-amyloid protein (beta AP1-40) was studied in rats. A synthetic peptide with the reverse sequence (beta AP40-1) or the vehicle alone were injected in the contralateral hemisphere as control. The size of the resulting lesions was quantified in serial sections using an image analyzer. Counts of cholinergic and noradrenergic fibers were also obtained around the lesion area. The results revealed that beta AP1-40 was significantly more toxic than both reverse peptide and the vehicle. The latter two, however, also caused considerable neurotoxicity. beta AP1-40 was toxic to both cholinergic and noradrenergic fibers to the same extent, and this toxicity was limited to the immediate vicinity of the lesion. This study confirms and extends the results of previous studies reporting neurotoxic effects of intracerebrally injected beta-amyloid in the rat. Our results also show that beta AP1-40 itself is not the source of the altered acetylcholinesterase enzyme activity that has been described in the plaques and tangles of Alzheimer's disease.

Clinical comparison of Tourette's disorder and obsessive-compulsive disorder.

The authors report on 16 outpatients with Tourette's disorder, 16 outpatients with obsessive-compulsive disorder, and 16 normal control subjects who underwent structured interviews and psychological testing. Previous findings of a high incidence of obsessive-compulsive disorder in patients with Tourette's disorder were confirmed. There was a significantly greater incidence of tics in the patients with obsessive-compulsive disorder and their relatives. Both patient groups had high rates of unipolar depressive and generalized anxiety disorders. Panic and phobic disorders were frequent in the patients with obsessive-compulsive disorder but not in the patients with Tourette's disorder. The patients with obsessive-compulsive disorder showed less coprolalia, echo phenomena, self-destructive behavior, and childhood attention deficit.

Acetylcholinesterase-rich neurons of the human cerebral cortex: cytoarchitectonic and ontogenetic patterns of distribution.

Layers 3 and 5 of the adult human cerebral cortex contain a very large number of pyramidal neurons that express intense acetylcholinesterase (AChE) enzymatic activity and AChE-like immunoreactivity. The density of these neurons is high in motor, premotor, and neocortical association areas but quite low in paralimbic cortex. These AChE-rich neurons are located predominantly within layer 3 in the premotor and association cortex, within layer 5 in the non-isocortical components of the paralimbic cortex, and are equally prominent in layers 3 and 5 in the motor cortex. Almost all Betz cells in the motor cortex and up to 80% of layer 3 pyramidal neurons in some parts of the association neocortex yield an AChE-rich staining pattern. The existence of a specific laminar and cytoarchitectonic distribution suggests that the AChE-rich enzymatic pattern of these neurons is selectively regulated. The AChE-rich enzymatic reactivity of the layer 3 and layer 5 neurons is not detectable during early childhood, becomes fully established during adulthood, and does not show signs of decline during advanced senescence in mentally intact individuals. The AChE activity (or enzyme synthesis) in these neurons is therefore held in check for several years during infancy and childhood and begins to be expressed at a time when the more advanced motor and cognitive skills are also being acquired. The absence of immunostaining with an antibody to choline acetyltransferase suggests that these AChE-rich neurons are not cholinergic. The regional distribution of these AChE-rich neurons does not parallel the regional variations of cortical cholinergic innervation. Whereas the AChE-rich pyramidal neurons of layers 3 and 5 almost certainly represent one subgroup of cholinoceptive cortical neurons, their AChE-rich enzymatic pattern is probably also related to a host of non-cholinergic processes that may include maturational changes and plasticity in the adult brain.

Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase.

