REVIEW
A review on primary progressive aphasia
Gabriel C Léger 1,2
Nancy Johnson 3
1
Neurology Service, Hôtel-Dieu du
Centre Hospitalier de l’Univertité de
Montréal, Montréal, Québec, Canada;
2
Faculty of Medicine, Université de
Montréal, Montréal, Québec, Canada;
3
Cognitive Neurology and Alzheimer’s
Disease Center, Department of
Psychiatry and Behavioral Science,
Northwestern University Feinberg
School of Medicine, Chicago, IL, USA
Abstract: Primary progressive aphasia (PPA) is a neurodegenerative disease of insidious onset
presenting with progressive isolated loss of language function, without significant impairment in
other cognitive domains. Current diagnostic criteria require the language dysfunction to remain
isolated for at least two years, and to remain the salient feature as the disease progresses, usually
to involve other domains such as behavior, executive functions, and judgment. Although PPA
in its early stages can usually be differentiated from probable Alzheimer’s disease (PRAD)
and the behavioral variant of frontotemporal lobar degeneration by the absence of significant
changes in memory and behavior, and the preservation of activities daily living, progression of
the disease often leads to deficits more consistent with the latter. Underlying etiologies remain
heterogeneous: the neuropathological characteristics associated with frontotemporal lobar
degeneration, cortocobasal degeneration, and motor neuron disease are usually found. There
is a strong genetic susceptibility with affliction of first-degree relatives with similar disease
in up to 40 to 50% in some series. Pathogenic mutations in genes coding for the proteins tau
and progranulin have been isolated. These are leading to a better understanding of the neuropathological mechanisms and hopefully targeted disease-modifying therapy. Current therapy is
limited to improving mood symptoms and targeting behavior changes as they develop. Referral
to specialized centers where speech therapy, counseling, and education for both patient and
caregiver are available may be helpful.
Keywords: primary progressive aphasia
Introduction
Primary progressive aphasia (PPA) is a clinical syndrome defined by the insidious
onset and progressive dissolution of language skills (Mesulam 1982, 2001, 2003).
Although additional cognitive symptoms may emerge later in the course of illness,
deficits must be grossly confined to the area of language for at least 2 years to fulfill
the criteria for a diagnosis of PPA. The first description of the syndrome is attributed
to Mesulam (1982), but reports of similar clinical findings have been in the literature
for over 100 years (Mesulam and Weintraub 1992).
The neuropathological underpinnings of PPA are varied (see section on neuropathology), but the most frequent etiology may be one of the pathological processes
leading to frontotemporal lobar degeneration (FTLD). As defined by Neary et al (1998),
FTLD may present clinically as either a behavioral disorder, called frontotemporal
dementia (FTD) or occasionally behavioral variant FTD (bv-FTD), or one of two so
called language disorders: semantic dementia (SD) and progressive non-fluent aphasia
(PNFA). These disorders and their relation to PPA will be discussed.
Differential diagnosis
Correspondence: Nancy Johnson
Cognitive Neurology and Alzheimer’s
Disease Center, 675 N. St. Clair, Galter
20-100, Chicago, IL 60611, USA
Tel +312 695 4478
Fax +312 695 6072
Email johnson-n@northwestern.edu
PPA can be usually be differentiated from the clinical syndrome of Probable
Alzheimer’s Disease (PRAD) by the relative preservation of memory, and from FTD
by the relative sparing of frontal lobe functions and appropriateness of behavior.
Although the language disorder in PPA may interfere with the ability to memorize
word lists or solve reasoning tasks, the patient typically has no difficulty recalling daily
Neuropsychiatric Disease and Treatment 2007:3(6) 745–752
© 2007 Dove Medical Press Limited. All rights reserved
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Léger and Johnson
events or behaving with good judgment, indicating that
explicit memory, executive functions and social skills remain
intact.
