INTRODUCTION

 

There is growing evidence that the motor dysfunction in patients with PD is just the tip of the iceberg of the multifaceted and complex disorder. Cognitive impairment (CI) was considered one of the most common non-motor complications in PD and it was found to be associated with significant disability for patients and burden for caregivers. Similar to motor symptoms, the characteristics of CI in PD can be quite variable, both in terms of impaired cognitive domains, and the timing of onset and rate of progression. Cognitive impairment in PD includes mild cognitive impairment (MCI), cognitive impairment (CIND) and Parkinson’s disease dementia (PDD)¹

Cognitive impairment in PD was found to be present even in the earlier stages of PD but it may be asymptomatic and can be detected only with specific neuropsychological tests² Mild deterioration of such subclinical cognitive dysfunction can occur in 20-25% of PD patients producing MCI³. Four-year follow-up

 

study of PD- MCI patients found that 62% of these patients progressed to PDD. The cognitive changes in PD are characterized by a frontal-subcortical impairment in which there is decreased attention and executive function with associated impairment in visuospatial skills and memory⁴.

The microstructural changes in cerebral grey and white matter were recently explored as being one of the radiological biomarkers for cognitive impairment in PD. DTI plays an important role in highlighting the cerebral microstructural damage not visible when conventional sequences are used.  The most DTI metrics used are mean diffusivity (MD), which measures overall water motion without any directionality, and fractional anisotropy (FA), which reflects the prevalence of diffusivity along one direction. MD is a quantitative metric of water diffusion; the higher the MD value, the higher the diffusivity. FA is a scalar value ranging from zero to one that is highest in compact WM tracts, decreases in the GM, and approaches zero in the CSF. Anisotropy was correlated to axon density and myelin content, while diffusivity was correlated mainly to the amount of myelin. However, both MD and FA have more recently been shown to be affected mainly by myelin content and, to a lesser extent, by axonal density.⁵

In a DTI study on patients with PD it was found that there was decreased FA in the frontal lobe, including the medial frontal, cingulate (anterior and posterior), and dorsolateral prefrontal cortex⁶.

Concerning cognitive function, it has been found that there was a significant FA reduction in the frontal, temporal, and occipital white matter in both PD patients with dementia (PDD) and PD patients with no dementia (PD-ND) compared with controls. In this study, PDD subjects showed a significant FA reduction in the bilateral posterior cingulate bundles compared to PD-ND subjects that was correlated with global cognition and memory function⁷.

 

Aim of work

      To explore the cognitive profile of patients with Parkinson's disease and to correlate the microstructural changes in cerebral grey and white matter assessed by DTI, with the cognitive pattern in PD.

 

PATIENTS AND METHODS

 

Study design and population: This is a case-control study carried out on 40 patients with idiopathic Parkinson’s disease and 20 normal controls matched for age, sex and level of education. They were recruited in the period between December 2012 and October 2013 from the Neurology Outpatient Clinics of Kasr El Aini Hospital and Bani-Suef University Hospital.

Inclusion criteria: 40 patients fulfilled the criteria for diagnosis of idiopathic Parkinson's disease based on British Brain Bank criteria⁸. Selected patients had a score ˃ 24 on Mini-mental state examination (MMSE) ⁹ and had the ability to read, write and do simple calculations.

Exclusion criteria: Patients with major language disturbance, severe physical, auditory or visual impairment affecting their ability to complete testing, patients with secondary or atypical parkinsonism, patients with evidence of concomitant cerebrovascular stroke temporally related to the onset of the disease or the cognitive impairment, patients with concomitant medical, metabolic illness or major psychiatric disorder known to affect cognition, patients with marked tremor interfering with the imaging session, patients with MRI brain showing structural lesion and patients with contraindications for MRI examination.

Methods: The cognitive function of the PD patients and controls were assessed using Parkinson’s Disease - Cognitive Rating Scale (PD-CRS) that covers the full spectrum of cognitive deficits associated with PD including: attention, episodic memory (immediate and delayed recall), naming, visuospatial abilities (visuoconstructional  and visuoperceptual abilities) and executive function (working memory, action verbal fluency and alternating verbal fluency).¹⁰

 

Brain imaging:

