Progressive focal cortical atrophies

Progressive focal cortical atrophies are degenerative conditions characterised by the insidious onset and gradual exacerbation of an impairment in a single cognitive domain related to circumscribed cerebral atrophy. Several focal cortical syndromes with deficits in the realm of cognition are reviewed: progressive impairment of language (primary progressive aphasia), speech (progressive anarthria), semantic memory (semantic dementia), episodic memory (pure progressive amnesia), vision (progressive perceptual or visuo-spatial deficits) and gesture (progressive apraxia). These conditions are histologically heterogeneous and can be associated with focal non-specific neuronal loss and gliosis with some spongiform changes (non-specific lesions), pathological features of Pick's disease (inclusion bodies and swollen neurones) or Alzheimer's disease (AD) (senile plaques and neurofibrillary tangles). A relationship between neuropsychological profiles and lesional types emerges from this review of the literature. Non-fluent primary progressive aphasia, semantic dementia and progressive anarthria are usually associated with non-specific lesions and Pick-type pathology. Progressive disorders of episodic memory and progressive visuo-spatial deficits are more often related to AD. If adequate clinical characterisation can determine the underlying disorder, it appears even more important to establish the neuropsychological profile in patients with cortical degenerative disease. Progressive deficits of only one domain of cognition may well be due to preferential involvement of anatomically and functionally defined neural systems and could therefore be considered as "system atrophies". There remains no doubt that these syndromes are particularly well suited models for studies on the relationship between cerebral functions and their neural substrate.     

Presenile non-Alzheimer dementia with motor neuron disease and laminar spongiform degeneration

We describe the clinicopathological findings in three autopsy cases of presenile dementia with motor neuron disease. These patients had a relatively rapid course involving dementia and muscle weakness with a distal pattern of atrophy in the upper extremities. Postmortem examination revealed features of motor neuron disease and spongiform cortical degeneration. The latter change was most marked in the second layer of the frontal or temporal cortex and included minimal to mild neuronal cell loss and mild to moderate gliosis. In this report we relate these patients' laminar spongiform degeneration to three other conditions; frontal lobe dementia, primary progressive aphasia and dementia lacking a distinctive histology. These three conditions and presenile dementia with motor neuron disease may fall within the spectrum of the non-Alzheimer type frontotemporal degenerative dementia.     

Primary progressive aphasia with focal neuronal achromasia

We describe the clinical, radiologic, neuropsychological, and neuropathologic features of a 69-year-old man with a 3-year history of progressive transcortical expressive aphasia. Neuropsychological testing showed progressive dysfunction of expressive language. Neuropathologic examination demonstrated focal cortical degeneration involving the left superior frontal gyrus, with swollen achromasic neurons and no evidence of Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Lewybody disease, or other dementing disorders. This case adds to the known heterogeneity of the underlying pathology of patients with primary progressive aphasia.     

Aphasia with left occipitotemporal hypometabolism: A novel presentation of posterior cortical atrophy?

Alzheimer’s disease is a common neurodegenerative disease often characterized by initial episodic memory loss. Atypical focal cortical presentations have been described, including the logopenic variant of primary progressive aphasia (lvPPA) which presents with language impairment, and posterior cortical atrophy (PCA) which presents with prominent visuospatial deficits. Both lvPPA and PCA are characterized by specific patterns of hypometabolism: left temporoparietal in lvPPA and bilateral parietoccipital in PCA. However, not every patient fits neatly into these categories. We retrospectively identified two patients with progressive aphasia and visuospatial deficits from a speech and language based disorders study. The patients were further characterized by MRI, fluorodeoxyglucose F18 and Pittsburgh Compound B (PiB) positron emission tomography. Two women, aged 62 and 69, presented with a history of a few years of progressive aphasia characterized by fluent output with normal grammar and syntax, anomia without loss of word meaning, and relatively spared repetition. They demonstrated striking deficits in visuospatial function for which they were lacking insight. Prominent hypometabolism was noted in the left occipitotemporal region and diffuse retention of PiB was noted. Posterior cortical atrophy may present focally with left occipitotemporal metabolism characterized clinically with a progressive fluent aphasia and prominent ventral visuospatial deficits with loss of insight.     