Clinical presentation and evolution
By definition, language disturbances are the most salient
feature in the early clinical picture of PPA. In fact, the
diagnostic criteria require at least two years of relatively
isolated language impairment with generally intact functioning in other cognitive abilities such as episodic memory,
visuospatial skills, reasoning, and comportment (Mesulam
and Weintraub 1992). It may often be difficult to confirm
normal function in other cognitive when significant language
deficits are present. Modification of standard testing paradigms to reduce their dependence on language skills can
be useful (Wicklund et al 2004). Deficits in other cognitive
domains eventually emerge after the initial few years, but the
language dysfunction remains the most salient feature and
advances most rapidly, throughout the course of the illness
(Mesulam 2003). Primary progressive aphasia is distinct
from states of pure progressive dysarthria or phonological disintegration where the articulation rather than usage
of words becomes disrupted. Patients with PPA may also
show mild ideomotor (usually buccofacial) apraxia, dyscalculia, disinhibition, and constructional deficits (Joshi et al
2003). These additional symptoms indicate a progression
or spread of dysfunction to prefrontal and parietal cortices
immediately adjacent to the language network. The term
PPA-plus has been proposed to designate this advancing
state (Mesulam 2001).
PPA may be considered a syndromic entity that results
from any one of a number of initially focal neuropathological
processes, beginning in the language network (Kertesz et al
1994) (see section VI). With progression, these processes lead
to more generalized clinical involvement resulting in recognizable diseases that can additionally include the behavioral
variant of frontotemporal lobar degeneration, corticalbasal
degeneration (CBD) (Kertesz et al 1994; Ikeda et al 1996;
Gorno-Tempini, Murray et al 2004; McMonagle et al 2006),
and even amyotrophic lateral sclerosis (ALS) (Bak et al
2001; Caselli et al 1993). Occasionally, Alzheimer’s disease
(Pogacar and Williams 1984; Greene et al 1990, 1996) or
Creutzfeldt-Jakob disease (Shuttleworth et al 1985; Mandell
et al 1989; Ghorayeb et al 1998) is diagnosed. Although
the neurological examination may be completely normal
in the early stages, the presence of increased muscle tone,
apraxia, or subtle signs of parkinsonism may be harbingers
of what is to follow. As PPA progresses, it blends into the
746
symptomatology of FTD, CBD or the motor neuron disease
of ALS so that significant dysarthria, primitive reflexes
(particularly from the dominant hemisphere), hemiparesis,
tremor, rigidity, bradykinesia or akinesia, alien hand phenomenon, hemisensory deficits, and fasciculations may be
observed. Regardless of the underlying etiology, the unique
feature of PPA is the initial predominance of the language
deficit and the corresponding initial selectivity of the neurodegeneration for the language network.
Subtypes of PPA
Although he included detailed descriptions of the nature and
evolution of the aphasia in each of his original 6 patients,
Mesulam did not attempt to divide PPA into subgroups.
Instead, he emphasized the remarkable selectivity that the
disease seemed to demonstrate for the language network,
regardless of the exact nature of the aphasia. Attempts to use
traditional aphasia subtypes such as Broca’s, Wernicke’s,
or Conduction Aphasia to classify language deficits in PPA
have not been entirely successful (Clark et al 2005; George
and Mathuranath 2005). Unlike aphasia due to stroke
where the lesions tend to be more severe in a focal brain
region, in PPA the degeneration is less severe and more
widespread and the clinical symptoms are quite variable
(Thompson et al 1997) and most do not conform to the
traditional anatomical patterns based on stroke subjects.
These difficulties notwithstanding, with the increasing
number of cases being evaluated in detail, it has been possible for many groups to propose classification systems.
These systems vary considerably in their complexity. The
simplest of these follows Mesulam’s contention that PPA is
a single disease entity showing a smooth clinical spectrum
spread over a continuum, with fluent, grammatically intact,
but content poor speech reminiscent of Wernike’s aphasia
at one extreme, and non-fluent, agrammatic, effortful, and
content rich speech, more in keeping with Broca’s aphasia,
at the other. Other investigators have proposed classifications based on at least three (Snowden et al 1992; Grossman
and Ash 2004), and up to six (Kertesz et al 2003) categories.