Diffusion tensor imaging (DTI): It was performed for all PD patients included in the study. Technique was performed using a standard 1.5 Tesla unit. A standard head coil was used. Patient position is supine. The sequences obtained were axial, sagittal and coronal T1W, T2W, FLAIR and diffusion tensor, which consisted of a single shot, spin-echo echo planar sequence in 25 encoding directions and a diffusion-weighting factor of 800 s/mm2. Other parameters include T1WI: TR 450, TE 15, matrix 80 x 81, FOV 230 X177, slice thickness 5 mm, T2WI: TR 3612, TE 100, matrix 208 x 127, FOV 230 X 177, slice thickness 5 mm, FLAIR : TR 6000, TE 120, matrix 240 x 111, FOV 230 X 184, slice thickness 5 mm and DTI :  TR 10951, TE 67, matrix 128 x128, FOV 224 X 224 mm, number of excitations 2, slice thickness: 2.0/00 and flip angle 90 (degrees). All the diffusion-weighted images were transferred to the workstation supplied by the manufacturer. Images were post-processed using the Philips software.  The maps obtained were FA 2D grey maps, directionally encoded color FA maps and fused FLAIR/DTI maps. Fractional anisotropy (FA) was measured (through application of multiple color-coded regions of interest (ROI)) in the following structures (in the contralateral side to the side of motor onset): caudate, putamen, globus pallidus (GP), thalamus, substantia nigra (SN), hippocampus, and prefrontal white matter.

 

Statistical Methods

The data were coded and entered using: the statistical package for social science version 15 (SPSS v 15). Student t- test was used for comparison between means of two groups of quantitative variables. Chi square test was used for comparison between two groups of categorical data or frequency of events. The Pearson correlation coefficient (r) was used to describe the degree of relationship between two variables. The sign of correlation coefficient (+, -) defines the direction of the relationship, either positive or negative. The probability/significance value (P value) ≥ 0.05 is not statistically significant and <0.05 is statistically significant.

RESULTS

 

The current study is a case controls study conducted on 40 patients diagnosed as having Parkinson’s disease and 20 normal healthy controls. The mean age of PD patients was 59.85±7.51 years, while the mean age of controls was 56.35±5.07 years. 60% (n=24) of the included PD patients were males with a male: female ratio = 1.5:1. Regarding controls, 55% (n=11) were males with a male: female ratio = 1.22:1. The years of education for PD patients ranged from 2-16 years with a mean value of 7.5 (SD=4.9) years, and the years of education for controls ranged also from 2-16 years but with a mean value of 9.6(SD=4.86) years (Table 1).

PD patients were classified also according to PD-MCI diagnostic criteria proposed by Movement Disorders Society (MDS) Task Force¹¹ into patients having pre clinical cognitive impairment (pre clinical CI) [n=23 (57.5%)] and patient having clinical cognitive impairment (MCI) (clinical CI) [n=17 (42.5%)].

The cognitive function of PD patients and controls were assessed using Parkinson’s disease - Cognitive Rating Scale (PD-CRS). PD patients were found to have significantly lower scores than controls in attention, working memory, immediate recall, delayed recall, naming, visuoperceptual abilities, visuoconstructional abilities, action verbal fluency, alternating verbal fluency and the total score (Table 2).

Comparison between PD patients with clinical CI and those with pre clinical CI revealed that PD patients with clinical CI have significantly lower scores than those with pre clinical CI in the scores of the examined cognitive subsets except naming (Table 3). On comparing PD patients with pre clinical CI to controls, PD patients with pre clinical CI were found to have significantly lower scores than controls in working memory and action verbal fluency only.

Diffusion tensor imaging was done for all PD patients included in this study. FA was measured in the contralateral side to the side of onset of the motor symptoms in the following regions: thalamus [mean=0.395 (SD=0.124)], globus pallidus [mean=0.375 (SD=0.141)], putamen [mean=0.416 (SD=0.165)], caudate [mean=0.411 (SD=0.164)], substantia nigra [mean=0.497 (SD=0.194)], hippocampus [mean=0.318 (SD=0.135)] and prefrontal region [mean=0.462 (SD=0.182)] (Table 4).

PD patients with clinical CI were found to have significantly lower FA than those with pre clinical CI in thalamus, GP, putamen, caudate and prefrontal region, but there was no statistically significant difference between PD patients with clinical CI and those with pre clinical CI in FA in SN or hippocampus (Table 5).