Familial progressive aphasia: its relationship to other forms of lobar atrophy.

Two brothers presented with slowly progressive aphasia. One brother, who became behaviourally disturbed only at the end of his illness, was found at necropsy to have predominant left frontotemporal atrophy. The other brother developed severe behavioural disturbances shortly after the onset of language impairment. His brain revealed bilateral frontotemporal atrophy. In both there was non-Alzheimer's disease pathology with the histological features of loss of large cortical nerve cells, spongiform change and mild gliosis. The differential anatomical atrophy supports the view that clinical manifestations of lobar atrophy are dictated by the topographical distribution of a common underlying pathology, linking the syndromes of progressive aphasia to dementia of frontal lobe type (DFT) and DFT with motor neuron disease.     

Asymmetric cortical degenerative syndromes: clinical and radiologic correlations.

Eight patients presented with slowly progressive focal neurologic syndromes that conformed to one of three clinically defined categories: progressive nonfluent aphasia (three patients), progressive perceptual-motor impairment (four patients), and progressive frontal lobe syndrome (one patient). Planar MRI and MRI-based surface or volume renderings demonstrated focal areas of atrophy that correlated well with clinical deficits. Single-photon emission computed tomography (SPECT) showed areas of cortical hypoperfusion that corresponded to focally atrophic regions revealed by MRI, but abnormal areas with SPECT were larger than those suggested by MRI. MRI and SPECT are useful in defining the regional structural and functional cerebral abnormalities that underlie slowly progressive focal neurologic syndromes caused by asymmetric cortical degeneration.     

Dementia of frontal lobe type: neuropathology and immunohistochemistry.

Brains from 12 patients dying with a clinical diagnosis of frontal lobe dementia have been examined at post mortem. In pathological terms four groups were encountered. Groups A and B showed severe frontal and temporal lobe atrophy characterised histologically in group A by severe neuronal loss, spongiform change of the superficial laminae, and mild astrocytosis; in group B severe neuronal loss was accompanied by intense gliosis but with little or no spongiform change. Two patients in this latter group also showed inclusions in frontal cortex and hippocampus typical of "Pick bodies"; such patients were considered as having classic "Pick''s disease". Group C patients showed severe striatal atrophy with variable cortical (frontal or temporal) involvement, with histological changes similar to patients in groups A and B. The single patient in group D showed mild frontotemporal atrophy with spongiform degeneration of the superficial laminae of the cortex and nigral damage, and was considered to have motor neuron disease with dementia. This study is consistent with previous reports showing that the clinical syndrome of frontal lobe dementia is pathologically heterogeneous. However, the nosological relationships within these pathological variants, and between them and conditions such as progressive aphasia were similar histopathological changes are present, remain uncertain.     

Posterior cingulate neurometabolite profiles and clinical phenotype in frontotemporal dementia.

Proton magnetic resonance spectroscopy was used to compare metabolite levels from a posterior cingulate voxel in a group of patients with 2 syndromic subtypes of frontotemporal dementia (n=10) and an age and education-matched group with Alzheimer disease (n=10). Overall, frontotemporal dementia was indistinguishable from Alzheimer disease, though differences in N-acetylaspartate emerged between patients with the SD and progressive nonfluent aphasia subtypes, attributable to 2 atypical results among the latter. Such values may index cases with atrophy in posterior cortical regions presenting with progressive nonfluent aphasia.     

Unilateral Creutzfeldt-Jakob disease

A 73-year-old woman had progressive right hemiparesis, aphasia, and focal motor seizures. EEG showed periodic discharges on the left. She died 8 weeks after onset. At autopsy, there was marked spongiform change, neuronal loss, and severe proliferation of astrocytes predominantly on the left and most prominently in the insular and centroparietal cortex. The changes were consistent with Creutzfeldt-Jakob disease (CJD), but pathology was slight or absent on the right side. This case appears as the first report of what might be called unilateral CJD. Such a condition should be included within the differential diagnosis of progressive unilateral cerebral disorders.     