All present with and are characterized by the presence of
anomia, and differentiated on the basis of measures of
fluency, the presence or absence of logopenia or word
finding difficulties, and loss of word meaning or comprehension. Part of the difficulty in classifying presentations
of PPA lies in the nature of the disease process in any given
individual, which begins with a distinct ‘anatomy of disease
onset’ and evolves according to a variable ‘progression
trajectory’(Mesulam 2001).
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Primary progressive aphasia
It is not surprising that there exists some controversy
concerning the most natural approach to categorizing the
progressive aphasias. An optimal classification system
applicable during life would be clinically relevant, betray
the underlying disease process, and predict its evolution.
Classifying the presentation helps localize the brain areas
initially affected and, as the extent of the pathology progresses
to involve neighboring systems, predicts the manifestations to
follow.
In addition to the clinical criteria for the diagnosis of the
behavioral presentation of FTD (bvFTD), Neary et al (1998),
in their description of the possible clinical entities resulting
from the pathological processes involved in FTLD, also
distinguished two forms of language presentations: PNFA
and SD. The term SD (Hodges et al 1992; Snowden et al
1992; Neary et al 1998) was introduced to designate a unique
syndrome in which a prominent fluent aphasia with impaired
comprehension emerges in the presence of prominent deficits
of visual recognition (agnosia). There is also belief that
patients with SD can be shown to have circumscribed deficits
in semantic knowledge that contributes to their language difficulties (Snowden et al 1989; Hodges et al 1992). In clinical
practice, this term has also been used to denote patients with a
fluent aphasia and verbal comprehension deficits, even in the
absence of visual processing deficits. The term PNFA denotes
patients with a non-fluent aphasia and relatively preserved
comprehension. Patients with PNAF and non-agnostic SD
would also fulfill criteria for a diagnosis of PPA. Because
fluency and grammaticism are the most clinically obvious
differences between these two presentations, the term ‘fluent
PPA’ is sometimes equated to SD, and ‘non-fluent PPA’ or
‘agrammatic PPA’ to PNFA.
There has evolved an extensive literature comparing
various subtypes of PPA in terms of the associated cognitive and behavioral manifestations, structural and functional
imaging findings, and pathological underpinnings. Although
a complete analysis of this literature is beyond the scope
of this short review, key references will be made within
relevant sections.
Gorno-Tempini, Dronkers et al (2004) described three
subtypes of PPA, logopenic, agrammatic, and semantic,
which correspond to distinctive patterns of brain atrophy.
The logopenic variant is characterized by word-finding
difficulties and decreased output, but relatively preserved
syntax, grammar and comprehension. The agrammatic
subtype, which is similar to the Neary et al (1998) criteria
for the PNFA subtype of FTLD, is characterized by labored
speech, agrammatism in production and/or comprehension,
Neuropsychiatric Disease and Treatment 2007:3(6)
variable degrees of anomia, and phonemic paraphasias, in
the presence of relatively normal word comprehension. The
semantic variant is characterized by fluent, grammatically
correct speech, loss of word and object meaning, surface
dyslexia and relatively preserved syntactic comprehension
skills.
Loss of semantic memory and non-verbal deficits in progressive aphasias were recognized initially by Warrington
(1975). Deficits of this kind are found in patients with SD
(Snowden et al 1989; Hodges et al 1992). Debate about the
ability to confirm such deficits in patients with language
impairment has generated experimental paradigms that rely
more on pictures, such as the ‘Pyramids and Palm Trees’
test (Howard and Patterson 1992), which assesses semantic
associations non-verbally, tasks involving coloring of black
and white line drawing of well known animals, and on tests
matching environmental sounds to target pictures (Bozeat
et al 2000).
In a comprehensive review of the literature, Grossman
and Ash (2004) conclude that there is enough evidence to
support the notion that PPA can in fact be divided into PNFA
and SD (without visual agnosia). Their conclusions are based
on an analysis of both the linguistic profiles and imaging
characteristics of these variants. In a novel data driven
hierarchical cluster analysis of the clinical characteristics
of patients with PPA, Knibb et al (2006) also confirmed the
importance of two major presentations that roughly conform
to these variants.
