Classic Pick's disease type with ubiquitin-positive and tau-negative inclusions: case report

We report on a patient presenting Pick's disease similar to the one reported by Pick in 1892, with ubiquitin-positive and tau-negative inclusions. His diagnosis was made on the basis of clinical (language disturbance and behavioural disorders), neuropsychological (progressive aphasia of the expression type and late mutism), neuroimaging with magnetic resonance (bilateral frontal and temporal lobes atrophy) and brain single photon emission computed tomography (frontal and temporal lobes hypoperfusion) studies. Macroscopic examination showed atrophy on the frontal and temporal lobes. The left hippocampus displayed a major circumscribed atrophy. The diagnostic confirmation was made by the neuropathological findings of the autopsy that showed neuronal loss with gliosis of the adjacent white matter and apearance of status spongiosus in the middle frontal and especially in the upper temporal lobes. There were also neuronal swelling (ballooned cell) and argyrophilic inclusions (Pick's bodies) in the left and right hippocampi. Anti-ubiquitin reaction tested positive and anti-tau tested negative.     

Diagnostic criteria for fronto-temporal lobe degeneration

Circumscribed atrophy of the frontal and temporal lobes (frontotemporal lobar degeneration) accounts for about one fifth of cases of primary degenerative dementia occurring before the age of 65. It produces three prototypical clinical syndromes. The most common is frontotemporal dementia, characterized by personality change and profound alteration in social conduct and associated with bilateral atrophy of the frontal and anterior temporal lobes. Progressive non-fluent aphasia is characterized by difficulty in verbal expression, anomia and phonemic errors in the presence of relative preservation of comprehension and associated with atrophy predominantly of the left hemisphere. In semantic dementia there is fluent speech with semantic errors and severely impaired comprehension and naming, together with a visual associative agnosia, resulting from bilateral atrophy of the inferior and middle temporal gyri. The clinical syndromes occur with either of two main histological types: prominent microvacuolar change, without specific histological features (frontal lobe degeneration-type), severe astrocytic gliosis with or without ballooned cells and inclusion bodies (Pick-type). To improve clinical recognition and advance understanding of this relatively common form of cerebral degeneration, members of an international workshop on Frontotemporal Lobar Degeneration developed consensus criteria, building upon earlier published clinical diagnostic guidelines for frontotemporal dementia. The consensus criteria reported here specify core and supportive features for each of the prototypical clinical syndromes: frontotemporal dementia, progressive aphasia and semantic dementia, as well as providing broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration.     

A case of developmental deep dyslexia: What's left is right

Primary progressive aphasia (PPA) is a progressive neurodegenerative disorder characterized by the deterioration of language functions. The Han language bears some unique features from the Latin languages; however, the features of PPA in the Han language-speaking population are not well understood. In this study, we performed a 3-year follow-up on a Han language-speaking PPA patient with corresponding changes in magnetic resonance imaging (MRI). During the early stage, linguistic analysis revealed several symptoms including difficulty with auditory comprehension, right–left disorientation, reading disorders, and agraphia, specifically the execution of serial oral instructions. This Chinese PPA patient presented with a reading disorder, but his word comprehension ability remained intact. There are two different possible modalities of incorrect writing in this case. The patient also presented with noun–verb double dissociation. The early-stage MRI showed atrophy of the left frontal lobe, which was most severe in the inferior frontal gyrus. Three years later, the patient was found to have progressive atrophy in the parietal, frontal, and temporal lobes, among which the frontal lobe remained the most severely affected region. The brain imaging of the Chinese-speaking PPA patient showed changes similar to those of a Latin language-speaking PPA patient. The prominent change was asymmetrical atrophy in the frontal and temporal lobes. This is the first report of noun–verb double dissociation existing in a Chinese-language speaking PPA patient. The dissociation may be related to an impaired function of the inferior frontal gyrus, which is likely associated with verb-naming in Chinese-speaking people. Several unique features were observed in this case, including impairment in writing ability.     