There was a statistically significant positive correlation between FA in thalamus and the scores of attention, working memory, immediate recall, delayed recall, alternating verbal fluency, action verbal fluency and the total score. There was a statistically significant positive correlation between FA in GP and the scores of attention, working memory, alternating verbal fluency, action verbal fluency and the total score. On the other hand, there was a statistically significant positive correlation between FA in putamen and the scores of immediate recall and delayed recall only. There was a statistically significant positive correlation between FA in caudate and the scores of attention, working memory, alternating verbal fluency, action verbal fluency and the total score. Lastly, there was no statistically significant correlation between FA in SN and the scores of the examined cognitive subsets (Table 6).

There was a statistically significant positive correlation between FA in hippocampus and the scores of immediate recall and delayed recall only. On the other hand, There was a statistically significant positive correlation between FA in prefrontal region and the scores of attention, working memory, immediate recall, delayed recall, alternating verbal fluency, action verbal fluency and the total score, but there was no statistically significant correlation between FA in prefrontal region and the scores of naming, visuoperceptual abilities, or visuoconstructional abilities (Table 7).

 

 

Table 1. Demographics of PD patients and controls.

 

		Patients (n=40)	Controls (n=20)	P-value
Age [mean (SD)]		59.85 (7.51)	56.35 (5.07)	0.065
Sex	Male [n (%)]	24 (60%)	11 (55%)	0.711
	Female [n (%)]	16 (40%)	9 (45%)
Years of education [mean (SD)]		7.5 (4.9)	9.6 (4.86)	0.122

 

Table 2. Comparison between PD patients and controls in the psychometric tests.

 

	PD patients (n=40) Mean (SD)	Controls (n=20) Mean (SD)	P-value
Attention	5.08 (2.04)	6.55 (1.32)	0.005**
Working memory	4.35 (1.99)	6.35 (1.53)	< 0.001**
Immediate recall	5.53 (1.6)	6.45 (1.1)	0.024*
Delayed recall	3.75 (1.52)	4.6 (0.75)	0.022*
Naming	16.05 (2.16)	17.25 (1.45)	0.029*
Visuoperceptual	7.8 (1.73)	8.7 (1.08)	0.038*
Visuoconstructional	6.45 (1.63)	7.45 (1.05)	0.017*
Alternating verbal fluency	6.5 (1.9)	8.25 (1.45)	0.001**
Action verbal fluency	12.18 (3.09)	15.8 (3.14)	< 0.001**
Total score	67.88 (13.64)	81.4 (8.54)	< 0.001**

*Significant at P<0.05 ** Significant at P<0.01

 

 

Table 3. Comparison between PD patients with clinical CI and those with pre clinical CI in the psychometric tests.

 

	Clinical CI (n=17) Mean (SD)	Pre clinical CI (n=23) Mean (SD)	P-value
Attention	3.59 (1.37)	6.17 (1.75)	< 0.001*
Working memory	3.18 (1.63)	5.22 (1.81)	0.001*
Immediate recall	4.41 (1.18)	6.35 (1.37)	< 0.001*
Delayed recall	2.76 (1.25)	4.48 (1.28)	< 0.001*
Naming	15.71 (1.93)	16.3 (2.32)	0.393
Visuoperceptual	6.59 (1.66)	8.7 (1.15)	< 0.001*
Visuoconstructional	5.24 (1.35)	7.35 (1.27)	< 0.001*
Alternating verbal fluency	4.94 (1.14)	7.65 (1.47)	< 0.001*
Action verbal fluency	9.41 (2.21)	14.22 (1.76)	< 0.001*
Total score	56.12 (7.25)	76.57 (9.86)	< 0.001*

* Significant at P<0.01

 

Table 4. FA in thalamus, basal ganglia, hippocampus and prefrontal region in PD patients.

 

	Patients (n=40)
	Mean	SD
FA in thalamus	0.395	0.124
FA in globus pallidus (GP)	0.375	0.141
FA in putamen	0.416	0.165
FA in caudate	0.411	0.164
FA in substantia nigra (SN)	0.497	0.194
FA in hippocampus	0.318	0.135
FA in prefrontal	0.462	0.182

 

 

Table 5. Comparison between PD patients with clinical CI and those with pre clinical CI in DTI parameter.