That PPA can present in fluent or non-fluent forms is
clear; however, Mesulam has argued that the use of the term
SD, to denote the fluent form of PPA is not entirely accurate
because it should, as defined by Neary (1998), include a
visual associative agnosia, and is therefore not strictly a
language disorder (Weintraub et al 1990; Mesulam 2001,
2003). He has advocated the use of the term SD only in
the context of demonstrable agnosia and suggested that SD
must represent an affliction of at least two separate systems
(Mesulam 2001). In response, Adlam et al (2006) have
described seven patients who met Mesulams criteria for the
diagnosis of PPA (Mesulam 2001, 2003), but additionally
had subtle non-verbal deficits in semantic memory when
these were expressly sought using sensitive paradigms that
they developed. Although there still remains much debate
concerning the use of the term SD to describe what is initially
perceived as a ‘pure’ language disorder, its historic impact
and commonplace usage has made it important to discuss.
The US National Alzheimer’s Coordinating Center
(NACC), in an effort to standardize data collection and
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diagnostic criteria for Alzheimer’s disease and related
dementias, has collated complete lists of diagnostic criteria,
with relevant references. In their treatment of the progressive
aphasias, they recommend the use of the criteria defined by
Mesulam, but further subcategorize according to the Neary,
into PNFA and SD, with special attention to the presence
or absence of agnosia associated with SD, and add a fourth
category ‘other’ that includes logopenic, anomic, transcortical,
word deafness, syntactic comprehension, and motor speech
disorder (https://www.alz.washington.edu/NONMEMBER/
UDS/DOCS/VER1_2/pubguide.pdf, p 54–8).
Behavior, emotion, and mood
Although not a salient feature of PPA in its early stages
(Weintraub et al 1990), the emergence of behavioral
changes generally signal progression of the disease, as has
been quantified using various measures including Kertesz’
Frontal Behavioral Inventory (FBI) (Kertesz et al 1997;
Marczinski et al 2004) and the NPI-Q (Kaufer et al 2000;
Banks and Weintraub, in press). The types of behavioral
changes that emerge seem to depend on the aphasia variant at
hand and reflect progression of the disease from the variants
epicenter to adjacent areas. In this way, patients with SD were
found to develop apathy and changes in food preferences,
while patients with a non-fluent form exhibited later onset
irritability (Snowden et al 1992). Stereotypic behavior,
changes in eating preference, disinhibition and reduced social
awareness can also be demonstrated as earlier features of SD
(Bozeat et al 2000).
Depression in PPA is being recognized (Medina and
Weintraub, in press), perhaps as a reaction to their ongoing
losses and preserved insight (Eslinger et al 2005). Depressive
symptoms such as irritability seem to remain present for
longer periods (Kertesz et al 2000).
Imaging
Patients with PPA typically show gyral atrophy of the
left hemisphere involving frontal, temporal, insular and
parietal components of the language network (Mesulam
and Weintraub 1992; Rosen, Kramer et al 2002). In PPA,
metabolic abnormalities tend to parallel predominant language dysfunction, in that non-fluent patients have reduced
metabolism in left frontal areas, including the insula, while
fluent patients with impairments in comprehension tend to
have reduced left temporal metabolism (Abe et al 1997;
Rosen, Gorno-Tempini et al 2002; Nestor et al 2003).