The nucleus basalis (NB) of the human brain is a large, complex, and highly differentiated structure. Many of its neurons are magnocellular, hyperchromic, isodendritic, acetylcholinesterase-rich, and choline-acetyltransferase-positive. Concurrent histochemical and immunological staining demonstrated that all choline-acetyltransferase-positive NB neurons in the human brain also contain acetylcholinesterase enzyme activity. Only a small minority of acetylcholinesterase-rich magnocellular cell bodies in the NB failed to show choline acetyltransferase immunoreactivity. Sections that were counterstained for Nissl substance showed that 80-90% of all magnocellular neurons in the NB were choline-acetyltransferase-positive and therefore cholinergic. These characteristics, which are very similar to those of the NB in the monkey brain, justified the designation of these cholinergic neurons in the human brain as the Ch4 (or NB-Ch4) complex. On morphological grounds, the compact parts of the human NB-Ch4 complex were divided into distinct sectors which appeared to show a greater level of differentiation than in the monkey brain. In addition to the compact sectors, interstitial elements of NB Ch4 were embedded within adjacent fiber bundles. The putative cortical projections from NB-Ch4 were identified in the form of acetylcholinesterase-rich fibers. These fibers formed a dense plexus in all cortical regions but also displayed laminar and regional variations. Limbic and paralimbic areas had higher concentrations of these fibers than the immediately adjacent neocortical association areas. Alzheimer's disease was associated with a marked depletion of cortical acetylcholinesterase. Two cases of Alzheimer's disease with relatively selective NB-Ch4 cell loss supported the hypothesis that the corticopetal cholinergic pathways in the human brain may have a topographical organization similar to that in the monkey brain.

Acetylcholinesterase fiber staining in the human hippocampus and parahippocampal gyrus.

The AChE fiber distribution within the human hippocampus and parahippocampal gyrus was studied in order to provide normative data for the examination of cholinergic fiberarchitecture in human pathology and to clarify the cytoarchitectonic organization of these structures. A modification of the Koelle method was used to stain temporal lobe serial sections from 6 neurologically normal human brains collected at autopsy. The hippocampal formation contains some of the densest staining of any cortical area. Regions with the heaviest concentrations of AChE fibers include a thin band along the inner edge of the molecular layer of the dentate gyrus (ml-DG) and parts of the CA2, CA3, and CA4 sectors of Ammon's horn. Staining is of intermediate intensity in the CA1 region. The subiculum (S) is more lightly stained than the CA fields. Staining in the parahippocampal gyrus is generally less dense than in the hippocampal formation. The most conspicuous feature of the human entorhinal cortex (EC) is the AChE-rich fiber patches seen overlapping the stellate cell islands in layer II. An additional band of relatively dense AChE staining is identified in layers IV-V. Prominent AChE-rich polymorphic neurons are present within the hilum of the dentate gyrus. The CA1/subiculum transition in Nissl preparation is characterized by an oblique interdigitation of CA1 cells. The transition from EC to prorhinal cortex occurs along the medial bank of the rhinal sulcus and is characterized by a band of AChE staining, which slopes obliquely away from layer II until it joins an intermediate pyramidal cell layer. Some comparisons with AChE staining in the monkey were made. The monkey has a similar pattern except in DG, where the intensely AChE staining band along the inner ml-DG is thicker and much more prominent. In comparison to the human, the monkey has more conspicuous AChE staining in the parasubicular region.

Insula of the old world monkey. I. Architectonics in the insulo-orbito-temporal component of the paralimbic brain.

