Functional Neuroanatomy of Primary Progressive Aphasias

Introduction to Primary Progressive Aphasia (PPA) Syndromes #

Primary Progressive Aphasia (PPA) is a clinical syndrome characterised by progressive language impairment with distinct anatomical and behavioural presentations. The following is a summary of a Lecture that we attended in August 2025 given by Jason Gravano PhD (UCSF) and hosted by KnowNeuropsychology. This 2025 update on functional neuroanatomy of PPAs emphasised the importance of understanding the cortical and subcortical structures involved in these syndromes, as well as the white matter tracts that connect them.

The three main PPA variants discussed were:

• Logopenic variant: Primarily involves the temporal-parietal junction, including the posterior superior temporal gyrus (Wernicke’s area), supramarginal gyrus, angular gyrus, and posterior middle temporal gyrus.
• Semantic variant: Mainly affects the anterior temporal lobe, including the amygdala, perihippocampus, and inferotemporal regions.
• Non-fluent/agrammatic variant: Primarily involves frontal regions associated with language production, grammatical processing, and motor planning for speech.

These variants show overlapping but distinct patterns of cortical atrophy and white matter tract involvement, such as the arcuate fasciculus and frontal-occipital fasciculus in the non-fluent variant.

Neuroanatomical Framework and Functional Networks #

The lecture highlighted a conceptual framework dividing brain regions into unimodal, heteromodal, and limbic association areas. Primary sensory information is processed in unimodal areas, then integrated in heteromodal association areas through networks including U-fibres. This framework aids in localising clinical symptoms to specific brain regions and networks.

White matter tracts connecting these cortical regions are crucial in understanding the spread and impact of pathology in PPA. For example, disruption of the arcuate fasciculus affects language repetition and fluency, particularly in the logopenic and non-fluent variants.

Clinical and Cognitive Correlates of Neuroanatomy #

Clinical features of PPA variants correlate with specific neuroanatomical changes:

Naming deficits #

Naming impairments are associated with atrophy in the anterior temporal lobes and, to a lesser extent, the inferior frontal regions, with different patterns depending on the PPA variant. These deficits are most prominent in the semantic variant of PPA (svPPA), where loss of semantic knowledge leads to impaired object naming. In contrast, the logopenic variant (lvPPA) is characterised by word-finding difficulties despite preserved semantic understanding, reflecting phonological retrieval issues.

Repetition and phonological loop impairments #

Difficulties with repetition, particularly of sentences and phrases, are linked to dysfunction in the left temporoparietal junction and associated frontal circuitry, with differences in forward and backward verbal span tasks reflecting working memory and executive involvement, suggestive of phonological loop disruption. These deficits are a hallmark of the logopenic variant (lvPPA), where verbal working memory is significantly impaired. Forward and backward digit span tasks may highlight differing contributions of working memory and executive control processes.

Executive dysfunction #

Executive impairments are more prominent in the non-fluent (nfvPPA) and logopenic (lvPPA) variants, due to involvement of the left inferior frontal gyrus and other frontal structures. In nfvPPA, this may manifest as difficulties with planning, sequencing, and inhibition, often alongside apraxia of speech. In contrast, the semantic variant (svPPA) tends to show behavioural rather than cognitive executive changes, such as loss of empathy, disinhibition, or altered social conduct, typically related to anterior temporal and orbitofrontal atrophy, particularly when right-sided.

Emotional communication disorders #

Impairments in emotional perception and expression are linked to degeneration in the right hemisphere homologues of language areas, particularly the right anterior temporal and inferior frontal regions. These can affect recognition of facial expressions, emotional prosody, and appropriate emotional responses. While such difficulties may appear across PPA variants, they are particularly relevant in non-fluent variant PPA, where frontal involvement may impact expressive prosody and regulation of emotional tone.

🧠 Table: Clinical Features, Neural Correlates, and PPA Variant Associations #

Pathological and Genetic Considerations #

Underlying pathology varies among PPA variants, with Alzheimer’s disease pathology common in the logopenic variant, and TDP-43 proteinopathies in the semantic variant. Genetic factors, such as progranulin mutations, influence clinical presentation but are not fully predictive of syndrome type.

Pathological heterogeneity is reflected in regional atrophy patterns and metabolic changes, with some proteinopathies showing layer-specific cortical involvement that may affect cortical-cortical and cortical-subcortical connectivity.

Progression and Broader Cognitive Impact #

PPA syndromes progress over time with distinct trajectories:

• Non-fluent variant tends to progress within frontal lobes.
• Semantic variant progresses primarily in temporal lobes.
• Logopenic variant shows broader progression across heteromodal association areas.

Beyond language deficits, PPA patients may develop impairments in memory, executive function, visuospatial skills, and behaviour. For example, abnormal behaviours are more frequent in semantic variant, linked to temporal and orbitofrontal changes.

Implications for Clinical Practice and Research #

Understanding the functional neuroanatomy of PPA aids in diagnosis, prognosis, and targeted interventions. The integration of structural imaging with functional and metabolic studies, including EEG connectivity analyses, provides insights into network disruptions beyond focal atrophy.

Recognition of heterogeneity within and between PPA variants is essential for personalised approaches to management and rehabilitation, including language support strategies that consider preserved brain regions and networks.

Value to Clinical Neuropsychologists of Understanding the Functional Neuroanatomy of Primary Progressive Aphasias #

• Enhances diagnostic accuracy by clarifying PPA variant neuroanatomy and clinical features.
  Rationale: Precise diagnosis informs prognosis and individualized care plans.
• Improves understanding of neuropathological underpinnings.
  Rationale: Knowledge of proteinopathies aids interpretation of clinical presentations and research findings.
• Supports integration of neuroimaging into clinical assessment.
  Rationale: Imaging biomarkers assist in variant differentiation and monitoring disease progression.
• Raises awareness of cognitive and behavioural symptom heterogeneity.
  Rationale: Recognizing non-language deficits enhances comprehensive patient evaluation.
• Informs development of tailored rehabilitation and management strategies.
  Rationale: Understanding symptom progression guides therapeutic interventions and patient support.

Summary #

This update on the functional neuroanatomy of PPAs provided an overview of the cortical and subcortical substrates underlying the clinical syndromes, highlighting the importance of network-level understanding. This knowledgebase supports clinical neuropsychologists in refining diagnostic frameworks and developing nuanced therapeutic approaches for patients with progressive language disorders.

Video #

For further details, please watch the KnowNeuropsychology Video below:

Further Reading #

• Spinelli, E. G., Mandelli, M. L., Miller, Z. A., Santos-Santos, M. A., Wilson, S. M., Agosta, F., … & Gorno-Tempini, M. L. (2017). Typical and atypical pathology in primary progressive aphasia variants. Annals of Neurology, 81(3), 430-443.
• Mesulam, M. M., Wieneke, C., Rogalski, E., Cobia, D., Thompson, C. K., & Weintraub, S. (2019). Quantitative classification of primary progressive aphasia at early and mild impairment stages. Brain, 142(10), 3444-3467.
• Josephs, K. A., Duffy, J. R., Strand, E. A., Whitwell, J. L., Layton, K. F., Parisi, J. E., … & Dickson, D. W. (2018). Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain, 141(1), 254-272.
• Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F., … & Grossman, M. (2011). Classification of primary progressive aphasia and its variants. Neurology, 76(11), 1006-1014.
• Rogalski, E., Cobia, D., Harrison, T. M., Wieneke, C., Thompson, C. K., & Mesulam, M. M. (2016). Anatomy of language impairments in primary progressive aphasia. Journal of Neuroscience, 36(25), 6752-6760.