Understanding Primary Progressive Aphasia

Neurodegenerative dementia may, in rare cases, initially manifest as isolated language deficits in the absence of other cognitive symptoms. These deficiencies are loosely referred to as difficulty “finding the word.”

There are several variants of this form of dementia, each caused by different underlying neuropathologies. Sometimes, problems with speech rather than language predominate.

Patients may have exclusively language or speech-related symptoms for several years, but eventually all progress to generalized dementia.

This clinical review describes primary progressive aphasia (PPA), a collective term for forms of dementia that begin with language disorders. The term PPA refers to dementia in which the dominant symptom during the first 1 to 2 years is aphasia.

The diagnosis is not used in cases of language impairments that arise later in the course of dementia. Its prevalence is estimated to be almost 3-4/100,000 individuals.

In a recent registry study, the incidence of progressive aphasia (all types) was estimated at 1.14/100,000 person-years, compared with 35.7/100,000 person-years for typical Alzheimer’s dementia. In a frequently cited consensus report, a distinction is made between 3 variants of progressive aphasia: semantic, logopenic, and nonfluent/agrammatical.

Not all cases of the disease fit into these 3 categories and, therefore, a fourth variant has been identified, which was called mixed primary progressive aphasia. The classification system is under continuous review. Some authors refer to the semantic variant as “semantic dementia”, while others reserve this name for more extensive diseases, such as the non-fluent variant, also known as “progressive non-fluent aphasia”.

New research techniques, such as those based on imaging methods that reflect the distribution of pathology in the brain, may well suggest alternative subdivisions.

The purpose of this article is to provide a brief description of the different variants of the APP. The article is based on a discretionary selection of recent reviews and research articles, textbook chapters and the clinical experience of the authors.

In the authors’ clinical experience, whenever dementia manifests with speech or language disturbances as the only symptom, one of 3 things tends to happen:

1) The patient receives a diagnosis of aphasia, but the aphasia is attributed to a stroke. 

2) Patients suffering from Alzheimer’s disease with progressive aphasia are mistakenly diagnosed with frontotemporal dementia, as many doctors know that language difficulties can be a symptom of that condition. 

3)  Language difficulties are attributed to “memory failures,” apparently supported by poor performance on verbal tests.

Contrary to what was previously assumed, speech and language therapy may have an unclear beneficial effect on PPA. Therefore, these patients should be referred to a speech and language therapist with experience in this condition. The authors consider that language tests should be included in the evaluation of cognitive impairment and that patients with suspected language disorders should be referred to a memory specialist.

The doctor asks, “Can you tell me something about your history?”

The patient responds: History? What is that?

The central problem in the semantic variant of the APP is the difficulty with understanding the words, as demonstrated in the example shown here. The semantic variant is the best-defined variant in terms of signs and symptoms, imaging findings, and neuropathology.

The meaning of rare words is what is lost earliest in the course of the disease, but over time, the patient does not understand the most common words either.

Patients also develop pronounced difficulties naming images and objects. The patient’s altered understanding leads him, during the conversation, to ask the meaning of a certain word. However, patients with this variant usually have spontaneous and fluent speech, mostly with correct grammar.

In a normal everyday conversation, one will often not notice any alteration in language. Episodic memory is relatively intact. For example, patients have no difficulty describing things that have happened recently or remembering appointments. However, deterioration in their word comprehension leads to poor results on verbal memory tests.

Other characteristics of the semantic variant are the difficulty in knowing objects, as well as the presence of surface dyslexia and dysgraphia.

Impaired knowledge of objects refers to a lack of understanding of what they are for or what they are used for. Surface dyslexia means that words are pronounced exactly as they are spelled.

Superficial dysgraphia means that words are written the way they are pronounced.

The progression of the disease may be slow, but eventually the language impairment worsens and becomes more extensive. Most patients with this type of PPA develop the behavioral variant of frontotemporal dementia. Alternatively, they may develop a semantic dementia with failures to recognize objects and faces, and more extensive semantic impairment.

Magnetic resonance imaging ( MRI) of the brain and fluorodeoxyglucose positron emission tomography (FDG-PET) reveal atrophy and hypometabolism, respectively, in the anterior temporal lobe–usually with left-sided predominance.

The characteristic findings on MRI have high sensitivity (98%) and specificity (93%) while the typical findings on FDG-PET reach almost 100% sensitivity and specificity.

Analysis of dementia markers in the cerebrospinal fluid (CSF) does not reveal a reduction in ß-amyloid substance or the elevation of total tau and phosphorylated tau, characteristic of Alzheimer’s disease, but total tau may be slightly elevated. The biomarker neurofilament light chain (NfL) is highly elevated in 80% of pathological cases and is found with pathological aggregates of DNA binding protein TAR (43 kDa transactive response protein binding). to DNA TDP-43), a form of neuropathology that is also common in frontotemporal dementia and amyotrophic lateral sclerosis.

The doctor asks, “Can you tell me a little about your background?”

The patient responds: “Yes, you know, I worked for many years in a..., a..., what’s it called again, a..., yes, you know.”

