Language difficulties associated with primary progressive aphasia differ depending on a person’s native language

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English and Italian speakers with dementia-related language impairment experience distinct kinds of speech and reading difficulties based on features of their native languages, according to new research by scientists at the UC San Francisco Memory and Aging Center and colleagues at the Neuroimaging Research Unit and Neurology Unit at the San Raffaele Scientific Institute in Milan.

Neurologists had long assumed that brain diseases that impact language abilities would manifest in essentially the same way in patients around the world. But recent discoveries have begun to question that assumption.

For instance, Italian speakers with dyslexia tend to have less severe reading impairment than English or French speakers due to Italian’s simpler and more phonetic spelling.

“Clinical criteria for diagnosing disorders that affect behavior and language are still mainly based on studies of English speakers and Western cultures, which could lead to misdiagnosis if people who speak different languages or come from another cultural background express symptoms differently,” said study senior author Maria Luisa Gorno-Tempini, MD, PhD, a professor of neurology and psychiatry and the Charles Schwab Distinguished Professor in Dyslexia and Neurodevelopment at the UCSF Memory and Aging Center.

“It is critical going forward that studies take language and cultural differences into account when studying brain disorders that affect higher cognitive functions — which we know are greatly impacted by culture, environment, and experience.”

The new study, published January 10, 2020 in Neurology, the medical journal of the American Academy of Neurology, focused on patients with primary progressive aphasia (PPA), a neurodegenerative disorder that affects language areas in the brain, a condition often associated with Alzheimer’s disease, frontotemporal lobar degeneration, and other dementia disorders.

The researchers recruited 20 English-speaking PPA patients from the UCSF Memory and Aging Center and 18 Italian-speaking PPA patients from San Raffaele Hospital, all of whom shared a variant of PPA characterized by difficulty producing or pronouncing words — so-called non-fluent PPA.

“We wanted to study patients with PPA to understand whether people from different language backgrounds actually experienced the disease differently, and what that might mean for how we try to help patients remain resilient to the disease,” said study lead author Elisa Canu, PhD, a neuropsychologist and researcher in the San Raffaele Scientific Institute’s Neuroimaging Research Unit, which is led by co-author Massimo Filippi, MD, full professor of neurology at the affiliated Vita-Salute San Raffaele University, and director of the neurology and neurophysiology units at the San Raffaele Hospital.

Cognitive tests and MRI brain scans revealed similar cognitive function and comparable levels of brain degeneration in the two groups. But when the researchers compared their performance on a battery of linguistic tests, they observed a key difference.

English speakers had more trouble pronouncing words — the traditional hallmark of nonfluent PPA — and tended to speak less than usual.

In contrast, Italian speakers with the same disorder had fewer pronunciation difficulties but tended to produce much shorter and grammatically simpler sentences.

For example, when asked to describe a drawing of a family at a lake house picnicking and flying a kite, Italian speakers with non-fluent PPA might respond (in Italian): “The man and the woman and the dog”; “Boat in the water”; “Family have picnic”; “There is a kite”.

“We think this is specifically because the consonant clusters that are so common in English pose a challenge for a degenerating speech-planning system,” said Gorno-Tempini, who directs the language neurobiology laboratory at the UCSF Memory and Aging Center, and is co-director of the UCSF Dyslexia Center and the recently launched UCSF-UC Berkeley Schwab Dyslexia and Cognitive Diversity Center.

“In contrast, Italian is easier to pronounce, but has much more complex grammar, and this is how Italian speakers with PPA tend to run into trouble.”

English speakers had more trouble pronouncing words — the traditional hallmark of nonfluent PPA — and tended to speak less than usual.

In contrast, Italian speakers with the same disorder had fewer pronunciation difficulties but tended to produce much shorter and grammatically simpler sentences.

The results are important for efforts to ensure accurate diagnoses for patients with PPA across different cultures: in the current study the Italian speakers do not match the established diagnostic criteria for nonfluent PPA as closely as the English speakers, since the criteria are based on studies of English-speaking patients.

“This means that there are probably many people around the world — including non-native English speakers in the U.S. — who are not getting the right diagnosis because their symptoms don’t match what is described in clinical manuals based on studies of native English speakers,” said Gorno-Tempini.

The researchers acknowledge that this is a small study and cannot completely exclude the possibility that differences in dementia severity, undetected anatomical differences and differences in education level between Italian and English participants could be confounding factors in the results.