The insula of the rhesus monkey has a surface area of approximately 160 mm2 and can be divided into three architectonic sectors. The agranular sector is coextensive with prepiriform allocortex and is characterized by three agranular cellular strata, a zonal layer of myelinated fibers, and a high level of intracortical acetylcholinesterase (AChE). The dysgranular sector adjoins the agranular sector and shows first the emergence of a granular L4 and then a gradual differentiation of L2. Cortical myelin is low and mostly within deep layers; the AChE level is less than in the agranular sector. The third and granular sector covers the posterior aspect of the insula and contains granular L4 and L2, incipient sublamination of L3, increased cortical myelin with an emergent outer line of Baillarger, and a very low density of AChE. These observations indicate that AChE histochemistry can be used for the architectonic analysis of cortex. The lateral orbital cortex and the temporal pole can also be subdivided into agranular, dysgranular, and granular regions. In the insula as well as in lateral orbital and temporopolar areas, the agranular sector is directly contiguous with prepiriform cortex. When these three brain regions are considered jointly, they are seen to be organized in the form of increasingly more differentiated agranular, dysgranular, granular, and hypergranular sectors arranged concentrically around prepiriform allocortex. The term paralimbic is suggested as a generic term for all regions where such transitions occur from allocortex to granular isocortex. The insula, lateral orbital surface, and temporal pole are paralimbic areas with an olfactory allocortical focus. The parahippocampal, retrosplenial, cingulate, and subcallosal regions constitute a second group of paralimbic areas with a hippocampal-induseal focus. In the most general sense, the functional specilizations of paralimbic areas are predominantly for behaviors which require an integration between extrapersonal stimuli and the internal milieu. The human insula has a plan of organization virtually identical to that in the rhesus monkey. In the human, the insulo-orbito-temporopolar component of the paralimbic brain may become involved in conditions which range from epilepsy to psychosomatic disease.

Insula of the old world monkey. II: Afferent cortical input and comments on the claustrum.

The afferent connections of the insula in the rhesus monkey were studied with axonal transport methods. Injections of horseradish peroxidase (HRP) in the insula revealed labeled neurons in the prefrontal cortex, the lateral orbital region, the frontoparietal operculum, the cingulate gyrus and adjacent medial cortex, the prepiriform olfactory cortex, the temporal pole, the cortex of the superior temporal sulcus, the rhinal cortex, the supratemporal plane, and the posterior parietal lobe. Tritiated amino acid (TAA) injections in some of the cortical regions which contained retrogradely labeled neurons confirmed projections to the insula from prefrontal granular cortex, orbital frontal cortex, prepiriform cortex, temporal pole, rhinal cortex, cingulate gyrus, frontal operculum, and parietal cortex. In these studies, cortical areas that projected to the insula also projected to the claustrum. However, the topographic and quantitative relationships between the projections into the insula and those into the claustrum were inconsistent. Moreover, the claustrum has additional connections which it does not share with the insula. A selected review of the literature suggests that the claustrum and insula differ widely also with respect to ontogenesis and functional specialization.

Insula of the old world monkey. III: Efferent cortical output and comments on function.

The insula sends neural efferents to cortical areas from which it receives reciprocal afferent projections. A collective consideration of afferents and efferents indicates that the insula has connections with principal sensory areas in the olfactory, gustatory, somesthetic (SI and SII), and auditory (AI and AII) modalities. There are additional connections with association areas for the visual (TEm), auditory (supratemporal plane), and somesthetic (posterior parietal cortex) modalities; with paramotor cortex (area 6 and perhaps MII); with polymodal association cortex; and with a wide range of paralimbic areas in the orbital, temporopolar, and cingulate areas. The topographic distribution of these connections suggests that the posterodorsal insula is specialized for auditory-somesthetic-skeletomotor function whereas the anteroventral insula is related to olfactory-gustatory-autonomic function. Most of the insula, especially its anteroventral portions, have extensive interconnections with limbic structures. Through its connections with the amygdala, the insula provides a pathway for somatosensory, auditory, gustatory, olfactory, and visceral sensations to reach the limbic system. The cortical areas connected with the granular sector of the insula are also granular in architecture whereas virtually all the connections of the agranular insula arise from allocortical, agranular, or dysgranular areas. Thus, there is a correspondence between the architecture of insular sectors and the areas with which they have connections. The insula is heavily interconnected with temporopolar and lateral orbital areas. Furthermore, many cortical connections of the lateral orbital cortex are quite similar to those of the insula. These common connectivity patterns support the conclusion, based on architectonic observations, that the insulo-orbito-temporopolar component of the paralimbic brain should be considered as an integrated unit of cerebral organization.