Progressive anarthria with secondary parkinsonism: a clinico-pathological case report.

The pathological process and lesion topography in patients with the syndrome of progressive aphasia are heterogeneous and few necropsy examination cases have been investigated. This is a case report of a 53 year old right handed man with progressive anarthria and secondary Parkinsonism over a period of six years. Positron emission tomography (PET) showed a decreased cerebral blood flow and metabolism in the frontal cortex, which was more pronounced on the left. Neuropathology disclosed a spongiform vacuolation in layer II of the frontal cortex, mostly in the Broca area, and neuronal loss in the substantia nigra. This original case reinforces the view that there are different entities of the syndrome of progressive aphasia which can be identified on the basis of clinical, neuroimaging and anatomical data.     

MM2‐cortical‐type sporadic Creutzfeldt‐Jakob disease with early stage cerebral cortical pathology presenting with a rapidly progressive clinical course

We report the case of a 67‐year‐old man with MM2‐cortical‐type sporadic Creutzfeldt‐Jakob disease (sCJD) with a rapidly progressive clinical course of 5 months. Initial symptoms were progressive memory disturbance and dementia. MRI revealed high signal‐intensity lesions on diffusion‐weighted images in the bilateral frontal and occipital cortices. Myoclonus and periodic sharp‐wave complexes on the electroencephalogram were observed in the early disease stage. The clinical diagnosis was typical sCJD. Neuropathologic examination at autopsy showed widespread, characteristic cerebral neocortical involvement with large confluent vacuole‐type spongiform change. Spongiform degeneration was also evident in the striatum and medial thalamus. In the cerebellar cortex, slight depletion of Purkinje neurons was evident without spongiform change in the molecular layer or apparent neuron loss in the granule cell layer. The inferior olivary nucleus showed slight hypertrophic astrocytosis without neuron loss. Prion protein (PrP) immunostaining showed widespread, characteristic perivacuolar‐type PrP deposits with irregular plaque‐like PrP deposits in the cerebral neocortex, striatum and medial thalamus. We believe this patient showed early‐stage cerebral cortical pathology of MM2‐cortical‐type sCJD, which may provide clues regarding the pathologic progression of this rare sCJD subtype. Although MM2‐cortical‐type sCJD generally shows slow progression without myoclonus or periodic sharp‐wave complexes, the present patient showed a rapidly progressive clinical course similar to that of MM1‐type sCJD.     

Hereditary dysphasic dementia and the Pick-Alzheimer spectrum

Hereditary dysphasic dementia is described in terms of its clinicopathological, ultrastructural, and transmissibility characteristics. Its mode of inheritance is autosomal dominant, and its clinical manifestations of progressive dementia and severe dysphasic disturbances are expressed in late adulthood. Complete neuropathological examination of four patients reveals findings typical for Pick's disease (asymmetrical focal cerebral atrophy), Alzheimer's disease (profuse neuritic plaques), and paralysis agitans (neuronal depigmentation, depletion, and Lewy body formation in substantia nigra) in addition to a striking but nonspecific spongiform degeneration of superficial cortical layers. This unique combination of gross morphological and histopathological features qualifies hereditary dysphasic dementia as a distinct entity, but its precise relationship to the well-recognized adult cortical dementias has been difficult to establish by conventional classification methods. This disorder and other unusual dementing illnesses may be best considered as part of a Pick-Alzheimer spectrum of cortical neuronal degenerations.     

