Primary Progressive Aphasia (PPA)

Primer

Primary Progressive Aphasia (PPA) is a clinically diverse neurological syndrome most commonly associated with Alzheimer’s Disease or frontotemporal dementia. It can also rarely occur in Parkinson's-plus disorders. PPA typically begins with gradual, subtle language deficits that progresses to a nearly complete inability to speak.

Epidemiology

The age of onset is 50s to early 60s. It affects males and females equally. In terms of incidence within diagnosed dementias, frontotemporal dementia represents approximately 15% of all dementia cases, and PPA accounts for between 20 to 40% of the these patients.

Prognosis

The progression of PPA begins with asymptomatic changes in the language centres, followed by early signs of symptoms of mild cognitive impairment. The progression of non-amnestic MCI continues, until prominent aphasia is observed.[1] The disease further progresses into mutism for most cases. Loss of independence occurs 7 years into the diagnosis in about 50% of cases. The average survival time is 7 to 10 years. After the diagnosis of PPA, patients will typically be diagnosed with a secondary syndrome (e.g. - frontotemporal dementia, progressive supranculear palsy, or corticobasal degeneration).[2]

Risk Factors

Developmental disability is a risk factor for PPA.[3]

Variants

There are three variants of PPA:

  1. Semantic (the dominant type and is present in most instances of PPA)
  2. Logopenic (LPA), due to atrophy in the left posterior temporal cortex and inferior parietal lobule
  3. Non-fluent/agrammatic (stumbling for words, grammar is very poor)

Scales

PPA Scales

Name Rater Description Download
Progressive Aphasia Symptom Severity (PASS) Clinician The PASS is a clinical instrument used to rate presence and severity of impairment in specific domains of speech and language, as opposed to making a single global language rating. The clinician make ratings on a 5 point scale from “normal” (0) to “questionable/very mild” (0.5), “mild” (1.0), “moderate” (2.0), or “severe” (3.0) impairment.[4] Download

Diagnosis

The 2011 Criteria proposed by Gorno-Tempini et al are:[5]

For any PPA subtype, there is all of:

  1. Aphasia is the most prominent feature, and occurs at onset and for initial phase of disease (~2yrs)
  2. Causes impairment in activities of daily living (ADLs)

Exclusion Criteria

Alternative diagnoses should be considered if:
  • If symptoms are better accounted for by other neurodegenerative, medical or psychiatric disorder
  • If there are prominent initial memory (visual or episodic), visuoperceptual impairments, or behavioural disturbance within the first 2 years of language impairment

Semantic

In the semantic subtype (also known as semantic dementia or PPA-S), individuals will have receptive dysfunction and loss of word meaning. There can be prosopagnosia and remote memory loss as well. Speech remains fluent.

Both of:

  1. Impaired confrontation naming (i.e. - showing an object or a line drawing of an object (e.g. - a spoon) to a patient and requesting the correct verbal label for that object)
  2. Impaired single word comprehension

At least 3 of 4:

  1. Impaired object knowledge
  2. Surface dyslexia/dysgraphia
  3. Spared repetition
  4. Spared speech production

Semantic is More Behavioural

Of the 3 subtypes of PPA, semantic dementia is associated with more behavioural changes.

Logopenic

The logopenic variant (PPA-L or lvPPA) is characterized by impairment in word retrieval with phonological deficits, and impaired repetition.

Both of:

  1. Impaired single word retrieval
  2. Impaired repetition

At least 3 of 4:

  1. Speech errors in spontaneous speech and naming
  2. Spared single-word comprehension and object knowledge
  3. Spared motor speech
  4. Absence of frank agrammatism

Digit Span is Worse

Individuals with lvPPA have an impaired phonological loop and are significantly worse on the repetition tasks (even compared to Alzheimer's), on tasks such as on forward and backward digit span.[6]

Non-fluent/Agrammatic

The Non-fluent subtype (also know as progressive non-fluent aphasia, PNFA, or also called agrammatic variant, PPA-G) is characterized by distortion of word and sentence construction. This includes abnormal order of words (i.e. - syntax), distortion of word endings, misuse of pronouns, and a lack of grammatical words such as articles (words that define a noun as specific or unspecific, e.g. - a, an, the) and prepositions (these are words show the relationship between the noun and pronoun in a sentence, e.g. - at, for, in, off, on, over, under, into, upon, onto, out of, from within)

At least 1 of 2:

  1. Agrammatism
  2. Apraxia of speech

At least 2 of 3:

  1. Impaired complex comprehension
  2. Spared single-word comprehension
  3. Spared object knowledge

Neuroanatomy Findings

In patients with PNFA, there is asymmetric perisylvian and anterior insular atrophy with the dominant language hemisphere most affected (usually the left hemisphere, assuming the individual is right-handed).[7]

Symptoms

Depression, anxiety, and dysphoria are the most common symptoms across all subtypes of PPA.[8] Commonly, patients have also have apathy. Changes in eating behaviors are more evident in PPA patients, including hyperorality. Psychotic symptoms in PPA are rare. Disinhibition in patients should make the clinician think of an underlying FTD pathology rather than Alzheimer's pathology for the PPA.

