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Regular Article   |    
Psychiatric Symptoms Associated With Cortical-Subcortical Dysfunction in Alzheimer's Disease
Oscar L. Lopez, M.D.; Saša Živković, M.D.; Gwenn Smith, Ph.D.; James T. Becker, Ph.D.; Carolyn Cidis Meltzer, M.D.; Steven T. DeKosky, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2001;13:56-60. doi:10.1176/appi.neuropsych.13.1.56
View Author and Article Information

Alzheimer's DiseaseApathyDepressionPET Studies

Received September 15, 1999; revised February 7, 2000; accepted March 24, 2000. From the Alzheimer's Disease Research Center, and Departments of Neurology, Psychiatry, and Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Address correspondence to Dr. Lopez, Neuropsychology Research Program, 3501 Forbes Avenue, Suite 830, Pittsburgh, PA 15213.

Positron emission tomography was used to evaluate 3 Alzheimer's disease (AD) patients: 1 with major depression, 1 with emotional lability, and 1 with apathy. Compared with 5 non—mood-disordered AD patients, the patient with depression had diminished relative regional cerebral blood flow (rel-CBF) in the anterior cingulate and superior temporal cortices, bilaterally. This patient also showed diminished rel-CBF in the left dorsolateral prefrontal and right medial temporal and parietal cortices. The patient with emotional lability had diminished rel-CBF in the anterior cingulate and dorsolateral prefrontal cortices, bilaterally, and left basal ganglia. The patient with apathy had diminished rel-CBF in the basal ganglia and dorsolateral prefrontal cortex, bilaterally. Results are consistent with the hypothesis of a common frontal-temporal-subcortical substrate (e.g., involving aminergic nuclei) in the etiology of depression in AD. Frontal-subcortical dysfunction may also be associated with emotional lability and apathy in AD, although these may be related to a greater involvement of frontal—basal ganglia circuits.

Abstract Teaser
Figures in this Article

N;t4>europathological and neuroimaging data indicate that disruption of frontal-subcortical circuits is critical for the development of affective and behavioral symptoms in individuals with and without dementia.1 Positron emission tomography (PET) studies have shown that individuals with idiopathic depression have diminished glucose metabolism in the prefrontal cortex and caudate nuclei,2 and that depressed Huntington's disease and Parkinson's disease patients have diminished metabolism in the orbitofrontal cortex compared with control subjects.3,4 More recent studies conducted in elderly individuals with major depression have shown decreased (absolute) regional cerebral blood flow in the left anterior cingulate and left dorsolateral prefrontal cortex.5 Furthermore, magnetic resonance imaging volumetric studies in elderly individuals have shown that minor depression is associated with smaller prefrontal volume6 and major depression is associated with reduced frontal and temporal lobe volumes.7 Damage to frontal-subcortical circuits may be a common substrate for affective disorders in late-life mood disorders,7 and perhaps in other neurological diseases as well (e.g., Huntington's disease, Parkinson's disease).

Neuropathological studies in AD patients with depression have shown a greater neuronal loss in the central superior raphe nucleus, locus ceruleus, and substantia nigra than found in AD patients without depression.8,9 However, single-photon emission computed tomography (SPECT) studies have shown that AD patients with depression have lower left temporoparietal blood flow than those without depression,10 and PET studies have found lower metabolism in parietal lobes11 or in the anterior cingulate gyrus.12

Emotional lability, described as episodes of crying that cannot be suppressed, has been reported in 10%13 to 25%14 of AD patients. AD patients with emotional lability have more depression, anxiety, and dysthymia than those without.14 In addition, there is a greater subcortical atrophy in patients with affective pathological crying, which may indicate a greater frontal-subcortical dysfunction.14

Apathy, described as a lack of energy and anhedonia with or without depressed moods, has been reported in AD patients,15 and SPECT studies have shown that AD patients with apathy have lower blood flow in the right temporal-parietal area16 or frontal areas.17,18 However, apathy appears to be more common in subcortical syndromes (e.g., Parkinson's disease, progressive supranuclear palsy).19,20

In this study we examined the hypothesis that depression, emotional lability, and apathy in AD patients are associated with cortical-subcortical dysfunction.

We reviewed the psychiatric characteristics of 8 patients with the diagnosis of probable AD21 who were participating in a longitudinal study of dementia at the University of Pittsburgh Alzheimer's Disease Research Center and who had completed a PET scan. Each patient underwent an extensive evaluation, including medical, neurological, psychiatric, social work/nursing, and neuropsychological evaluations, as previously described.22 None of the patients had significant signs of cerebrovascular disease, and those with a score greater than 4 on the Hachinski Rating Scale23 or evidence of possible infarction on neuroimaging studies (either CT or MR scan) were not included in this study.