Future studies in partnership with the Global Brain Health Institute (GBHI), a joint effort of UCSF and Trinity College Dublin to reduce the impact of dementia around the world, will attempt to replicate the findings in larger groups of patients, and look for further differences between speakers of even more diverse, non-Western languages, such as Chinese and Arabic.

“We hope that such studies will advance our understanding of the brain science underlying language and language disorders, raise awareness of health disparities in dementia treatment, and ultimately improve care for all patients,” Gorno-Tempini said.

Funding: This study has been supported by the U.S. National Institutes of Health (NINDS R01 NS050915; NIDCD K24 DC015544; NIAU01 AG052943; NIA P50 AG023501; NIA P01 AG019724), the Italian Ministry of Health (GR-2010-2303035; GR-2011-02351217), the Alzheimer’s Disease Center of California (03-75271 DHS/ADP/ARCC), the Larry L. Hillblom Foundation, the John Douglas French Alzheimer’s Foundation, the Koret Family Foundation, the Consortium for Frontotemporal Dementia Research, and the McBean Family Foundation.

Disclosures: See study online for listing of potential conflict of interest disclosures.


Language is a uniquely human faculty that enables the communication and elaboration of thoughts and experiences through the mediation of arbitrary signs and symbols. Acquired abnormalities of language are known as aphasias.

Nearly all right-handed individuals and many left-handed people exhibit severe aphasia only after injury to a specific set of regions in the left hemisphere of the brain, leading to the conclusion that language is under the control of an asymmetrically distributed large-scale neural network (Box 1).

According to contemporary concepts, the Sylvian fissure divides this neural network into dorsal and ventral components.15 The dorsal components, including Broca’s area in the inferior frontal gyrus (IFG), display a relative specialization for phonological encoding, fluency, and grammatical structure, whereas the ventral components, located predominantly in the temporal lobe, display a relative specialization for lexicosemantic associations that link words to their meaning;15 however, these distinctions of functional anatomy are far from absolute.

Box 1

Properties of distributed large-scale neural networks

The term ‘large-scale distributed neural network’ was introduced to designate computationally plausible and anatomically anchored substrates of cognitive and behavioural domains.97 For the language domain, network components are located in the perisylvian cortex and surrounding parts of the frontal, parietal and temporal lobes of the language-dominant (usually left) hemisphere of the brain.15 The following principles apply to the use of the term ‘network’ in this Review.160

  • ▪ Network components can operate as critical hubs or ancillary nodes, both of which contribute to the function of the relevant domain, but only damage to critical hubs causes clinically relevant and sustained impairments. Critical hubs have the properties of transmodal cortex,86 and bind disseminated information into integrated representations
  • ▪ The hubs and nodes function collaboratively, but are not interchangeable, and each displays relative specializations for separate components of the relevant cognitive and behavioural domain. The output represents an emergent property of the network, rather than the additive product of its components
  • ▪ Critical hubs within a particular network are interconnected and are usually coactivated in the course of mediating the relevant cognitive and behavioural domain. Damage to one hub or its connections will, therefore, cause at least partial disruption in the functionality of the others
  • ▪ Hubs and nodes are not dedicated to a unique network. Thus, damage confined to a single hub or node, or its connections, can also trigger perturbations in the function of intersecting networks
  • ▪ Partial damage to a network component can give rise to minimal or transient deficits if other modules of the network undergo compensatory reorganization

Following the seminal work of Paul Broca,6 Carl Wernicke7 and their contemporaries in the 19th century, research into the neurology of language was largely focused on aphasias caused by focal cerebrovascular accidents.

This perspective has now broadened to include language disorders associated with neurodegenerative brain diseases. In particular, the syndrome of primary progressive aphasia (PPA), in which the language-dominant (usually left) cerebral hemisphere is the selective target of progressive neurodegeneration, leading to aphasia in the absence of marked impairment in other cognitive and behavioural domains, has emerged as a new area of fruitful research.

Indeed, the rapidly expanding literature relating to PPA is providing new insights into the neural components of the language network and its vulnerability to neurodegenerative diseases. In this article, we review the advances that have been made to date with regard to PPA, encompassing diagnosis and subclassification of the syndrome, its various clinical and neuropathological manifestations, potential aetiological factors, and disease trajectory and treatment. We also highlight how increased knowledge of PPA has advanced our understanding of language processing in the brain, necessitating revision of some traditional concepts.