With regard to specific subtypes, Gorno-Tempini,
Dronkers et al (2004) used voxel-based morphometry (VBM)
748
to demonstrate the differential involvement of distinct brain
regions in the three variants that they defined clinically. In
PNFA, atrophy involved the left inferior frontal and insular
cortex. In their semantic variant, the anterior temporal
regions were preferentially affected, while in the logopenic
patients, involved areas were the left posterior temporal and
inferior parietal cortices. The same group also demonstrated
a relationship between the appearance of mutism in PNFA
and further atrophy of the pars opercularis and extension into
the left basal ganglia (Gorno-Tempini et al 2006). Bilateral
temporal atrophy, left greater than right, has also previously been demonstrated in SD by Mummery et al (2000)
and Rosen, Gorno-Tempini et al (2002). In their report,
Mummery et al (2000) also demonstrated a relationship
between the degree of semantic impairment and the extent
of left anterior temporal lobe atrophy. Rosen, Kramer et al
(2002) had also previously demonstrated similar changes
in their report of 3 patients with variants of PPA. In their
combined PET and VBM analysis of patients with PNFA,
Nestor et al (2003) demonstrated hypometabolism in the left
anterior insula/frontal opercular region, and atrophy in the
left peri-Sylvian region. PET and SPECT imaging may be
able to differentiate the underlying etiology of PNFA (Nestor
et al 2007). When only Alzheimer’s disease-like changes
(see pathology section below) were found at autopsy, nuclear
imaging during the initial diagnostic workup more consistently demonstrated hypoperfusion deficits in the posterior
temporoparietal association cortex, a pattern very specific
for PRAD, in contrast to changes in the left anterior insula/
frontal opercular region noted above that are associated with
‘FTD-spectrum’ pathology (Nestor et al 2007).
Although often present with aphasia, the development of
apraxia of speech suggests involvement beyond the language
network. Using VBM, Josephs et al (2006) demonstrated
that the presence of non-fluent aphasia was associated with
anterior peri-sylvian atrophy, while the presence of speech
apraxia followed changes in left premotor and supplemental
motor cortex.
Despite marked left hemisphere dysfunction in
non-fluent PPA, the metabolic state of the contralateral
right hemisphere tends to remain within the normal range
(Chawluk et al 1986; Tyrrell et al 1990). When asked to
identify homonyms or synonyms in the course of functional
MRI (fMRI) experiments, PPA patients (fluent and nonfluent) and controls activate the same components of the
language network (Sonty et al 2003). However, in contrast
to neurologically intact subjects, the PPA patients display
aberrant (possibly compensatory) activations within
Neuropsychiatric Disease and Treatment 2007:3(6)
Primary progressive aphasia
regions of the brain outside of the classic language network
(Mummery et al 1999; Sonty et al 2003). Using fMRI
and a grammatically complex sentence comprehension
paradigm, Cooke et al (2003) showed that patients with
PNFA produce less activation within the ventral portion
of the inferior frontal cortex, an area felt to be crucial to
the processing of complex sentences. They further postulate that this interruption of a putative large-scale neural
network for sentence comprehension (Cooke et al 2006)
forms the basis for the complex grammatic comprehension
deficits seen in these patients.
Neuropathology
Generally, as a group, the various neuropathological
findings associated with PPA and FTD have been called
frontotemporal lobar degeneration (FTLD) (Neary et al
1998). These are not uniform and their characterization
is changing as a result of improvements in genetics and
staining techniques. Specifically, the neuropathological
findings are a function of a number of possible underlying
etiologies. At autopsy, the most uniform finding is that of
focal degeneration, which is usually found preferentially
and more intensely in language areas, and characterized by
neuronal loss, gliosis, and spongiform changes involving the
superficial cortical layers. Cortex may also contain occasional
ballooned neurons, called Pick cells. Staining with silver
and newer histochemical stains for either the microtubule
associated protein tau (MAPT or simply tau) or ubiquitin can
reveal neuronal and glial inclusions in a pattern particular to
the exact neurpathological process at hand. Pick bodies are
argyrophilic (silver staining) spherical neuronal inclusions
diagnostic of Pick’s disease. Similar neuronal inclusions may
only be visible with tau immunostaining, thus defining the
underlying disorder as a ‘tauopathy’ such as in certain forms
of FTD, CBG, and progressive supranuclear palsy (PSP).