We first examined the relative regional cerebral blood flow (rel-CBF) of the 8 AD patients and 9 nondemented elderly control subjects to determine specific differences between groups (t1). None of the nondemented control subjects had experienced any psychiatric illness or were taking psychiatric medication. Second, the rel-CBF values of the 3 AD patients with mood disorders (1 with major depression, 1 with emotional lability, and 1 with apathy) were compared with those of 5 AD patients without major depression, emotional lability, apathy, psychosis, or mood-related disorders who were matched by education level and severity of dementia as measured by the Mini-Mental State Examination (MMSE).24 All 3 patients were experiencing these symptoms at the time of the PET scan session, and none of them were taking psychotropic medication.

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Psychiatric Assessment

The psychiatric evaluations were conducted by board-certified psychiatrists using a semistructured interview25 with both patients and primary caregivers. The Hamilton Rating Scale for Depression26 interview was completed by the psychiatrists on the basis of data from each patient and primary caregiver. The diagnosis of major depression was made according to the DSM-IV criteria.27 Lability of mood was considered to be present when patients developed a sudden onset of laughing or crying that they were unable to suppress and that was associated with altered moods. We differentiated emotional lability from pathological laughing or crying when these symptoms occurred without alteration of the mood.

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Positron Emission Tomography

Subjects were scanned in a Siemens 951R/31 PET scanner. At the end of the transmission scan, 40—50 mCi of [15O]-water was injected as an intravenous bolus to measure rel-CBF. Data acquisition began 30 seconds after [15O]-water injection. The actual rel-CBF values were calculated from the [15O]-water time activity data by using a standard compartment model with correction for dispersion and timing delays in the blood activity curve.28 The rel-CBF was examined in 9 regions of interest (ROIs): orbitofrontal, anterior cingulate, frontal dorsolateral, superior temporal, middle temporal, parietal, occipital, basal ganglia, and thalamus. The rel-CBF data for each ROI were normalized to the whole brain activity by computing an average of all of the ROIs and dividing each ROI by this denominator. The patients' MR scans and a neuroanatomy atlas29 were used to identify the ROIs. The MR images were not digitally coregistered to the PET images, but they were used to visually guide the identification of the ROIs.

Nondemented control subjects showed higher rel-CBF in the left dorsolateral prefrontal cortex, right superior temporal, and right and left parietal cortex than AD patients. The MMSE24 and Mattis Dementia Rating Scale30 scores were higher in nondemented control subjects than in AD patients (see t1).

All AD subjects had at least 12 years of education. The patients were matched to their non—mood-disordered control subjects by age and MMSE24 scores, but the patients with emotional lability and apathy were older than the AD control subjects. The demographic characteristics of the patients are shown in t2.

The rel-CBF comparisons between the two AD patient groups are shown in t3. The patient with major depression had decreased rel-CBF in the anterior cingulate and superior temporal, bilaterally, as well as in the left dorsolateral prefrontal, right middle temporal, and right parietal cortices. The patient with emotional lability showed decreased rel-CBF in the anterior cingulate and dorsolateral prefrontal cortices, bilaterally, and in the left basal ganglia. The patient with apathy had decreased rel-CBF in the basal ganglia and the dorsolateral prefrontal cortex, bilaterally.

All three patients showed increased rel-CBF in occipital areas. In addition, the patient with depression showed increased rel-CBF in the thalamus; and the patient with apathy showed increased rel-CBF in the right middle temporal area (see t3). These results are a consequence of normalizing the data relative to the whole brain, which accentuated the relatively higher rel-CBF found in these regions.

These findings support the hypothesis that a frontal-subcortical abnormality is associated with depression in dementia. It has been suggested that damage to the dorsolateral and orbitofrontal cortex serves as a common anatomic substrate in primary and secondary mood disorders in psychiatric and neurological disease. In this study, we examined the role of cortical-subcortical circuits in the etiology of depression, emotional lability, and apathy in patients with AD—where the primary site of abnormality is "cortical," with subsequent subcortical involvement due to deafferentation.