Evaluating atypical dementia syndromes using positron emission tomography with carbon 11 labeled Pittsburgh Compound B

CONTEXT: A progressive decline in episodic memory affecting activities of daily living is the usual clinical presentation of Alzheimer disease. However, patients presenting with atypical or focal clinical symptoms such as language or visuospatial dysfunction often pose a diagnostic challenge. OBJECTIVE: To explore the presence and topography of beta amyloid (Abeta) as measured by carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) in patients with atypical presentations of dementia. DESIGN, SETTING, AND PARTICIPANTS: At a tertiary referral center for memory disorders, 15 healthy controls, 10 patients with Alzheimer disease, a patient with primary progressive aphasia (PPA), and a patient with posterior cortical atrophy (PCA) underwent (11)C-PiB positron emission tomographic studies. Retention of (11)C-PiB was compared between different groups using statistical parametric mapping. MAIN OUTCOME MEASURE: The topography of cortical (11)C-PiB binding in atypical vs typical Alzheimer disease. RESULTS: Cortical (11)C-PiB binding was higher in the group with Alzheimer disease and in the patients with PPA and PCA than the controls (P < .001). Both patients with atypical dementia had a similar (11)C-PiB binding pattern to Alzheimer disease although (11)C-PiB retention was higher on the left cerebral hemisphere in the patient with PPA (P < .01) and higher in the occipital cortex in the patient with PCA (P < .01). CONCLUSIONS: The presence of distinctive focal (11)C-PiB retention patterns was demonstrated in 2 patients with atypical onset of dementia. Pittsburgh Compound B has the potential to facilitate differential diagnosis of dementia and identify patients who could benefit from specific therapeutic strategies aimed at beta amyloid reduction.     

Neuropsychiatric symptoms in behavioral variant frontotemporal dementia and primary progressive aphasia

Neuropsychiatric symptoms are well defined in behavioral variant frontotemporal dementia but are not as well studied in primary progressive aphasia. This study compared caregiver reported neuropsychiatric symptoms in these 2 forms of dementia at short and long disease duration. Patients with behavioral variant frontotemporal dementia had more symptoms than patients with primary progressive aphasia. However, when divided by duration of disease, patients with primary progressive aphasia with long duration had a similar number of symptoms to patients with behavioral variant frontotemporal dementia at either duration. Furthermore, this group of patients with primary progressive aphasia had more symptoms typical of behavioral variant frontotemporal dementia and less mood-related symptoms which were more common in patients with primary progressive aphasia with shorter duration. This study illustrates the emergence of neuropsychiatric symptoms as primary progressive aphasia progresses and highlights the increasing overlap with behavioral variant frontotemporal dementia because the disease affects areas outside of the language network.     

Corticobasal degeneration presenting with nonfluent primary progressive aphasia: a clinicopathological study

A 62-year-old woman initially presented with slowly progressive nonfluent aphasia with minimal intellectual involvement. Echolalia and personality change were prominent whereas parkinsonian features and signs suggesting parietal lobe dysfunctions were not present. The patient's language deficit was consistent with transcortical motor aphasia. She did not manifest extrapyramidal signs. The patient was diagnosed as having Pick's disease or frontal lobe dementia. She died at age 65, 2 years and 9 months following disease onset. Neuropathological findings including cytoskeletal abnormalities, however, were clearly distinct from those of classical Pick's disease and were consistent with those reported in corticobasal degeneration (CBD). The distribution of her cortical lesions was accentuated in the frontal language-related area. The clinical manifestations in CBD are diverse, and primary progressive nonfluent aphasia should be considered as an initial symptom of CBD. Neuropathological examination of such patients should include cytoskeletal abnormality studies.     

Corticobasal degeneration with primary progressive aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review