An autopsied case of corticobasal degeneration with onset of nonfluent aphasia revealing symmetrical cerebral involvement

Herein we describe a patient with established corticobasal degeneration with onset of nonfluent aphasia and showing symmetrical cerebral involvement. A 64-year-old man with a speech disorder for 2 years visited our hospital. He had nonfluent aphasia (reduced spontaneous speech, loss of intonation, anomia, repetition disorder, and difficulty in speaking short sentences). He also showed right-sided motor neglect, hypertonus of the left lower limb, a mask-like facial expression, and difficulty in closing his eyes. He was restless and walked around even during examination, suggesting frontotemporal dementia (FTD). Single-photon emission computed tomography (SPECT) revealed symmetrical reduction of cerebral blood flow in the bilateral fronto-temporo-parietal lobes. His neurological condition deteriorated gradually and a year later he could not speak comprehensive sentences. Magnetic resonance imaging (MRI) of the head at age 70 showed symmetrical atrophy of the bilateral fronto-temporal lobes. He died of respiratory failure after clinical problems lasting ten years. On pathological examination, the fixed brain weighed 1,010 g and showed bilateral symmetrical atrophy of the frontal lobes. Histopathological examination revealed neuronal loss and gliosis in the frontal lobes, especially in the frontal convexity, superior frontal gyrus and precentral gyrus. Gallyas-Braak silver staining showed astrocytic plaques, argyrophilic threads and coiled bodies mainly in the frontal lobes. The substantia nigra showed severe neuronal loss on both sides and presence of free melanin. Pathological diagnosis was corticobasal degeneration (CBD). We believe that the patient had nonfluent aphasia and FTD reflected in bilateral degeneration of the frontal lobes. Some cases of CBD may present with symmetrical degeneration of the brain, even though left-hemisphere symptoms such as aphasia reveal themselves at an early stage.     

A case of motor neuron disease with presenile dementia showing bilateral degeneration of the pyramidal tract on cranial MRI]

A 58-year-old man developed dysarthria followed by a personality change. Subsequently, he developed muscle weakness and atrophy of the left upper and lower limbs, leading to repeated falls when he tried to walk. Neurological examination showed mild dementia, dysarthria, dysphagia, atrophy and fasciculation of the tongue, and muscle weakness and atrophy of all four extremities, particularly on the left side. Deep tendon reflexes were slightly diminished in the upper limbs and slightly exaggerated in the lower limbs without Babinski's sign. Cranial MRI revealed marked atrophy of the medial portions of the temporal lobes, more striking on the right, and T2-weighted imaging revealed symmetrical high-intensity signals from the posterior limbs of the internal capsules to the cerebral peduncles in the midbrain, extending to the pons on the left. 125I-IMP SPECT showed diffuse reduction of RI uptake in the frontal and temporal lobes, which was more marked on the right. We diagnosed this is a case of motor neuron disease with presenile dementia, which Mitsuyama et al. proposed as a new clinical entity, as well as a rare example of bilateral degeneration of the pyramidal tract on cranial MRI.     

A case of motor neuron disease with dementia, presenting motor aphasia as an initial symptom]

We report a case of motor neuron disease (MND) with dementia, presenting motor aphasia as an initial symptom. A 67-year-old man was admitted to our hospital because of speech disturbance slowly progressing for 2 years. On physical examination, he showed no neurological abnormalities except for non-fluent aphasia and increased deep tendon reflexes without laterality. MRI demonstrated bilateral fronto-temporal atrophy, dominating the left hemisphere. This finding was confirmed by surface anatomy scanning (SAS), showing an obvious atrophy in the left inferior frontal gyrus, compared with the right one. SPECT with 123I-IMP revealed some irregular defects in the bilateral frontotemporal region. Because he showed dementia, bulbar palsy with tongue atrophy, weakness of upper extremities and facial muscles, snout reflex, and the atrophy and fasciculation in limbs in addition to motor aphasia soon after the discharge from our hospital, he was diagnosed as having MND with dementia. At age 68, he died of a respiratory failure 3 years after the onset of the disease. MND with dementia seldom shows motor aphasia as an initial symptom. We must include, however, the MND with dementia as an differential diagnosis when we see the patients with progressive aphasia.     

A case of slowly progressive aphasia accompanied with auditory agnosia]

A 68-year-old right-handed woman was admitted to our hospital because of difficulty to speak and understand conversation over 10 years. She was able to make herself by writing. No change in her personality or behavioral abnormality was observed so that she could live without help. Although her WAIS score and auditory brain stem response were normal, she could not understand the speech or distinguish the sound. She also spoke plenty of words fluently, resulting in undifferentiated jargon. She did not make any effort in speaking. Her speech was, however, unclear and hard to understand. Brain MRI scan disclosed a moderate atrophy of bilateral temporal lobe and enlargement of Sylvius fissure. A three-dimension reconstructed brain surface image showed enlargement of the perisylvian fissure, and atrophy of the gyrus frontalis inferior, operculum, gyrus temporal superior, bilaterally. Reduced cerebral blood flow was demonstrated on 99mTc-ECD SPECT in the left thalamus and bilateral fronto-temporal lobe. A diagnosis of slowly progressive aphasia with auditory agnosia was made. Our case suggests that bilateral disturbance of neuronal network between the primary auditory area and the secondary auditory area is responsible to the consequence of auditory agnosia.     

