Advances in semantic dementia: Neuropsychology, pathology & neuroimaging.

Semantic dementia is a kind of neurodegenerative disorder, characterized by prominent semantic impairments and anterior temporal lobe atrophy. Since 2010, more studies have devoted to this rare disorder, revealing that it is more complex than we think. Clinical advances include more specific findings of semantic impairments and other higher order cognitive deficits. Neuroimaging techniques can help revealing the different brain networks affected (both structurally and functionally) in this condition. Pathological and genetic studies have also found more complex situations of semantic dementia, which might explain the huge variance existing in semantic dementia. Moreover, the current diagnosis criteria mainly focus on semantic dementia's classical prototype. We further delineated the features of three subtypes of semantic dementia based on atrophy lateralization with three severity stages. In a broader background, as a part of the continuum of neurodegenerative disorders, semantic dementia is commonly compared with other resembling conditions. Therefore, we summarized the differential diagnosis between semantic dementia and them. Finally, we introduced the challenges and achievements of its diagnosis, treatment, care and cross cultural comparison. By providing a comprehensive picture of semantic dementia on different aspects of advances, we hope to deepen the understanding of semantic dementia and promote more inspirations on both clinical and theoretical studies about it.

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient.

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.

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. Clinicopathological correlations show that object naming and word comprehension are critically dependent on the language-dominant (usually left) temporopolar region, whereas behavioural control and non-verbal object recognition display a more bilateral representation with a rightward bias. Neuroanatomical experiments in macaques and neuroimaging in humans show that the temporoparietal region sits at the confluence of auditory, visual and limbic streams of processing at the downstream (deep) pole of the 'what' pathway. The functional neuroanatomy of this region revolves around three axes, an anterograde horizontal axis from unimodal to heteromodal and paralimbic cortex; a radial axis where visual (ventral), auditory (dorsal) and paralimbic (medial) territories encircle temporopolar cortex and display hemispheric asymmetry; and a vertical depth-of-processing axis for the associative elaboration of words, objects and interoceptive states. One function of this neural matrix is to support the transformation of object and word representations from unimodal percepts to multimodal concepts. The underlying process is likely to start at canonical gateways that successively lead to generic (superordinate), specific (basic) and unique levels of recognition. A first sign of left temporopolar dysfunction takes the form of taxonomic blurring where boundaries among categories are preserved but not boundaries among exemplars of a category. Semantic paraphasias and coordinate errors in word-picture verification tests are consequences of this phenomenon. Eventually, boundaries among categories are also blurred and comprehension impairments become more profound. The medial temporopolar region belongs to the amygdalocentric component of the limbic system and stands to integrate exteroceptive information with interoceptive states underlying social interactions. Review of the pertinent literature shows that word comprehension and conduct impairments caused by temporopolar strokes and temporal lobectomy are far less severe than those seen in temporopolar atrophies. One explanation for this unexpected discrepancy invokes the miswiring of residual temporopolar neurons during the many years of indolently progressive neurodegeneration. According to this hypothesis, the temporopolar regions become not only dysfunctional but also sources of aberrant outputs that interfere with the function of areas elsewhere in the language and paralimbic networks, a juxtaposition not seen in lobectomy or stroke.

A case of semantic variant primary progressive aphasia with Pick's pathology.

Neurodegenerative diseases are caused by aggregation of specific proteins that catalyze a cascade of changes that ultimately lead to neurodegeneration. This concept guides current diagnostic approaches, as well as clinical trials, that focus on detecting or removing amyloid or tau from the brain. The semantic variant of primary progressive aphasia (svPPA), a clinical syndrome associated with frontotemporal lobar degeneration (FTLD) pathology, is usually associated with the molecular pathology TDP-C, but there are cases with TDP-B and Pick's disease. The existing literature on the clinical differentiation of these pathologies is limited. Here, we present a case study, in conjunction with a cross-sectional voxel-based morphometry (VBM), to elucidate the clinical and imaging features of a patient with svPPA due to Pick's disease.