17.1 Clinical History – Chief Complaint

This is about a 56-year-old man who presented to the neurology clinic because of reading difficulty.

17.2 General History

Five years before the evaluation, the patient’s wife noted that he became “forgetful” and would require gentle prompting to complete tasks. She also noticed that he had “lost interest” in reading. Bilateral cataracts were found on ophthalmologic examination but their removal did not improve his reading.

At the time of evaluation in the cognitive disorders clinic, the patient reported difficulty with reading. He described knowing the letters of the alphabet but said that “I have difficulty putting them together.” He said that he could not follow written instructions, but had no difficulty with writing. Other cognitive symptoms were present as well. He would begin familiar tasks at home (i.e., walking the dog, mowing the lawn, taking out the trash) but could not complete them without verbal cueing. He had difficulty following multistep commands. He could no longer set the table for dinner. Nevertheless, he still managed the family’s checkbook, paying bills without making errors. He continued to drive but required others in the car to read street signs for him. However, he was still able to identify symbols on traffic signs. His family reported that he had become sedentary and lacked motivation. His attention to personal hygiene was mostly preserved but he had stopped brushing his teeth regularly. An 8-month trial of donepezil 10 mg at bedtime produced no benefit.

17.3 Family History

His daughter was diagnosed with dyslexia. There was no history of dementia or neurodegenerative disorder in the immediate family.

17.4 Examination

The patient had a detailed clinical exam at the Alzheimer’s Disease Research Center at the University of Pittsburgh.¹ His initial score on the Folstein Mini-Mental State Examination (MMSE) was 27/30.² He was oriented to person only. He correctly calculated the number of quarters in $6.75 (but he thought that his answer was incorrect). He named the months of the year in reverse order correctly. He had rare phonemic paraphasic errors and could not read written text when presented to him but he could identify the individual letters. There was no ideational or ideomotor apraxia, or neglect. Stereognosis was intact but he had mild agraphesthesia on the right side. No frontal release signs were noted.

Blood tests and chemistries were normal. The MRI of the brain showed mild left temporal lobe atrophy. A SPECT scan at the time of initial evaluation showed bilateral parietal hypoperfusion, left worse than right.

17.5 Diagnosis

The initial diagnosis was non-Alzheimer’s dementia/partial angular gyrus syndrome with alexia without agraphia.

17.6 Follow-Up

One year later, the MMSE score was 22/30. The alexia had worsened. He could no longer read labels (his family described his misidentifying a can of black spray paint as “wasp spray”). He could not find a particular object in a group of objects (i.e., locate a box of garbage bags in a full pantry). He had started to make financial errors with his checkbook. On exam, color agnosia and phonemic paraphasias were present as were a right palmomental and snout reflex.

Two years later, the MMSE was 21/30. Word-finding difficulties and color agnosia persisted. In addition, he tended to forget portions of conversations, and developed obsessive ideas and perseverative behaviors. He preferred to wear the same set of clothes each day. He assisted with drying dishes but could not place them in the correct cupboard. On exam, he could not read a sentence but was able to compose a simple one.

Three years after his initial evaluation, the MMSE was 20/30, and it continued to decline over the ensuing 2 years. A graph of the annual MMSE scores is shown in Figure 17.1. A graph with his scores on the modified Rey-Osterrieth Figure Copy scores is shown in Figure 17.2,³ demonstrating preservation of the copying skills with a decline in drawing the diagram from memory.

Figure 17.1 The Mini-Mental State Examination scores during follow-up.

Figure 17.2 The copy and delayed recall of the modified Rey-Osterrieth figure.