 

	Clinical  CI (n=17) Mean (SD)	Pre  clinical CI (n=23) Mean (SD)	P-value
FA in thalamus	0.344 (0.108)	0.433 (0.124)	0.023*
FA in GP	0.314 (0.122)	0.42 (0.139)	0.017*
FA in putamen	0.331 (0.177)	0.479 (0.126)	0.004**
FA in caudate	0.346 (0.132)	0.46 (0.171)	0.029*
FA in substantia nigra	0.455 (0.195)	0.527 (0.192)	0.249
FA in hippocampus	0.309 (0.132)	0.325 (0.139)	0.726
FA in prefrontal	0.388 (0.176)	0.516 (0.171)	0.026*

*Significant at P<0.05 ** Significant at P<0.01

 

Table 6. Correlation between FA in thalamus & basal ganglia and psychometric tests.

 

	FA in thalamus		FA in GP		FA in putamen		FA in caudate		FA in SN
	(r) coef.	P- value	(r) coef.	P-value	(r) coef.	P- value	(r) coef.	P- value	(r) coef.	P-value.
Attention	0.339	0.032*	0.365	0.021*	0.273	0.089	0.355	0.025*	0.155	0.341
Working memory	0.317	0.046*	0.345	0.029*	0.154	0.344	0.367	0.02*	0.079	0.628
Immediate recall	0.429	0.006**	0.169	0.298	0.437	0.005*	0.182	0.261	0.182	0.262
Delayed recall	0.453	0.003**	0.164	0.312	0.328	0.039*	0.268	0.094	0.258	0.109
Naming	0.042	0.797	0.297	0.063	0.084	0.606	0.131	0.422	0.026	0.876
Visuoperceptual	0.289	0.07	0.189	0.242	0.253	0.116	0.276	0.085	0.246	0.126
Visuoconst-ructional	0.287	0.072	0.309	0.053	0.155	0.338	0.286	0.074	0.221	0.17
Alternating verbal fluency	0.406	0.009**	0.327	0.039*	0.185	0.235	0.453	0.003**	0.265	0.098
Action verbal fluency	0.48	0.002**	0.331	0.037*	0.128	0.429	0.404	0.01**	0.257	0.109
Total score	0.427	0.006**	0.362	0.022*	0.27	0.092	0.397	0.011*	0.251	0.118

(r) Using Pearson coefficient,

*Significant at P<0.05** Significant at P<0.01

 

Table 7. Correlation between FA in hippocampus & prefrontal region and psychometric tests.

 

(r) Using Pearson coefficient

*Significant at P<0.05** Significant at P<0.01

 

DISCUSSION

 

Several studies worldwide have thoroughly investigated the cognitive impairment in PD. The exact pattern of this impairment and its frequency is still a subject of considerable controversy. However, most of the cognitive changes in PD are characterized by a frontal-subcortical impairment in which there is decreased attention and executive function with associated impairment in visuospatial skills and memory⁴

On comparing patients with pre clinical CI to control, patients with pre clinical CI were found to have significantly lower scores than control in working memory and action verbal fluency only, and this denotes that executive functions are the earliest cognitive domains to be affected in patients with PD.

Our finding replicates previous results that point towards both verbal fluency and working memory tasks as the most sensitive tasks to detect mild cognitive defects in PDND¹². Additionally, action VF was found to be an early indicator of the conversion from PD-ND to PDD¹³.

With the development of neuroimaging techniques such as PET and fMRI, it has been proved that the deficits in executive functions (measured by verbal fluency and working memory tasks) observed in the initial phase of PD, depend partly on the reduction in activity of frontostriatal circuits that connect the basal ganglions with the prefrontal dorsolateral cortex¹².

In the present study, on comparing patients with clinical CI to control, patients with clinical CI were found to have significantly lower scores than control not only in executive function, but also in attention, episodic memory, naming and visuospatial abilities.

The present results agreed with the results of several studies who addressed attention, memory, visuospatial and executive functions as being the most affected cognitive domains in patients with PD⁴

         Regarding the reported affection of naming in PD patients in our studies, some studies agreed with our findings and attributed this affection to the presence of cortical pathology which is considered a risk factor for developing PDD¹⁴.

In the present study, correlative results revealed that decreased FA in thalamus was associated with impairment in attention, executive function and episodic memory. Comparative results revealed that PD patients with clinical CI had significantly lower FA values than those with pre clinical CI in thalamus.

Our findings agreed with those obtained by Van Der Werf et al. (1999) and Van Der Werf et al.  (2003). The investigators found that severe deficits in executive functioning and attention were noted in patients with thalamic lesions^15,16. Such reported relationship between thalamus and, attention, executive function & memory can be attributed to the presence of functional connectivity between thalamus and hippocampus & prefrontal cortex¹⁷.