原发性进行性失语的临床、影像及语言特征

目的 探讨原发性进行性失语（PPA）的临床、影像及语言特征.方法 PPA患者7例,其中语义性痴呆（SD）6例,进行性非流利性失语（PNFA）1例,收集患者的人口学资料、病史,进行头MRI检查,采用汉语失语成套测验进行语言评估.结果 患者平均发病年龄56岁,均缓慢起病,以语言表达、命名障碍为首发症状.MRI示左侧颞极萎缩为主,病程长的患者左侧额叶和顶叶、右侧颞叶也明显萎缩.语言评估发现所有患者的自发语言、复述、命名、听理解、阅读和书写均不同程度损害.SD患者言语流利,复述、朗读能力下降相对较轻,命名、复杂语句的理解能力损害突出.PNFA言语顿挫吃力,患者列名能力明显下降,但命名相对保存完好.结论 PPA多为老年前期发病,语言障碍为最早、最突出的症状.MRI特征性的改变为额叶和颞极萎缩,左侧为著.其中SD表现为命名性失语和经皮质感觉性失语,PNFA表现为经皮质运动性失语的特征.     

Abstracts Presented at the British Neuropsychological Society Autumn Meeting,October/November 2006

Classifying primary progressive aphasia (PPA) into variants that may predict the underlying pathology is important. However, some PPA patients cannot be classified. A 78-year-old woman had unclassifiable PPA characterized by anomia, dysarthria, and apraxia of speech without agrammatism. Magnetic resonance imaging revealed left mesial temporal atrophy and 18-flourodeoxy-glucose positron emission tomography showed left anterior temporal and posterior frontal (premotor) hypometabolism. Autopsy revealed a mixed tauopathy (argyrophilic grain disease) and transactive response-DNA-binding-protein-43 proteinopathy. Dual pathologies may explain the difficulty classifying some PPA patients and recognizing this will be important as new imaging techniques (particularly tau-positron emission tomography) are introduced and patients begin enrollment in clinical trials targeting the underlying proteinopathy.     

Aphasia and dementia

Primary progressive aphasia (PPA) is an uncommon neurodegenerative syndrome characterized by a relatively isolated dissolution of language function at the beginning, followed by deterioration of general cognitive function and of activities of daily living after 2 or more years. On account of neuropathological and clinical findings, PPA is supposed to form part of the spectrum of frontotemporal lobar degeneration. We present a case study of a 66-year-old woman with a probable fluent progressive aphasia. She initially experienced word amnesia and developed after 2 - 3 years gradual regression of word comprehension, over-fluent speech with semantic paraphasias, and at last generalized dementia. In addition to minor bilateral cortical volume reduction on CCT, MRI showed left temporal lobe atrophy involving hippocampus, SPECT revealed reduced uptake left frontal and temporal.     

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.     

A case progressive dementia developed after repeated head trauma

A 46-year-old man who developed progressive dementia after repeated head trauma was reported. At the age of 30 and 36, he encountered traffic accidents and suffered from blows to his head. At 37 years old, he noticed impairment of memory and comprehension. At 41 years old, he was observed to become easily angered. These symptoms were slowly progressive, and at age 46 he was examined by us. He had no particular family history of dementia. Neurological examination revealed a disturbance of cognitive ability. The brain CT and MRI showed marked atrophy of the cerebral cortex, especially in the frontal and temporal lobes without any demonstrable lesions in the white matter. A single photon emission computed tomography (SPECT) using inhalation of 133Xenon disclosed hypoperfusion of the cerebral blood flow localized in the bilateral frontal and parietal lobes. He was supposed to suffer from juvenile Alzheimer's disease which might have developed after repeated head trauma. One similar case had been reported as a posttraumatic premature Alzheimer's disease. Finally, we discussed other causes of dementia including metabolic, infectious and vascular diseases. The present case also suggests that head trauma might be one of the provoking or promoting factors of Alzheimer's disease.     