During his last clinical examination, it was noted that he could no longer pick out clothes from his closet. He could not identify the family car. He could not identify relatives by name and was unable to recognize his own daughter. He misidentified objects (i.e., a bag of potato chips for a coffee cup, an apple for an orange). He repeated himself. On exam, he could not state his date of birth nor his age. He could not calculate the number of quarters in a dollar amount (e.g., $6.75). He could not add a pair of two-digit numbers. He could not read the word “CAT.” He could not transcribe a four-word sentence. He could not identify objects (i.e., a cotton ball or piece of aluminum foil) by either sight or feel. His diagnosis was changed to probable Alzheimer’s disease with an atypical presentation.⁴ He died at the age of 69, 18 years after the onset of the symptoms, and 12 years after his initial evaluation.

17.7 Autopsy

Gross examination of the brain revealed lobar atrophy of frontal and temporal lobes with extension into inferior parietal lobe but relative preservation of pre/postcentral gyri. The atrophy was asymmetric with more severe changes seen on the left side. Microscopic examination found severe neuronal loss and gliosis in the anterior mesial temporal cortex, insular cortex, mid-frontal, temporal cortex, and inferior parietal cortex. Numerous Pick bodies were seen throughout most of the cortex (Figure 17.3), mixed with pre-tangles, neuropil threads, and glial tau pathology in the form of ramified astrocytes and oligodendroglial coiled bodies. No amyloid deposition was found. Moderate atherosclerotic and mild arteriolosclerotic changes were seen. The final neuropathological diagnosis was Pick’s disease.

Figure 17.3 Histopathological examination demonstrates numerous round basophilic inclusions on hematoxylin & eosin stained tissue sections (panel A). These Pick bodies are highlighted by immunohistochemical stains for phospho-tau (PHF1; panel B) and 3-repeat tau (RD3; panel C), but are negative on a Gallyas silver stain which only labels 4-repeat tau aggregates (panel D). PHF1 stains also highlight numerous neuropil threads and ramified astrocytes. [400× all images; arrows indicate Pick bodies; arrowheads indicate ramified astrocytes].

17.8 Discussion

The determination of the neuropathological basis of dementing disorders based on clinical data can be difficult in cases with unusual signs and symptoms, especially in younger individuals (e.g., 60 years old). In addition while clinicians expect to identify clearly defined clinical entities, there can be both significant overlap between syndromes and a blurring of the boundaries between syndromes often occurs as the dementia progresses.

Frontotemporal degeneration (FTD) is a term used to include a group of non-Alzheimer dementias, whose pathological basis includes focal neuronal loss and gliosis in the frontal and temporal lobes lobes.^{5, 6} In approximately 70% of the patients the symptoms start before age 65, and the prevalence ranges from 1 to 26/100,000,000.⁷ Clinically, patients with FTD can present a variety of syndromes including behavioral symptoms (the behavioral variant of FTD), primary progressive aphasia,⁸ semantic dementia,^{9, 10} cortico-basal degeneration,¹¹ progressive supranuclear palsy,¹² or motor neuron disease,¹³ or a combination of one or more syndromes.¹¹ Pathologically, FTD is associated with deposition of tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (fus) proteins,^14–16 although FTD-tau accounts for >50% of the cases.¹⁷

Pick’s disease is a rare form of FTD first described by Arnold Pick in 1892.¹⁸ It accounts for <5% of the autopsy series of dementias¹⁹ and 30% of the FTD cases.¹⁷ It affects both men and women, and tends to progress faster than Alzheimer’s disease (AD).²⁰ The clinical symptoms usually involve abnormal behavior (e.g., disinhibition, impulsiveness),²¹ language disorders,²² or both, consistent with frontotemporal lobe dysfunction, as occurs with other non-Pick’s disease FTD cases. However, the clinical presentation and progression of the symptoms is not uniform,²³ and there are case reports with a predominantly apraxic syndrome that mimicked cortico-basal degeneration with an asymmetric involvement of the parietal lobes.^{24, 25} The most important neuropathological lesion is the presence of neuronal loss, gliosis, and round intraneuronal inclusions called “Pick’s bodies,” which are composed of tau proteins enriched with 3-repeat isoforms. Pick’s disease predominantly affects the limbic, paralimbic, and neocortical regions, and can extend to primary motor and visual regions, basal ganglia, cerebellum, and midbrain structures in more advanced stages.²⁶ Because of the involvement of the mesial temporal lobe structures (e.g., dentate gyrus of the hippocampus), some cases can present with memory loss indistinguishable from AD.^{27, 28}