Other non-argyrophilic tau negative inclusions may stain
only for ubiquitin, as is found when FTD is associated with
motor neuron disease. When ubiquitin inclusions are found
in the absence of clinical motor neuron disease, the finding
is termed FTD-MND type. FTD associated with ubiquitin
inclusions is also referred to as FTLD-U. When no inclusions
can be found, the pathology is often referred to as dementia
lacking distinctive histopathology (DLDH) (Knopman et al
1990), a diagnosis that is becoming increasingly scarce as
immunohistochemical techniques are refined (Mackenzie
et al 2006). Although these pathological findings are quite
distinct in their staining characteristics and even genetic
underpinnings (see below), they are generally considered
Neuropsychiatric Disease and Treatment 2007:3(6)
as representing the ‘FTD-spectrum’ of pathologies that are
most frequently found in FTLD.
Occasionally extracellular plaques and neuronal neurfibrillary tangles characteristic of Alzheimer’s disease are
found. In many instances their distribution is unusual and
follows a more frontotemporal pattern, rather than the classic
temporparietal one, resulting in brains with a macroscopic
appearance more in keeping with FTLD (Knibb et al 2006).
A recent clinicopathological study (Forman et al 2006)
suggests that tau pathology is more frequently associated
with extrapyramidal disorders while FTLD-U manifests
more frequently as bv-FTD, PPA, and motorneuron disease.
In their cluster analysis, Knibb et al (2006) found AD-like
changes accounted for roughly one third cases of fluent
and non-fluent PPA. They also noted that tau-based disease
was more common than FTLD-U in the non-fluent cluster
(43 vs 17%), while in the fluent group this trend was reversed
(13 vs 53%).
Genetics
The not uncommon familial association of PPA and FTD
supports a genetic link between them. Some 38 to 50% of
clinical FTD cases appear to be familial (Stevens et al 1998;
Grasbeck et al 2005). Countless kindred have been described
that demonstrate segregation of a disease in an autosomal
dominant pattern of inheritance. The clinical disease itself
is usually FTD, but can include parkinsonism, motor neuron
disease, or progressive aphasia, even in the same family. In
some families, a mutation in the gene coding for tau (found
on chromosome 17q21) can be demonstrated. Postmortem
analysis usually reveals tau pathology.
More recently, a genetic cause of FTD with tau-negative
ubiquinated inclusions (FTLD-U) was traced to progranulin
(PRGN) gene mutations, also found on chromosome 17q21
(Cruts et al 2006; Baker et al 2006). The mutations cause a
null allele and a reduction in the level of functional PRGN
protein. Replacement of this missing protein may represent
a new and exciting therapeutic avenue for this group of disorders. Snowden and colleagues have reported an increased
occurrence of PNFA variant of progressive aphasia associated
with mutations of this gene (Snowden et al 2006). Josephs
et al (2007) have also noted more frequent language impairment in patients with FTLD-U associated with this mutation
than patients without. These patients carried an initial diagnosis of PPA and developed early mutism.
Although the actual gene mutations have not yet been
described, other families with related clinical disorders
demonstrate linkage to different regions of chromosome 3
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(Brown et al 1995, 2004; Gydesen et al 2002) and 9 (Hosler
et al 2000; Kovach et al 2001; Morita et al 2006).
In most families described above, the PPA is either quickly
followed by the appearance of deficits in other cognitive
domains, or other affected family members do not have
“typical” PPA, and do not strictly meet the criteria of Weintraub
et al (1990) and Mesulam (2001). However, Krefft and
colleagues (2003) describe a family in which all three affected
siblings meet Mesulam’s more stringent criteria. The genetic
basis for this kindred, and another in which the affected siblings
also meet these criteria, have recently been shown to be a result
of two new PRGN mutations (Mesulam et al 2007).
Risk factors
Certain genetic risk factors have also been noted. These
include heterozygocity for codon 129 of the prion protein
(Li et al 2005), presence of the tau H1/H1 genotype, also
found to be associated with PSP and CBD (Li et al 2005), and
ApoE ε2-ε4 hereozygocity (Acciarri et al 2006). Vasectomy
may also increase the risk of developing PPA (Weintraub
et al 2006). The exact mechanism for this remains unknown,
but may involve a vasectomy induced immune response to
sperm that share antigenic epitopes with brain.