A 57-year-old woman showed progressive sensory aphasia as an initial symptom, and then developed total aphasia within 6 years and, finally, severe dementia. Neuropathologically, the cerebral cortex was most severely affected in the superior and transverse temporal gyri, and subsequently in the inferior frontal gyrus, especially in the pars opercularis. The degeneration in the subcortical grey matter was most severe in the substantia nigra, and it was moderate to mild in the ventral part of thalamus, globus pallidus and striatum. Cytopathologically, in addition to achromatic ballooned neurons, massive tau-positive types of cytosekeletal abnormalities were observed both in neurons and glia, mainly in the degenerating region. This cytoskeletal pathology coincided with that reported in corticobasal degeneration (CBD). On Bodian staining, only a few neurofibrillary tangles were found in the entorhinal pre-alpha layer and substantia nigra. Pick’s bodies and senile plaques could not be found. This case is thought to represent a type of CBD, but with its cortical lesion focus located in the speech area instead of the frontoparietal region. A survey of 28 pathologically evaluated cases of CBD revealed two similar cases, both of which began with progressive aphasia and presented cortical degeneration in the superior temporal gyrus. An overview of CBD cases clarified the features in another group of cases, in which the cerebral accentuated focus was shifted forward from the central region, clinically resembling Pick’s disease. The clinical manifestations in CBD seem to be the expression of these diverse cortical lesions. Primary progressive aphasia may include cases of CBD with involvement of the language center. Received: 5 February 1996 / Revised, accepted: 13 May 1996     

Progressive language disorder due to lobar atrophy.

Sixteen patients with progressive language disorder have been studied longitudinally. Anomia was a prominent presenting characteristic and mutism ultimately occurred. Patients, however, were clinically heterogeneous. Some exhibited nonfluent, agrammatic features, whereas others demonstrated a fluent aphasia, with profound loss of word meaning. Although language disorder remained the sole symptom in a minority of patients, in others an associative agnosia or personality and behavioral changes, or both, emerged. Findings on computed tomography and single photon emission tomography mirrored the areas of dysfunction suggested by the neuropsychological profiles and demonstrated abnormalities restricted to the left hemisphere or involving bilateral frontotemporal cortices. Brains of 3 patients, with distinctive clinical pictures, have been examined at autopsy. Each revealed a focal distribution of atrophy, gliosis and spongiform change, and an absence of senile plaques and neurofibrillary tangles. There was clinical and pathological overlap with frontal lobe dementia. We argue that progressive language disorder is clinically heterogeneous and forms part of a spectrum of clinical presentations of non-Alzheimer lobar atrophy.     

Progressive aphasia without dementia: further documentation

Two patients with progressive aphasia without dementia had magnetic resonance imaging findings of focal left temporal lobe abnormality. Unlike most of the other documented cases of progressive aphasia, onset was not presenile, occurring at ages 68 and 69.     

Progressive aphasia with Lewy bodies

Dementia with Lewy bodies (DLB) may include both Alzheimer and Lewy body pathology, but has never been reported to cause primary progressive aphasia. We report a 69-year-old woman who died 11 years after presenting with the syndrome of progressive aphasia. Six years after aphasia onset she developed visual hallucinations, and subsequently parkinsonism. Autopsy examination revealed Alzheimer's disease (AD), cortical Lewy bodies, and depigmentation and Lewy bodies in the substantia nigra and locus ceruleus. The aphasia most likely reflected the initial onset of AD, and the psychosis and parkinsonism most likely reflected the subsequent onset of Lewy body pathology. This first reported case of progressive aphasia occurring within the context of AD and Lewy body pathology uniquely illustrates the clinical and pathological nosological relationships between these two disease processes, and demonstrates a limitation of the general term, 'DLB'.     

Slowly progressive aphasia without generalized dementia

Six right-handed patients experienced a slowly progressing aphasic disorder without the additional intellectual and behavioral disturbances of dementia. The symptoms almost universally started in the presenium. The initial difficulty was an anomic aphasia in five of the patients and pure word deafness in the sixth. Continuous and gradual deterioration occurred in the five patients who presented with an anomic aphasia. They eventually experienced additional impairment of reading, writing, and comprehension. In four patients, other areas of comportment were not involved within the 5 to 11 years of follow-up. A more generalized state of dementia may have emerged in the other two patients, but only after 7 years of progressive and debilitating aphasia. Neurodiagnostic procedures were consistent with preferential involvement of the left perisylvian region. In one patient, cortical biopsy did not show any pathognomonic change; specifically, no neurofibrillary tangles, amyloid plaques, neuronal inclusions, or gliosis were seen. This condition may constitute a syndrome of relatively focal cerebral degeneration with a predilection for the left perisylvian region.