Comparison

PPA subtypes

Subtype Semantic (PPA-S) Logopenic (PPA-L) Agrammatic (PPA-G)
Other abbreviations or names • Semantic dementia (SD)
• Semantic variant PPA (svPPA) 		• Logopenic variant PPA (lvPPA) • Non-fluent variant PPA (nfvPPA)
• Progressive non-fluent aphasia (PNFA)
Grammar N N Imp
Repetition N Imp Imp
Single word comprehension Imp N N
Naming Imp (due to impaired word-retrieval and comprehension) Imp (due to impaired word-retrieval and anomia) N or Imp
Speech and Fluency Speech is vague but remains fluent, with circumlocutions and semantic paraphasias May appear normal during small talk. Word retrieval pauses leads to some degree of loss of fluency. Circumlocution and phonemic paraphasias are common. Effortful and apraxic, word-finding hesitations. Abnormal order of words, distortion of word endings, misuse of pronouns, and a lack of grammatical words such as (e.g. - a, the), or prepositions (e.g. - at, for, on, into)
Sample speech Saying “clock” instead of “watch” when asked to name a wristwatch Saying “baby flitter” instead of “baby sitter” Syntax and speech is abnormal, with poor use of tense and modifiers
Neuroimaging Atrophy in the anterior temporal lobe Atrophy in posterior temporoparietal part of language network Atrophy in left inferior frontal gyrus
Common Pathology FTD with TDP-43 type C (80-90% cases) Alzheimer's FTD with tauopathy (60% of cases)
Rarer Pathology Alzheimer's • FTD with TDP-43 type A
• FTD with tau 		• FTD with TDP-43 type A
• Alzheimer's
Clinical progression Cases may progress into symptoms characteristic of behavioural-variant frontotemporal dementia There is typically a mix of aphasia, and memory difficulties, characteristic of the predominant Alzhemier's pathology. Parkinsonism most commonly occurs in the non-fluent subtype, with a corticobasal or progressive supranuclear palsy (PSP) etiology being the most likely. In both cases, the underlying pathology is a tauopathy.[9]

Pathophysiology

Genetics

The vast majority of PPA cases are sporadic. Of the genes that have been identified, there is variability in transmission of these genes. Risk factor genes include GRN (granulin), MAPT (tau), C9ORF72 (protein C9orf72), and PSEN1 (presenilin1).

Pathology

Since PPA is a syndromic diagnosis, its' pathophysiological etiology can be divided into one of two underlying pathophysiological processes:[10]

For each PPA subtype, the most common neuropathologies are:[11]

  • Semantic: FTD with TDP-43 type C (80-90% of cases)
  • Logopenic: Alzheimer's
  • Non-fluent (agrammatic): FTD with tau (60% of cases)

Differential Diagnosis

Investigations

Cognitive Testing

Since PPA has disproportionate language impairment compared to other dementias, cognitive testing scores (especially on language-sensitive tests such as the Montreal Cognitive Assessment) can appear significantly worse compared to the patient's actual functional ability and stage of dementia.

Neuroimaging

  • PPA typically has a distinct asymmetric (language-dominant) perisylvian atrophy pattern on MRI. MRI findings for each subtype include:[13]
    • PPA-G, peak atrophy in left inferior frontal gyrus
    • PPA-S, peak atrophy in the anterior frontal lobe
    • PPA-L, peak atrophy in the temporoparietal junction

Treatment

Non-pharmacological

  • Speech language pathology (SLP) involvement is important to preserve function and improve quality of life.[14]. SLPs can teach patients to maximize communication through the use of nonverbal techniques. Intensive language therapy can also occur.[15]
  • Aphasia identification cards and assistive devices (e.g. - iPads)
  • Exercise can improve cognition, mood, and overall health in all dementias[16]
  • Addressing caregiver burden/burnout, safety (i.e. - wandering, stove/taps) is important, family members should be offered support groups for family living loved ones with dementia

Pharmacological

All current medications for PPA are off-label treatments. There are no treatments that can stop or alter the course of disease.

  • Cholinesterase inhibitors can be trialed if the underlying pathology is thought to due to Alzheimer's pathology (i.e. - logopenic PPA).
    • Galantamine has been shown to help with stabilizing language function[17]
    • If the pathology is thought to be due to behavioural variant FTD (bvFTD), then acetylcholinesterase inhibitors may worsen symptoms (as is seen in FTD), and should not be used![18][19]
  • There is no evidence for the use of memantine, and again may possibly worsen behavioural symptoms.[20]

Treatment of behavioural and psychological symptoms for PPA (due to bvFTD) include:

