A 75-year-old right-handed man presented to the Memory Disorders Unit of the Massachusetts Alzheimer Disease Research Center with a 3-year history of progressive forgetfulness and difficulty selecting the right words. Over the preceding 3 to 6 months he had experienced hallucinations and paranoid delusions, for which haloperidol was prescribed. He saw strangers in his house and on several occasions called the police to have them remove a man outside his door. He knew his daughters' names but thought he had two daughters named Carol, not one. His wife had died 3 years earlier, and since then the patient had lived alone and independently performed his daily activities. In general, he enjoyed good health. He had no complaints of depression, dysphagia, orthostatic hypotension, or urinary disturbances. Similarly, there was no history of strokes, hypertension, diabetes, toxic exposure, encephalitis, immunosuppression, or alcoholism. His only medications were haloperidol (0.5 mg/day) and weekly vitamin B12 injections. Four months previously, he had discontinued his optometry practice. His family history included a paternal grandmother who had impaired memory and hallucinations late in her life; however, an autopsy had not been performed.
The patient had a normal general examination. Blood pressure while seated was 120/80. He was alert, oriented to time (although he could not recall the day of month), person, and space. He exhibited abnormal immediate, short-term, and remote memories. He was unable to perform serial sevens. His speech was fluent but anomic. He showed slowness of thought, although his bradyphrenia was not formally tested. He demonstrated frontal lobe—type behaviors including apathy; difficulties with abstract thinking, analogies, and forming or switching concepts; imitation behavior; and inappropriate social behavior. He had constructive, but not dressing, apraxia. There was no agnosia. On formal testing, he had impaired performance of activities of daily living (32%; normal=0%) on a measure of his ability to manage his personal hygiene, health, money, travel, recreational activities, social relationships, communication skills, and household and employment responsibilities.1 In addition, he scored 10/37 on the Blessed Information, Concentration, and Orientation test (normal=0). On cranial nerve examination, III, IV, and VI were normal. There was normal pursuit and voluntary gaze; there was no nystagmus, ocular dysmetria, or eyelid apraxia. Cranial nerves V and VII—XII were unremarkable aside from mild bilateral hypoacusia. Motor examination showed full strength throughout; there were no fasciculations. Motor tone was generally increased (2/4), but there was no bradykinesia. Deep tendon reflexes were normal, and plantar responses were downgoing bilaterally. There was no tremor, dystonia, myoclonus, or alien limb syndrome. Coordination, gait, and postural reflexes were normal. Sensory examination was normal.
Laboratory testing showed normal blood cell counts, vitamin B12 levels, and renal, hepatic, and thyroid functions. EEG showed generalized slowing, most pronounced over the right hemisphere. A CT cranial scan displayed cortical and subcortical atrophy with ventricular enlargement. There were no intraparenchymal lesions.
The patient's symptoms progressed slowly and relentlessly over the following months. Six months after his presentation, he developed a right hand tremor without other abnormal movements. The patient's overall activity level slowed considerably. He became depressed and hopeless, and he once attempted suicide. Progressive gait difficulties and insomnia became problematic. He began to wander. Episodic disorientation occurred in response to some medications (e.g., lorazepam).
His last medical evaluation, 1 year after his initial presentation, revealed a normal general examination and normal blood pressure while seated (120/80). He was alert but was disoriented to time, space, and person. His attention and immediate, short-term, and remote memories were impaired. His speech was extremely slowed, and he uttered only a few simple phrases. He showed pronounced frontal lobe—type behaviors and constructive and dressing apraxia. There was no agnosia. He had prominent frontal release signs, including snout, sucking, and root reflexes. He was apathetic and disinhibited, and he continued to suffer hallucinations, paranoid delusions, and profound depression. He had marked difficulty performing activities of daily living (74%) and was considered untestable on the Blessed Dementia test. His cranial nerves were within normal limits. Motor examination showed an increased tone (1—2/4) and moderate slowness (3/4) throughout. Deep tendon reflexes (2—3/5) were normal, and plantar responses were downgoing. He had a right hand resting tremor (1/4) but no other abnormal movements. Coordination was normal. His posture was stooped, and his gait was bradykinetic, broad-based, small-stepped, and unsteady, with loss of associated movements and imbalance when turning. Sensory examination was normal.