Rates of hemispheric and lobar atrophy in the language variants of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance.     

A case of herpes simplex virus encephalitis characterized by prolonged psychotic symptoms in convalescence--a case report]

A 14-year-old girl was diagnosed as having herpes simplex encephalitis by a polymerase chain reaction examination of the cerebrospinal fluid. MRI showed diffuse high signal areas at the bilateral temporal lobes and right frontal lobe. She was treated with a total of 350 mg/kg of acyclovir for 23 days, and discharged without abnormal neurological findings. On the 90th day after the onset, however, she became excitable and aggressive to her family. She excessively seeked relations with several boy friends. MRI revealed dilation of the bilateral ventricles and atrophy of the temporal lobes. These pathologic changes including the atrophy of hippocampus may be responsible for the character changes in this case.     

Two cases of frontotemporal dementia with predominant temporal lobe atrophy

Frontotemporal dementia (FTD) is a subtype of frontotemporal lobar degeneration, which also includes semantic dementia (SD) and progressive non‐fluent aphasia. Frontotemporal dementia is characterized by changes in personality and behavioral abnormalities, generally associated with predominant frontal lobe atrophy. Conversely, SD is typically characterized by Gogi (word meaning) aphasia based on semantic memory impairment and is associated with predominant temporal lobe atrophy. However, in the present cases, we diagnosed FTD on the basis of clinical symptoms, such as disinhibition, indifference, and stereotypy, without semantic memory impairment, even though neuroimaging showed predominant temporal lobe atrophy. We suggest that clinical symptoms are the most important cues for an accurate clinical diagnosis and there is no exclusive relationship between the syndrome and atrophy of the temporal lobes.     

Amyotrophic lateral sclerosis presented with alexia of kanji and word meaning aphasia]

We report a 63-year-old right-handed Japanese man with progressive bulbar dysfunction and alexia of kanji (Japanese morphograms). He was well until his 62 years of age, when he noted difficulty of reading kanji, which was followed by disturbances in his speech. Reading of kana (Japanese phonograms) was preserved. He also showed naming difficulties with semantic memory loss for words, which were characterized for word meaning aphasia or semantic dementia. He showed dysarthria and mild dysphagia with atrophy and fasciculations of the tongue. The electromyographic studies disclosed diffuse neurogenic pattern. He was diagnosed as having bulbar type amyotrophic lateral sclerosis. Cranial magnetic resonance imaging and single-photon emission computed tomography revealed bilateral involvements of the temporal lobes. Our patient appeared to meet the clinical criteria for frontotemporal degeneration of motor neuron disease type, and is the first case of amyotrophic lateral sclerosis showing alexia of kanji and word meaning aphasia.     

Cognition and anatomy in three variants of primary progressive aphasia

We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E epsilon4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.     

Progressive loss of speech output and orofacial dyspraxia associated with frontal lobe hypometabolism.

Three patients are described with slowly progressive loss of speech and dysarthria associated with orofacial dyspraxia, initially with intact written language, who subsequently developed more widespread cognitive abnormalities. Positron emission tomography (PET) revealed bifrontal hypometabolism in all of the patients, most marked in the inferior and lateral portions of both frontal lobes, with some extension into the parietal and temporal cortices in one case. These patients may represent a further example of focal progressive cortical degeneration.     

Asymmetric cortical degeneration syndromes. A proposed clinical classification.

Twenty-six patients presented with slowly progressive focal neurologic symptoms that conformed clinically to one of three categories: asphasia, perceptuomotor dysfunction, or neuropsychiatric dysfunction. Of 12 patients with progressive aphasia, seven were dysfluent and five were fluent. Nine patients had progressive perceptuomotor impairment due to bilateral parietal lobe atrophy, which also included frontal lobe signs in seven patients and occipital lobe signs in three patients. The right hemisphere was more severely involved in five patients and the left hemisphere in four. Five patients had a progressive neuropsychiatric syndrome, and there was also generalized spasticity in three patients due to frontal lobe atrophy. The clinically suspected anatomic localization of cortical atrophy or hypoperfusion in all three categories was confirmed with neuroimaging techniques. A brain biopsy specimen from one patient showed mild, nonspecific degenerative changes. A clinical classification scheme incorporating our observations as well as the observations of others is presented to aid in the recognition of these syndromes.