In the present study, correlative results revealed that decreased FA in globus pallidus was associated with impairment in attention and executive function. Comparative results revealed that PD patients with clinical CI had significantly lower FA values than those with pre clinical CI in globus pallidus.

Our results agreed with the study led by Trepanier et al. (1998). They concluded that ventral pallidotomy for the treatment of a patient with PD can cause cognitive impairments¹⁸. Additionally, several studies have suggested that bilateral pallidal lesions may give rise to deficits on tests of executive function¹⁹

In the present study, correlative results revealed that decreased FA in putamen was associated with episodic memory impairment. Comparative results revealed that patients with clinical CI had significantly lower FA values than those with pre clinical CI in putamen.

In accordance with our findings, Ystad et al. (2010) and Sadeh et al. (2011 revealed that the putamen consistently interacts with the hippocampus during episodic memory formation^20,21. In addition, van Beilen & Leenders (2006) discovered a relationship between putaminal FDOPA uptake and measures for executive functioning, memory and fluency in patients with PD²².

In the present study, correlative results revealed that decreased FA in caudate was associated with impairment in attention and executive function. Comparative results revealed that PD patients with clinical CI had significantly lower FA values than those with pre clinical CI in caudate.

Our findings are consistent with the study conducted by McMurtray et al. (2008) on eight patients with caudate infarction. The studied patients were found to have defective performance on tests of memory and frontal executive functions²³. Similar findings were obtained by Lewis et al. (2003) who conducted a study using fMRI on patients with PD while they were performing a working memory task¹².

In the present study, correlative results did not reveal any relationship between FA in substantia nigra and cognitive functions. Comparative results revealed that there was no statistically significant difference between PD patients with clinical CI and those with pre clinical CI in FA in substantia nigra. In contrast to our findings, McKee et al. (1990) found that patients with substantia nigra lesions might demonstrate profound deficits in working memory tasks. This was attributed to the presence of channels in SNpr directed at prefrontal and inferotemporal areas of cerebral cortex²⁴.

In the present study, correlative results revealed that decreased FA in hippocampus was associated with episodic memory impairment. Comparative results revealed that there was no statistically significant difference between PD patients with clinical CI and those with pre clinical CI in FA in hippocampus.

Our findings were consistent with those reported by Carlesimo et al. (2012) who found that memory impairment in patients with PD without dementia may be predicted by the rate of microstructural alterations in the hippocampal formation as detected by diffusion tensor imaging analysis²⁵. Additionally, and Ibarretxe-Bilbao et al. (2008) found a significant association between smaller hippocampal volumes and poorer memory performance in PD subjects²⁶. Hippocampal atrophy has also been observed to a lesser degree, in PD-ND²⁷, and PDND-MCI²⁸, with a greater degree of atrophy being associated with worse performance on tests of memory function²⁹.

In the present study, correlative results revealed that decreased prefrontal FA was associated with impairment in attention, executive function, and episodic memory. Comparative results revealed that PD patients with clinical CI had significantly lower prefrontal FA than those with pre clinical CI.

Similar to our findings regarding cognitive function of prefrontal region, Stebbins et al. (2001) reported a statistically significant positive correlation between frontal FA and both processing speed and reasoning performance (components of executive function)³⁰.

 

Conclusion

The cognitive impairment in PD is present even in the earlier stages of PD but it may be asymptomatic and can be detected only with specific neuropsychological tests The cognitive impairment in PD patients can be attributed to the microstructural changes (decreased FA) in BG, thalamus, hippocampus and prefrontal white matter.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        Langston J. The Parkinson's complex: Parkinsonism is just the tip of the iceberg. Ann Neurol. 
2006; 59 (4): 591-6.

2.        Foltynie T, Goldberg T, Lewis S, Blackwell A, Kolachana B, Weinberger D, et al. Planning ability in Parkinson’s disease is influenced by the COMT val158met polymorphism. Mov Disord. 2004; 19: 885– 91.

3.        Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, et al. Mild 
cognitive 
impairment in Parkinson disease: a multicenter pooled analysis. Neurology. 2010; 75 (12): 1062-9.

4.        Muslimovic D, Post B, Speelman J, Schmand B. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology. 2005; 65 (8): 39-1245.