Patients with the logopenic variant of PPA often have difficulty finding words, especially nouns, both in spontaneous speech and in names. They also have a limited ability to repeat words, sentences, and series of numbers.

Phonological errors are common in spontaneous speech and naming, and speech sounds may be omitted or interchanged. However, patients have usually retained single word comprehension and object recognition, as well as normal speech motor control and speech melody. Their use of language is also grammatically correct, although spontaneous speech is interrupted by phonological errors and word searching. The missing words are replaced by general descriptors such as “that thing there.”

The logopenic variant is usually an aphasic variant of Alzheimer’s dementia, and patients eventually develop symptoms typical of Alzheimer’s disease. Brain MRI has low sensitivity (57%) but good specificity (95%) for this variant, while FDGPET is more sensitive (92%) and equally specific (94%). Typical imaging findings are left posterior parietal or perisylvian atrophy and hypometabolism.

In CSF analysis, dementia markers often reveal the profile of Alzheimer’s disease, i.e., reduced β-amyloid and increased total tau and phosphorylated tau. Levels of the NfL marker are also elevated but not to the same extent as in the semantic and non-fluent progressive variants.

The doctor asks, “Can you tell me a little about your background?”

The patient responds: “That… I… ing-ing-engineer… a long time.”

This is the most complex variant of PPA and is dominated by agrammatism and/or apraxia of speech. Agrammatism means that the patient uses short sentences that lack function words and inflections. Subtle difficulties with grammar may be more obvious in writing than during speech. Grammatical comprehension is also affected, particularly for long texts or complex sentences, negations and passive constructions. However, word comprehension and object recognition remain intact.

Apraxia of speech refers to difficulties with the flow of speech and the pronunciation of speech sounds.

Speech is strained and choppy, with variable errors in speech sounds. Patients and family members sometimes describe this as “stuttering.” The patient tries several times to say the same word, each time with different pronunciation errors.

Apraxia of speech also affects the prosody (melody of the sentence) and the stress of words, so that speech appears monotonous (“robotic”) or incorrectly underlined. The patient may have comorbid oral apraxia, meaning that he or she is unable to perform actions such as smacking his lips, clicking his tongue, or coughing or blowing his nose on command. Patients with apraxia of speech without agrammatism do not, strictly speaking, have aphasia, and it has been proposed that this should be classified as an aphasia with another diagnostic entity or “APP of speech.”

The non-fluent variant/agrammatic aphasia shows greater variation in terms of underlying pathology and greater disease progression than the other variants. The most common underlying pathology is frontotemporal lobar degeneration with tau inclusions (52%), followed by Alzheimer-type amyloid pathology (25%) and TDP-43 pathology (19%).

Some patients develop a behavioral variant of frontotemporal dementia while others develop Parkinson plus syndromes with general motor alterations (such as corticobasal syndrome).

Progression to Parkinson plus syndromes is more common when the clinical picture is dominated by apraxia of speech. Patients have atrophy and hypometabolism in the posterior frontal lobe, particularly in the dominant hemisphere. If the patient has apraxia of speech, Broca’s area is usually affected as well as the premotor and motor cortices.

For diagnosis, brain MRI has low sensitivity (29%) but better specificity (91%) while brain FDG-PET has a sensitivity of 67% and a specificity of 92%. The patterns of dementia markers in CSF vary, depending on the underlying neuropathy.

In essence, PPA should be diagnosed primarily by functional testing. functions described in Table 1.

Speech fluency . Fluency is assessed by listening to how the patient speaks. A simple test of speech fluency is to ask the patient to say "pa-ta-ka" quickly several times in a row. Normally it should be possible to say "pataka" 15 ± 5 times in 10 seconds. Significant difficulties in doing so may indicate apraxia of speech. A more comprehensive test recently published is the Norwegian test for apraxia of speech.

Denomination . The patient is shown images and asked to name what they portray. It is important to distinguish between knowledge of the object (describing what the image represents) and naming (being able to give the correct name).

Repetition . Words and sentences of varying length are spoken and the patient is asked to repeat them. The level of difficulty can be increased by using nonsense words.

Understanding words and concepts . The patient is asked the meaning of specific, preferably low-frequency words. Conceptual understanding can also be examined through semantic access tests such as the Pyramids and Palm Trees tests. This involves showing the patient 3 pictures or words, two of which belong to the same semantics. For example, the patient may be shown an image of a pyramid with the image of a spruce and a palm tree below it and asked which of the two images below best fit the image above.

Grammar . This can be tested by determining whether the patient can form sentences when describing an image. Questions can also be asked about the meaning of grammatically complex sentences: "The dog the man was chasing was old and gray. Who ran first?"

Various forms of dementia can manifest with language and/or speech difficulties as the only initial symptom. These forms of dementia have different symptom profiles and are caused by different underlying neuropathologies.

Knowledge of the conditions, detailed analysis of diagnostic imaging, and the use of specific cognitive tests to evaluate speech and language are important in making the correct diagnosis.

Patients with PPA are often initially misdiagnosed, for example their aphasia may be misattributed to a stroke. If initial studies suggest a language disorder, as part of a dementia condition, patients should be referred to an expert in language testing, as a correct diagnosis may allow effective specific treatment.