Neuropsychological testing revealed markedly reduced verbal fluency (5 words with the letter F in 1 minute [normal>13]; 2 animals [normal>16]; 1 vegetable [normal>15]) and naming abnormalities (Boston Naming: 10/42 [normal=38/42]). His performance was impeded by his advanced aphasia and his inability to understand the instructions (e.g., patient could not perform the Raven Colored Progressive Matrices or Picture Arrangement subtest of the WAIS-R). Immediate and delayed memories were abnormal (T1). He had difficulty performing the Stroop Test (words 19 [normal 104], colors 5 [normal 66]) and was unable to perform the mixed condition.
Over the course of the following months the patient continued to deteriorate, requiring three shifts of people to care for him and supervise his activities at home. He died 20 months after his presentation to the Memory Disorders Unit.
This elderly man meets the DSM-IV criteria for dementia. His cognitive deficits consisted of impaired memory (difficulty learning new information and forgetting of previously learned information) and disturbances in executive functioning and constructive apraxia sufficiently severe to cause his retirement from his optometry practice. Although there was an early complaint of word-finding difficulties, no detailed language examination was initially performed. There was no history or examination suggestive of ideomotor apraxia (impaired ability to execute motor activities despite intact motor abilities, sensory function, and comprehension of the required task) or agnosia (failure to recognize or identify objects despite intact sensory function). There were no changes in attention suggestive of a confusional state. The presence of memory disturbances and executive dysfunction are compatible with both cortical and subcortical types of dementia. However, the memory disturbance was perhaps more severe than that typically found in patients with subcortical dementia. Moreover, patients with subcortical dementia do not exhibit language disturbances other than reduced verbal fluency and mild anomia. Additionally, the memory disturbance in subcortical dementia occurs secondary to the frontal disturbances and is not typically an initial feature. The onset of memory disturbances with the later development of other cognitive disturbances is more compatible with a diagnosis of a cortical dementia such as Alzheimer's disease (AD). The absence of focal abnormalities on the CT scan of the brain excludes a vascular or neoplastic basis for the dementia. In addition, the laboratory results eliminate systemic disorders.
Although AD is the leading cause of dementia in the elderly, there are several features that make the diagnosis of AD unlikely in this case. The presence of severe hallucinations and delusions at relatively early stages of the disease is uncharacteristic of AD. Although hallucinations and delusions occur in AD, they usually develop during the late stages of the illness unless they are secondary to a drug-induced, metabolic, or infectious delirium. This patient's history, examination, and laboratory testing do not support the presence of a confusional state. His only medication was low-dose haloperidol, which was administered to treat his psychiatric disturbances. In addition, the presence of generalized rigidity is atypical for the early stages of the AD, although the patient's increased rigidity may be a complication of low neuroleptic doses.
Although AD is commonly associated with Parkinson's disease (PD), the features of the patient's illness do not support a diagnosis of PD. Rigidity was documented in the examination, but the patient did not have bradykinesia, an essential feature for the diagnosis of parkinsonism.2 Frontotemporal dementia, another cortical dementia, is also unlikely. Patients with this disorder initially present with frontal behavioral abnormalities without prominent memory disturbances, even though memory disturbances and parkinsonism may eventually develop.3 In addition, the EEG is usually normal in patients with frontotemporal dementia. Finally, although the rapid course of the patient's dementia might suggest Creutzfeldt-Jakob disease, this disorder typically develops in months rather than years, even though occasional cases with an atypical longer evolution have been described.
Early hallucinations and delusions with generalized rigidity are most consistent with another common cortical dementia, dementia with Lewy bodies (DLB). DLB typically presents with psychiatric disturbances, visual hallucinations, paranoid delusions, frontal dementia, and extrapyramidal, mainly parkinsonian, features,4—6 all of which were prominent in the patient under discussion. Furthermore, the clinical syndrome in DLB is often rapidly progressive, similar to the course in this patient. Patients with DLB may display other clinical features, such as autonomic dysfunction, myoclonus, confusional episodes, or rapid fluctuations in symptoms without obvious precipitants. Although the patient did not show these characteristics, his course was sufficiently distinctive to make us suspect DLB as the primary diagnosis.5 Under ideal conditions the presence or absence of orthostatic hypotension would be pursued by obtaining both supine and standing blood pressure measurements after 1 and 3 minutes, and specific inquiry would have been made regarding impotence and urinary disturbances. The lack of these documented investigations makes it unclear if these conditions were truly absent. Moreover, myoclonus in DLB is usually generalized and stimulus-sensitive, and it most commonly occurs late in the course.7,8
The evolution of this patient's symptoms confirms the diagnosis of DLB.5 Over the course of less than 2 years, the patient developed clear parkinsonism, including bradykinesia, generalized rigidity, and resting tremor, that evolved very rapidly (postural instability in less than 3 years).