Because the initial findings in this patient involved most prominently a loss of reading ability with a focal hypoperfusion of the parietal lobes, the initial diagnostic formulation for this patient was a neurodegenerative process involving the dominant inferior parietal lobe with components of the angular gyrus syndrome rather than AD. The angular gyrus syndrome includes alexia with agraphia, fluent aphasia, visuoconstructional deficits, and Gerstmann’s syndrome (i.e., acalculia, agraphia, right/left disorientation, and finger agnosia).^{29, 30} Reasoning was relatively preserved at baseline, but deteriorated over time,³¹ and no episodes of abnormal behavior (e.g., disinhibition, agitation, inappropriate behavior) were reported. The incomplete syndrome seen here represents a heterogeneous involvement of the inferior parietal lobes, and suggests that the disease process may have not started in the typical frontal-temporal lobe areas, as expected.³² The determinants of this unusual initial pathological involvement are not well understood and are difficult to examine when the disease has been present for several years, and the pathology is widely distributed at the time of the autopsy. However, the asymmetric involvement of the parietal lobes has been shown in patients with Pick’s disease whose initial presentation mimicked a cortico-basal degeneration syndrome.^{24, 25}

Alexia without agraphia, the loss of reading ability but with sparing of the ability to write, also known as pure alexia, is due to a disconnection between visual input and language areas of the brain.³³ The usual causes are lesions affecting the left calcarine cortex and the splenium of the corpus callosum.³⁴ Because of the distribution of the neurodegenerative process, the most likely explanation in our case is (a) a cortical deficit beginning in the parietal lobes, or (b) a cortical-cortical disconnection affecting the occipital inputs to the parietal lobes, or (c) both, which may also explain his color agnosia.³⁵ Interestingly, there are familial FTD cases whose initial symptom was agraphia.³⁶ However, it was difficult to determine whether that agraphia was part of a true aphasic syndrome, or it was related to a dysexecutive, apraxic, or visuoconstructive deficit. Nevertheless, these patients showed a frontotemporal lobe pattern of impairment in functional neuroimaging studies and had a more widespread language deficit.

Although the most salient initial symptom was alexia without agraphia, this patient also had a short-term memory loss. Over the first 5 years following his diagnosis, these deficits progressed and new cognitive-behavioral difficulties developed. These new symptoms involved practically all cognitive domains, especially those ascribed to the frontal and temporal lobes, as well as to the inferior parietal cortex. Importantly, his visuoconstructional functions remained relatively stable during the follow-up time, which is consistent with the relative sparing of the superior parietal lobe regions found at autopsy. In addition, he developed memory loss, nonfluent aphasia with significant semantic errors, impaired semantic knowledge, and deficits in planning and multitasking. This prompted a change in his clinical diagnosis from a non-AD dementia to an atypical presentation of AD. At autopsy 5 years later the sole neuropathological diagnosis was Pick’s disease.

The patient presented with language dysfunction in the form of alexia, and mild behavioral change, but that change was limited to a subtle lack of motivation and adoption of a sedentary lifestyle. As his cognitive difficulties progressed, so did his behavioral dysfunction. However, his cognitive difficulties were more noticeable to the patient and his family. His language dysfunction was very prominent, progressive, and easily quantifiable. This combination of factors led to the incorrect clinical diagnosis. Even with the clinical skills present in today’s cognitive neurology clinics, the clinical diagnosis of an unusual subtype of dementia can be incorrect. The use of biomarkers for amyloid deposition,³⁷ or tau proteins³⁸ will help to improve clinical diagnosis in these type of patients.