The anterior cingulate abnormality in the depressed patient is consistent with abnormalities found in recent PET studies conducted in elderly nondemented individuals with major depression.5 The presence of depression was also associated with bilateral temporal lobe hypoperfusion, which suggests the possibility of more widespread compromise of limbic structures. Indeed, nondemented untreated depressed subjects can have altered amygdala activity31 and diminished temporal lobes and amygdalar cerebral blood flow.32

The patient with emotional lability showed decreased rel-CBF in anterior cingulate cortex and basal ganglia. This finding is related to the fact that AD patients with pathological affect have more atrophy of caudate nucleus than AD patients without these symptoms.14 Furthermore, the patient with apathy showed a diminished rel-CBF in the right dorsolateral prefrontal cortex and basal ganglia. Studies of AD and Parkinson's disease patients have shown that the presence of apathy is associated with frontal lobe dysfunction.15,17,18 Interestingly, in stroke patients frontal and temporal lobe hypoperfusion was associated with apathy when the latter occurred with symptoms of major depression.33

Although this is a small case series, these data add to the growing evidence that specific mood-related disorders in AD patients, like those in nondemented subjects, are associated with a mesolimbic system dysfunction. Specifically, there is dysfunction of the prefrontal and temporal cortices, with a subsequent involvement of their afferent and efferent connections to the ventral tegmental area, substantia nigra, and ventral striatum (ventromedial caudate and nucleus accumbens), areas that appear to mediate motivation and affect.34

This study was funded by Grants AG03705 and AG05133 from the National Institute on Aging and Grants MH57078, MH49936, and MH01621 from the National Institute of Mental Health. J.T.B. is recipient of the Research Scientist Development Award, Level II (K02-MH01077).

 
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 1. Relative regional cerebral blood flow in Alzheimer's disease (AD) patients and nondemented control subjects
 
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 2. Demographic and neuropsychiatric characteristics of AD patients with and without mood disorders
 
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 3. Relative regional cerebral blood flow (rel-CBF) in Alzheimer's disease patients with and without mood disorders
Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol  1993; 50:873—880
[PubMed]
 
Baxter LR, Phelps ME, Mazziotta JC, et al: Cerebral metabolic rates for glucose in mood disorders: studies with positron emission tomography and fluorodeoxyglucose F18. Arch Gen Psychiatry  1985; 42:441—447
[PubMed]
 
Mayberg HS, Starkstein SE, Peyser CE, et al: Paralimbic frontal lobe hypometabolism in the inferior frontal lobe in depression associated with Huntington's disease. Neurology 1992; 42:1791—  1797
 
Mayberg HS, Starkstein SE, Sadzot B: Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease. Ann Neurol  1990; 28:57—64
[CrossRef] | [PubMed]
 
Bench CJ, Friston KJ, Brown RG, et al: Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med  1993; 23:579—590
[CrossRef] | [PubMed]
 
Kumar A, Schweizer E, Zhisong J, et al: Neuroanatomical substrates of late-life minor depression. Arch Neurol  1997; 54:613— 617
[PubMed]
 
Kumar A, Miller D: Neuroimaging in late-life mood disorders. Clin Neurosci  1997; 4:8—15
[PubMed]
 
Zubenko G, Moossy J: Major depression in primary dementia: clinical and neuropathological correlates. Arch Neurol 1988; 45:1182—  1186
 
Zweig R, Ross C, Hedreen JC: The neuropathology of aminergic nuclei in Alzheimer's disease. Ann Neurol  1988; 24:233—242
[CrossRef] | [PubMed]
 
Starkstein SE, Vazquez S, Migliorelli R, et al: A SPECT study of depression in Alzheimer's disease. Neuropsychiatry Neuro-psychol Behav Neurol  1995; 8:38—43
 
Sultzer DL, Mahler ME, Mandelkern MA, et al: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease. J Neuropsychiatry Clin Neurosci  1995; 7:476—484
[PubMed]
 
Hirono N, Mori E, Ishii K, et al: Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology  1998; 50:380— 383
[PubMed]
 
Lopez OL, Gonzalez MP, Becker JT, et al: Symptoms of depression and psychosis in Alzheimer's disease and frontotemporal dementia. Neuropsychiatry Neuropsychol Behav Neurol  1996; 9:154—161
 
Starkstein SE, Migliorelli R, Teson A, et al: Prevalence and clinical correlates of pathological affective display in Alzheimer's disease. Journal of Neurol Neurosurg Psychiatry  1995; 59:55—60
[CrossRef]
 
Kuzis G, Sabe L, Tiberti C, et al: Neuropsychiatric correlates of apathy and depression in patients with dementia. Neurology 1999; 52:1403—  1407
 
Ott BR, Noto RB, Fogel BS: Apathy and loss of insight in Alzheimer's disease: a SPECT imaging study. J Neuropsychiatry Clin Neurosci  1996; 8:41—46
[PubMed]
 