The progression of this patient's parkinsonism cannot be explained by the low dose of neuroleptics administered. The patient did not demonstrate neuroleptic sensitivity, a trait found in 50% to 80% of DLB patients.9,10 When patients with DLB show neuroleptic sensitivity, it is usually manifested by the development of drowsiness, parkinsonism, cognitive decline, and features of the neuroleptic malignant syndrome after the first neuroleptic doses9,10—not as slowly worsening parkinsonian and cognitive features over a 1- to 2-year period. It is possible that continuous exposure to low doses of neuroleptics prevented this patient from showing neuroleptic sensitivity, although the reaction is not usually dose related.
The patient's parkinsonism was characterized by a mildly asymmetric limb involvement and was associated with dementia at relatively early stages of the disease. These features suggest that this patient had an atypical parkinsonian disorder such as progressive supranuclear palsy (PSP) or DLB, but not PD.8 The patient did not show vertical supranuclear opthalmoplegia (i.e., difficulty moving his eyes voluntarily or in pursuit, with preserved oculocephalic reflexes), a required feature to make the diagnosis of PSP. Although rare cases of autopsy-confirmed PSP without ophthalmoplegia have been described,11,12 this patient also developed aphasia, a feature not observed in autopsy-confirmed cases with PSP. In PD, postural instability is a late feature; the parkinsonism is usually clearly asymmetric at onset and remains asymmetric, and it does not associate with dementia at early stages.
Although it is controversial whether DLB and PD represent different parts of the same disease spectrum—that of Lewy body disease—or are independent nosological entities,8 many investigators consider them separate disorders. Because patients with DLB have more rapid cognitive deterioration, more medical complications, and shorter survival than those with AD or PD,13 an accurate and early diagnosis is relevant for both therapeutic considerations and prognosis.
DLB and AD patients both benefit symptomatically from treatment with cholinergic agents,14 but DLB patients, in contrast to AD patients, are extremely sensitive to dopaminergic blockade.9,10 The underlying pathophysiologic mechanism of this sensitivity is thought to be related to a 60% to 70% reduction in dopaminergic neurons in the substantia nigra and a failure to upregulate the striatal dopamine D2 postsynaptic receptors in response to the dopaminergic deficit or to D2 antagonists. Neuroleptic sensitivity has been reported with conventional neuroleptics as well as with risperidone.9,10 Whether drugs with low D2 antagonism are the most appropriate antipsychotics in these patients is a question needing further investigation. To date, clozapine, which has a low D2 antagonism, does not appear to induce a neuroleptic malignant syndrome or worsen the parkinsonian features, but it does increase confusion and worsen behavioral symptoms.15 Neuroleptics should be avoided or used with extreme caution in this patient population.
Examination of the lungs at autopsy revealed bronchopneumonia with pulmonary hemorrhage of the right and left lower lobes. The brain weighed 1,220 grams and displayed mild diffuse atrophy that was slightly more prominent in the frontal regions. The leptomeninges were mildly fibrotic and the falx cerebri was focally ossified. The cranial nerves were unremarkable. The major cerebral arteries showed focal nonocclusive atherosclerosis at their bifurcation points, without distal extension into the sylvian and interhemispheric fissures. Coronal sections of the cerebral hemispheres revealed unremarkable white matter. The frontal horns of the lateral ventricles were mildly enlarged bilaterally. The hippocampus, amygdala, and entorhinal cortex were slightly smaller than normal. The deep gray matter structures were normal. The substantia nigra and locus ceruleus were mildly depigmented. The remainder of the brainstem, cerebellum, and upper cervical spinal cord appeared normal. No parenchymal vascular lesions or other focal abnormalities were present.
Microscopic examination of 24 brain regions stained with Luxol fast blue hematoxylin and eosin and Bielschowsky silver impregnation disclosed numerous Lewy bodies in the neuromelanin-containing neurons of the substantia nigra pars compacta. The Lewy bodies were distinctly eosinophilic, typically round, and ranged in size from 5 to 15 μm. Frequently, multiple Lewy bodies were found within a single neuron. In addition, there was mild to moderate neuronal loss, fibrillary astrocytosis, pigment phagocytosis by macrophages, and spheroid formation. Lewy bodies of similar appearance were found in the raphe nuclei and locus ceruleus.