Resources

For Patients

References

1) Dickerson, B. C. (2011). Quantitating severity and progression in primary progressive aphasia. Journal of Molecular Neuroscience, 45(3), 618-628.
2) Kertesz, A., McMonagle, P., Blair, M., Davidson, W., & Munoz, D. G. (2005). The evolution and pathology of frontotemporal dementia. Brain, 128(9), 1996-2005.
3) Rogalski, E., Johnson, N., Weintraub, S., & Mesulam, M. (2008). Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives. Archives of neurology, 65(2), 244-248.
4) Dickerson, B. C. (2011). Quantitating severity and progression in primary progressive aphasia. Journal of Molecular Neuroscience, 45(3), 618-628.
5) Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. E. E. A., ... & Manes, F. (2011). Classification of primary progressive aphasia and its variants. Neurology, WNL-0b013e31821103e6.
6) Meyer, A. M., Snider, S. F., Campbell, R. E., & Friedman, R. B. (2015). Phonological short-term memory in logopenic variant primary progressive aphasia and mild Alzheimer's disease. Cortex, 71, 183-189.
7) Rabinovici, G. D., & Miller, B. L. (2010). Frontotemporal lobar degeneration. CNS drugs, 24(5), 375-398.
8) Modirrousta, M., Price, B. H., & Dickerson, B. C. (2013). Neuropsychiatric symptoms in primary progressive aphasia: phenomenology, pathophysiology, and approach to assessment and treatment. Neurodegenerative disease management, 3(2), 133-146.
9) Doherty, K. M., Rohrer, J. D., Lees, A. J., Holton, J. L., & Warren, J. (2013). Primary progressive aphasia with parkinsonism. Movement Disorders, 28(6), 741-746.
10) Mackenzie, I. R., Neumann, M., Baborie, A., Sampathu, D. M., Du Plessis, D., Jaros, E., ... & Lee, V. M. (2011). A harmonized classification system for FTLD-TDP pathology. Acta neuropathologica, 122(1), 111-113.
11) Mackenzie, I. R., Neumann, M., Baborie, A., Sampathu, D. M., Du Plessis, D., Jaros, E., ... & Lee, V. M. (2011). A harmonized classification system for FTLD-TDP pathology. Acta neuropathologica, 122(1), 111-113.
12) Bonelli, R. M., & Cummings, J. L. (2008). Frontal-subcortical dementias. The neurologist, 14(2), 100-107.
13) Dickerson, B. C. (2011). Quantitating severity and progression in primary progressive aphasia. Journal of Molecular Neuroscience, 45(3), 618-628.
14) Kortte, K. B., & Rogalski, E. J. (2013). Behavioural interventions for enhancing life participation in behavioural variant frontotemporal dementia and primary progressive aphasia. International Review of Psychiatry, 25(2), 237-245.
15) Jokel, R., Kielar, A., Anderson, N. D., Black, S. E., Rochon, E., Graham, S., ... & Tang-Wai, D. F. (2016). Behavioural and neuroimaging changes after naming therapy for semantic variant primary progressive aphasia. Neuropsychologia, 89, 191-216.
16) Cheng, S. T., Chow, P. K., Song, Y. Q., Edwin, C. S., Chan, A. C., Lee, T. M., & Lam, J. H. (2014). Mental and physical activities delay cognitive decline in older persons with dementia. The American Journal of Geriatric Psychiatry, 22(1), 63-74.
17) Kertesz, A., Morlog, D., Light, M., Blair, M., Davidson, W., Jesso, S., & Brashear, R. (2008). Galantamine in frontotemporal dementia and primary progressive aphasia. Dementia and geriatric cognitive disorders, 25(2), 178-185.
18) Arciniegas, D. B., & Anderson, C. A. (2013). Donepezil-induced confusional state in a patient with autopsy-proven behavioral-variant frontotemporal dementia. The Journal of Neuropsychiatry and Clinical Neurosciences, 25(3), E25-E26.
19) Kimura, T., & Takamatsu, J. (2013). Pilot study of pharmacological treatment for frontotemporal dementia: risk of donepezil treatment for behavioral and psychological symptoms. Geriatrics & Gerontology International, 13(2), 506-507.
20) Boxer, A. L., Knopman, D. S., Kaufer, D. I., Grossman, M., Onyike, C., Graf-Radford, N., ... & Koestler, M. (2013). Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. The Lancet Neurology, 12(2), 149-156.
21) Chow, T. W., & Mendez, M. F. (2002). Goals in symptomatic pharmacologic management of frontotemporal lobar degeneration. American Journal of Alzheimer's Disease & Other Dementias®, 17(5), 267-272.
22) Herrmann, N., Black, S. E., Chow, T., Cappell, J., Tang-Wai, D. F., & Lanctôt, K. L. (2012). Serotonergic function and treatment of behavioral and psychological symptoms of frontotemporal dementia. The American Journal of Geriatric Psychiatry, 20(9), 789-797.
23) Finger, E. C., MacKinley, J., Blair, M., Oliver, L. D., Jesso, S., Tartaglia, M. C., ... & Mitchell, D. G. (2015). Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability. Neurology, 84(2), 174-181.