Treatment
Treatment of PPA should be considered along at least three
different avenues: (1) pharmacologic treatments to address
associated symptoms and potentially slow or stop progression,
(2) non-pharmacologic interventions to help maintain independent function and compensate for growing language deficits, and
(3) support and education of patients and their care givers.
Because of the uncommon nature of PPA, there have been
no large-scale clinical trials using any known pharmacologic
agents. The only published therapy trial in PPA is that of
Reed and colleagues (2004), who could not demonstrate a
benefit of the dopamine agonist bromocriptine in their small,
randomized, placebo-controlled trial.
A few clinical trials, as well as prospective and retrospective
case series have been published using various pharmacological
agents in patients with FTD (Chow 2005; Huey et al 2006;
Freedman 2007). Conclusions from these studies become
more relevant to PPA as the disorder progresses and behavioral
manifestations become more prominent. The use of antidepressants such as trazadone seem to help stabilize the behavioral
symptoms, but, unfortunately, without an impact on cognition
(Lebert et al 2004). Similar benefits have been found with the
cholinesterase inhibitor rivastigmine (Moretti et al 2004), and
the MAO-B inhibitor selegiline (Moretti et al 2002).
750
In a novel application of a research tool that is finding
more frequent use in neurological and psychiatric disorders,
Finocchiaro and colleagues (2006) have demonstrated that
high-frequency repetitive transcranial magnetic stimulation
(hf-rTMS) applied to the left prefrontal cortex produces
a significant and lasting improvement on language tasks,
including verb production. The exact mechanism of such
an improvement remains unknown, but it is believed that
hf-rTMS may strengthen neural connection in those areas
weakened by the disease process.
As has been demonstrated by Medina and Weintraub
(in press), the frustration of progressive language deficits,
particularly when insight is preserved, can lead to depressed
mood. Evaluation and treatment of depression with routine
antidepressants is indicated.
Disease modifying agents are not yet commercially
available, but potential application of tau reducing drugs
presently being developed for Alzheimer’s disease may
prove beneficial in PPA patients with tau-based disease
(Klafki et al 2006). When these become available, the need
to distinguish tau from non-tau based disease during life will
become important, and may be aided by genetic analysis,
new PET imaging ligands (Small et al 2004, 2006), and
cerebrospinal fluid tau species and levels (Hampel and Teipel
2004). Once the neuropathological mechanism involved in
null progranulin-mutation based disease is better understood,
these patients will likely benefit from some form of replacement therapy.
The frustration and helplessness experienced by family
and caregivers should not be overlooked. Counseling
and education are key. Although families can find much
information on the FTD website (http://www.ftd-picks.org)
and books (Radin et al 2004), some centers have developed
education and support seminars series that have been received
very positively (Diehl et al 2003; Banks et al 2006).
Finally, notwithstanding the progressive nature of PPA,
there remains a role for regular speech therapy assessments,
which can identify the impact of particular language deficits
on day-to-day function, and help with the implementation
of evolving communication strategies to help compensate
(Snowden et al 1995; Graham et al 1999; Galton et al 2001;
Jokel et al 2002, 2006). The detection of swallowing difficulties is also important as appropriate changes in diet and
feeding habits could be lifesaving.
Conclusion
Since its original description by Mesulam in 1982, our understanding of the clinical evolution and neuropatholgic and genetic
Neuropsychiatric Disease and Treatment 2007:3(6)
Primary progressive aphasia
basis of PPA has progressed steadily. PPA should be considered
in the differential diagnosis of dementias presenting with language dysfunction. It can be differentiated from PRAD and FTD
by the initial absence of significant memory loss or behavioral
changes, and the preservation of activities of daily living.
There exists presently no effective treatment for this
condition, although addressing mood and behavioral issues,
as well as helping caregivers better understand the disease
is useful. As the mechanisms leading to the related diseases
FTD, CBD, and ALS are unraveled, and pathology targeted
therapy is developed, the future is more promising.
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