In many neurons of the cerebral cortex, the cytoplasm was distorted by an ill-defined, usually round, eosinophilic Lewy body lacking a peripheral halo. Lewy body—containing neurons were most commonly found in the 5th cortical layer of the cingulate, inferior frontal, inferior parietal, and temporal cortices. In addition, Lewy bodies were abundant in the amygdala, entorhinal cortex, and pyramidal neurons of the hippocampus.
The cerebral cortex was mildly gliotic and contained scattered senile plaques at a density less than 10 per 200× field. The plaques varied from mature neuritic to diffuse plaques, with the latter predominating. Neurofibrillary tangles were rare and were limited to the hippocampus, amygdala, and entorhinal cortex. No neurofibrillary tangles were identified in the cerebral neocortex. In the temporal cortex, there was a striking spongiform change affecting all cortical layers. Gliosis was prominent in the amygdala. There was no evidence of cerebral amyloid angiopathy.
The presence of abundant Lewy bodies in the brainstem and the entorhinal, cingulate, temporal, frontal, and parietal cortices satisfies the essential criteria for the pathologic diagnosis of DLB, neocortical subtype, using the consensus criteria established by the Dementia with Lewy Bodies International Workshop.5 Another pathological feature typically found in DLB is the microvacuolation or spongiform change of the temporal cortex as seen in the case under discussion. Even though the change is similar in appearance to the spongiform change that occurs in Creutzfeldt-Jakob disease, there is no evidence that DLB is a transmissible disorder or is related to prion protein abnormalities. Many cases of DLB have some degree of Alzheimer-related pathology, so much so that some investigators consider DLB a variant of AD; most investigators commonly diagnose the combined condition, DLB plus AD. Although the case under discussion has a small number of neocortical diffuse plaques and a rare archicortical neurofibrillary tangle, the magnitude of these changes is not sufficient to warrant an additional diagnosis of AD. Thus, the case under discussion represents a case of "pure" DLB.
Over the past decade, and most notably in the past two years, great advances in the detection of Lewy bodies have been made through the use of immunohistochemical methods and antibodies to ubiquitin and α-synuclein.16—19 These techniques have markedly improved detection of Lewy bodies: recent neuropathological autopsy studies have found Lewy bodies in the brainstem and cortex of 15% to 25% of elderly demented patients, making DLB the most common pathological subgroup after pure AD.5
Lewy bodies vary in morphology depending on their location within the brain. Typical "brainstem" Lewy bodies are distinct, rounded intraneuronal inclusions with a clear peripheral halo that are found characteristically in the substantia nigra pars compacta, raphe nuclei, locus ceruleus, nucleus basalis of Meynert, thalamus, hypothalamus, and autonomic nervous system (F1 and F1). "Cortical" Lewy bodies are less discrete rounded inclusions typically found in small to medium-sized neurons of the transentorhinal, cingulate, insular, and frontotemporal cortices (F2 and F2). Immunohistochemical studies have consistently shown that the main components of Lewy bodies are neurofilament proteins, particularly the medium-weight neurofilament protein,20 ubiquitin,16,17,21 and the newly described α-synuclein.18,19 Furthermore, recent immunohistochemical studies show that in addition to the intraneuronal Lewy body, there is a wide array of abnormal ubiquitin and α-synuclein positive neurites throughout the brain in DLB, analogous to the widespread abnormalities of tau protein in AD22 (F3).
Alpha-synuclein is an abundant, highly conserved protein that is localized to axons and synapses of the normal human brain.23 Although the function of α-synuclein remains unknown, molecular experiments with song learning in the zebra finch indicate that it plays a role in neuronal plasticity.24 Furthermore, a fragment of the protein is found in senile plaques of brains affected by AD.25 Recently α-synuclein mutations were reported in 5 independent families with PD,26—28 although other reports suggest that these mutations are rare as a cause of familial PD.29,30 Determining the function of α-synuclein in normal human neurons, what effects are produced by mutations in the α-synuclein gene, and what triggers the dislocation and aggregation of α-synuclein into Lewy bodies—the unique intraneuronal inclusions that define PD and DLB—will be critical to developing future strategies for the early antemortem detection of these disorders and therapeutic approaches to ameliorate their progression.