Craig AH, Cummings JL, Fairbanks L, et al: Cerebral blood flow correlates of apathy in Alzheimer's disease. Arch Neurol 1996; 53:1116—  1120
 
Benoit M, Oygai I, Migneco O, et al: Behavioral and psychological symptoms in Alzheimer's disease: relation between apathy and regional cerebral perfusion. Dement Geriatr Cogn Disorder  1999; 6:511—517
 
Starkstein SE, Mayberg HS, Preziosi TJ, et al: Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci  1992; 4:134—139
[PubMed]
 
Litvan I, Mega MS, Cummings JL, et al: Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 1996; 47:1184—  1189
 
McKhann G, Drachman DA, Folstein MF, et al: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology  1984; 34:939—944
[PubMed]
 
Lopez OL, Larumbe MR, Becker JT, et al: Reliability of NINDS-AIREN criteria for vascular dementia. Neurology 1994; 44:1240— 1  1245
 
Hachinski VC, Iliff LD, Zihka E, et al: Cerebral blood flow in dementia. Arch Neurol  1975; 32:632—637
[PubMed]
 
Folstein MF, Folstein SE, McHugh PR: "Mini-Mental State": a practical method grading the cognitive state of patients for the clinician. Psychiatry Res  1975; 12:189—198
[CrossRef]
 
Mezzich JE, Dow JT, Cottman GA: Developing an information system for a comprehensive psychiatric institute, I: principles, design, and organization. Behavior Research Methods and Instrumentation  1981; 13:459—463
[CrossRef]
 
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry  1960; 23:56—62
[CrossRef] | [PubMed]
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Quarles R, Mintun M, Larson K, et al: Measurement of regional cerebral blood flow with positron emission tomography. J Cereb Blood Flow Metab  1994; 13:733—747
 
Talairach J, Tournoux P: Co-Planar Stereotaxic Atlas of the Human Brain. New York, Thieme Medical, 1988
 
Mattis S: Mental status examination for organic mental syndrome in the elderly patient, in Geriatric Psychiatry, edited by Bellak L, Karuso TB. New York, Grune and Stratton, 1976
 
Post RM: Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992; 149:999—  1010
 
George MS, Ketter TA, Post RM: SPECT and PET imaging in mood disorders. J Clin Psychiatry 1993; 54(suppl):6—13
 
Okada K, Kobayashi S, Yamagata S, et al: Poststroke apathy and regional cerebral blood flow. Stroke 1997; 28:2437—  2441
 
Swerdlow NR, Koob GF: Dopamine schizophrenia, mania and depression: toward a unified hypothesis of cortico-striato-pallido-thalamic function. Behav Brain Sci  1987; 10:197
[CrossRef]
 
Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and senile changes in the cerebral white matter of elderly subjects. Br J Psychiatry  1968; 114:797—811
[CrossRef] | [PubMed]
 
Hoehn M, Yahr M: Parkinsonism: onset, progression, and mortality. Neurology  1967; 17:427—442
[PubMed]
 
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 1. Relative regional cerebral blood flow in Alzheimer's disease (AD) patients and nondemented control subjects
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 2. Demographic and neuropsychiatric characteristics of AD patients with and without mood disorders
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 3. Relative regional cerebral blood flow (rel-CBF) in Alzheimer's disease patients with and without mood disorders
+

References

Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol  1993; 50:873—880
[PubMed]
 
Baxter LR, Phelps ME, Mazziotta JC, et al: Cerebral metabolic rates for glucose in mood disorders: studies with positron emission tomography and fluorodeoxyglucose F18. Arch Gen Psychiatry  1985; 42:441—447
[PubMed]
 
Mayberg HS, Starkstein SE, Peyser CE, et al: Paralimbic frontal lobe hypometabolism in the inferior frontal lobe in depression associated with Huntington's disease. Neurology 1992; 42:1791—  1797
 
Mayberg HS, Starkstein SE, Sadzot B: Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease. Ann Neurol  1990; 28:57—64
[CrossRef] | [PubMed]
 
Bench CJ, Friston KJ, Brown RG, et al: Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med  1993; 23:579—590
[CrossRef] | [PubMed]
 
Kumar A, Schweizer E, Zhisong J, et al: Neuroanatomical substrates of late-life minor depression. Arch Neurol  1997; 54:613— 617
[PubMed]
 
Kumar A, Miller D: Neuroimaging in late-life mood disorders. Clin Neurosci  1997; 4:8—15
[PubMed]
 
Zubenko G, Moossy J: Major depression in primary dementia: clinical and neuropathological correlates. Arch Neurol 1988; 45:1182—  1186
 