Diagnosis and classification of PPA

Criteria for the root diagnosis of PPA

The root diagnosis of PPA is justified if three criteria are met (Box 2).17 The first two criteria—the presence of a prominent language disorder that developed gradually, and its neurodegenerative nature—can be ascertained through clinical history, tests of language function, and neuroimaging procedures.

The third criterion, that is, the relatively isolated emergence of aphasia as the principal impediment to the pursuit of customary activities, is the most challenging to establish. Even experienced clinicians can have difficulty deciding whether a progressive aphasia is truly ‘primary’. It is preferable to be conservative and avoid a PPA diagnosis when disruptions in other cognitive and behavioural domains are prominent early in the course of the disease, even if a progressive (but nonprimary) aphasia is part of the overall syndrome (Box 3).

Box 2

The three criteria for the root diagnosis of primary progressive aphasia

Gradual impairment of language

The impairment of language should have developed gradually. Common manifestations include frequent word-finding pauses followed by uninformative filler words (such as ‘thing’ and ‘stuff’), ungrammatical and impoverished sentences (“words in the my head and cut up,” for example), the inability to name parts of objects (for instance, the strap of a watch, the stem of a flower, the lid of a jar), impaired repetition of phrases and sentences, failure to understand words (such as strap, stem, lid), and spelling errors of recent onset. Dysarthric or apraxic speech alone is insufficient to fulfil this criterion.

Confirmed neurodegenerative aetiology

Diagnostic brain imaging procedures should establish a neurodegenerative process as the only plausible cause by ruling out stroke, neoplasm or other potential causes of an acquired language disorder.

Disproportionate salience of aphasia

Aphasia should initially arise in relative isolation as the most prominent (that is, primary) impairment and should remain the principal factor underlying the disruption of daily living activities for at least 1–2 years. To fulfil this criterion, it is necessary to ascertain (through an informant, medical records, or clinical examination) that episodic memory, visuospatial skills, executive functions, face and object recognition, comportment, and motor function were mostly preserved during an initial period of 1–2 years after symptom onset.

Preferably, nonverbal standardized tests should be used to evaluate other cognitive and behavioural domains, such as the Visual Verbal Test for executive functions, the Three Words-Three Shapes Test for memory, and the Judgement of Line Orientation Test for visuospatial perception.15,161,162 

However, excessive reliance on test results must be avoided. If a patient with a prominent progressive inability to find words also has subnormal scores in memorizing a word list or in a sustained attention test, but without corresponding impairments of daily activities (such as forgetfulness of recent events, inability to multitask, or reduced initiative), a primary progressive aphasia diagnosis is justified.

Box 3

Nonprimary progressive aphasias

Progressive aphasias can arise in patients whose principal and initial impairment is an amnestic dementia of the Alzheimer-type, the posterior cortical atrophy syndrome, the behavioural variant of frontotemporal dementia, the corticobasal degeneration syndrome, the progressive supranuclear palsy syndrome, apraxia of speech, or motor neuron disease.

No patient with a progressive aphasia that arises as a secondary component of any of these syndromes would qualify for a primary progressive aphasia (PPA) diagnosis because the language impairments constitute ancillary features. Such patients can be described as having progressive aphasia in conjunction with the dominant syndrome.

Some patients display a combination of aphasia and nonverbal associative agnosia at the early stages of disease. This syndrome, known as semantic dementia, is also inconsistent with a diagnosis of PPA if the associative agnosia is initially prominent and responsible for consequential impairments, such as an inability to recognize familiar faces or the misuse of objects.

Conclusions

Although the frequency of the diagnosis is increasing, PPA remains a relatively rare syndrome; therefore, patients, clinicians and families might have limited access to appropriate information and assistance. A website dedicated to PPA, the International PPA Connection (IMPPACT),159 has been established to serve as a registry for patients and resources.

The purpose of this online resource is to improve the access of patients and clinicians to relevant local resources around the world and to facilitate the implementation of collaborative clinical trials when promising therapeutic interventions become available in the future. The site also provides demonstrations of key diagnostic features and a section on frequently asked questions.

A major long-term goal in PPA research is the development of effective treatments. In the meantime, the heterogeneous language disturbances associated with PPA, and their complex anatomical correlates, continue to provide new insights into core aspects of aphasia research. The selective degeneration of the language-dominant cerebral hemisphere also offers unique opportunities for exploring the biology of selective vulnerability and hemispheric asymmetry in the human brain.​

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

Source:
UCSF

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