Zweig R, Ross C, Hedreen JC: The neuropathology of aminergic nuclei in Alzheimer's disease. Ann Neurol  1988; 24:233—242
[CrossRef] | [PubMed]
 
Starkstein SE, Vazquez S, Migliorelli R, et al: A SPECT study of depression in Alzheimer's disease. Neuropsychiatry Neuro-psychol Behav Neurol  1995; 8:38—43
 
Sultzer DL, Mahler ME, Mandelkern MA, et al: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease. J Neuropsychiatry Clin Neurosci  1995; 7:476—484
[PubMed]
 
Hirono N, Mori E, Ishii K, et al: Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology  1998; 50:380— 383
[PubMed]
 
Lopez OL, Gonzalez MP, Becker JT, et al: Symptoms of depression and psychosis in Alzheimer's disease and frontotemporal dementia. Neuropsychiatry Neuropsychol Behav Neurol  1996; 9:154—161
 
Starkstein SE, Migliorelli R, Teson A, et al: Prevalence and clinical correlates of pathological affective display in Alzheimer's disease. Journal of Neurol Neurosurg Psychiatry  1995; 59:55—60
[CrossRef]
 
Kuzis G, Sabe L, Tiberti C, et al: Neuropsychiatric correlates of apathy and depression in patients with dementia. Neurology 1999; 52:1403—  1407
 
Ott BR, Noto RB, Fogel BS: Apathy and loss of insight in Alzheimer's disease: a SPECT imaging study. J Neuropsychiatry Clin Neurosci  1996; 8:41—46
[PubMed]
 
Craig AH, Cummings JL, Fairbanks L, et al: Cerebral blood flow correlates of apathy in Alzheimer's disease. Arch Neurol 1996; 53:1116—  1120
 
Benoit M, Oygai I, Migneco O, et al: Behavioral and psychological symptoms in Alzheimer's disease: relation between apathy and regional cerebral perfusion. Dement Geriatr Cogn Disorder  1999; 6:511—517
 
Starkstein SE, Mayberg HS, Preziosi TJ, et al: Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci  1992; 4:134—139
[PubMed]
 
Litvan I, Mega MS, Cummings JL, et al: Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 1996; 47:1184—  1189
 
McKhann G, Drachman DA, Folstein MF, et al: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology  1984; 34:939—944
[PubMed]
 
Lopez OL, Larumbe MR, Becker JT, et al: Reliability of NINDS-AIREN criteria for vascular dementia. Neurology 1994; 44:1240— 1  1245
 
Hachinski VC, Iliff LD, Zihka E, et al: Cerebral blood flow in dementia. Arch Neurol  1975; 32:632—637
[PubMed]
 
Folstein MF, Folstein SE, McHugh PR: "Mini-Mental State": a practical method grading the cognitive state of patients for the clinician. Psychiatry Res  1975; 12:189—198
[CrossRef]
 
Mezzich JE, Dow JT, Cottman GA: Developing an information system for a comprehensive psychiatric institute, I: principles, design, and organization. Behavior Research Methods and Instrumentation  1981; 13:459—463
[CrossRef]
 
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry  1960; 23:56—62
[CrossRef] | [PubMed]
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Quarles R, Mintun M, Larson K, et al: Measurement of regional cerebral blood flow with positron emission tomography. J Cereb Blood Flow Metab  1994; 13:733—747
 
Talairach J, Tournoux P: Co-Planar Stereotaxic Atlas of the Human Brain. New York, Thieme Medical, 1988
 
Mattis S: Mental status examination for organic mental syndrome in the elderly patient, in Geriatric Psychiatry, edited by Bellak L, Karuso TB. New York, Grune and Stratton, 1976
 
Post RM: Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992; 149:999—  1010
 
George MS, Ketter TA, Post RM: SPECT and PET imaging in mood disorders. J Clin Psychiatry 1993; 54(suppl):6—13
 
Okada K, Kobayashi S, Yamagata S, et al: Poststroke apathy and regional cerebral blood flow. Stroke 1997; 28:2437—  2441
 
Swerdlow NR, Koob GF: Dopamine schizophrenia, mania and depression: toward a unified hypothesis of cortico-striato-pallido-thalamic function. Behav Brain Sci  1987; 10:197
[CrossRef]
 
Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and senile changes in the cerebral white matter of elderly subjects. Br J Psychiatry  1968; 114:797—811
[CrossRef] | [PubMed]
 
Hoehn M, Yahr M: Parkinsonism: onset, progression, and mortality. Neurology  1967; 17:427—442
[PubMed]
 
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