5.        Sullivan E, Pfefferbaum A. Diffusion tensor imaging and aging. Neurosci Biobehav Rev. 2006; 30: 749–61.

6.        Karagulle Kendi A, Lehericy S, Luciana M, Ugurbil K,  Tuite P. Altered diffusion in the frontal lobe in Parkinson disease. AJNR Am J Neuroradiol. 2008; 29: 501–5.

7.        Matsui H, Nishinaka K, Oda M, Niikawa H, Kubori T, Udaka F. Dementia in Parkinson's disease: diffusion tensor imaging. Acta Neurol Scand. 2007; 116 (3): 177-81.

8.        Hughes A, Ben-Shlomo Y, Daniel S, Lees A. What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology. 1992; 42: 1142-6.

9.        Folstein M, Folstein S, McHugh P. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12: 189-98.

10.     Pagonabarraga J, Kulisevsky J, Llebaria G, García-Sánchez C, Pascual-Sedano B, Gironell A. Parkinson's disease-cognitive rating scale: a new cognitive scale specific for Parkinson's disease. Mov Disord. 2008; 23 (7): 998-1005.

11.     Litvan I, Goldman J, Tröster A, Schmand B, Weintraub D, Petersen R, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov Disord. 2012; 27 (3): 349-56.

12.     Lewis S, Dove A, Robbins T, Barker R, Owen A. Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J. Neurosci. 2003; 23: 6351–6.

13.     Piatt A, Fields J, Paolo A, Koller W,  Tröster A. Lexical, semantic, and action verbal fluency in Parkinson's disease with and without dementia. J Clin Exp Neuropsychol. 1999; 21(4): 435-43.

14.     Pahwa R, Paolo A, Troster A,  Koller W. Cognitive impairment in Parkinson's disease. Eur J Neurol. 1998; 5 (5): 431-41.

15.     Van Der Werf Y, Weerts J, Jolles J, Witter M, Lindeboom J, Scheltens P. Neuropsychological correlates of a right unilateral lacunar thalamic infarction. J Neurol Neurosurg Psychiatry. 1999; 66: 36–42.

16.     Van der Werf Y, Jolles J, Witter M,  Uylings H. Contributions of thalamic nuclei to declarative memory functioning. Cortex. 2003; 39 (4-5): 1047-62.

17.     Stein T, Moritz C, Quigley M, Cordes D, Haughton V, Meyerand E. Functional connectivity in the thalamus and hippocampus studied with functional MR imaging.  AJNR Am J Neuroradiol. 2000; 21 (8): 1397-401.

18.     Trepanier L, Saint-Cyr J, Lozano A,  Lang A. Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson's disease. Neurology. 1998; 51: 207–15.

19.     Haaxma R, van Boxtel A, Brouwer W, Goeken L, Denier van der Gon J, Colebatch J, et al. Motor 
function in a patient with bilateral lesions of the globus pallidus. Mov Disord. 1995; 10 (6): 761-77.

20.     Ystad M, Eichele T, Lundervold A, Lundervold A. Subcortical functional connectivity and verbal episodic memory in healthy elderly--a resting state fMRI study. Neuroimage. 2010; 52 (1): 379-88.

21.     Sadeh T, Shohamy D, Levy D, Reggev N,  Maril A. Cooperation between the hippocampus and the striatum during episodic encoding. J Cogn Neurosci. 2011; 23 (7): 1597-608.

22.     Van Beilen M, Leenders K. Putamen FDOPA uptake and its relationship to cognitive functioning in PD. J Neurol Sci. 2006; 248 (1-2): 68-71.

23.     McMurtray A, Sultzer D, Monserratt L, Yeo T, Mendez M. Content-specific delusions from right caudate lacunar stroke: association with prefrontal hypometabolism. J Neuropsychiatry Clin Neurosci. 2008; 20 (1): 62-67.

24.     McKee A, Levine D, Kowall N, Richardson E. Peduncular hallucinosis associated with isolated infarction of the substantia nigra pars reticulata. Ann Neurol. 1990; 27: 500–4.

25.     Carlesimo G, Piras F, Assogna F, Pontieri F, Caltagirone C, Spalletta G. Hippocampal abnormalities 
and memory deficits in Parkinson disease: a multimodal imaging study. Neurology. 2012; 78 (24): 
1939-45.

26.     Ibarretxe-Bilbao N, Ramírez-Ruiz B, Tolosa E, Martí M, Valldeoriola F, Bargalló N, et al. Hippocampal head atrophy predominance in Parkinson's disease with hallucinations and with dementia. J Neurol. 2008; 255 (9): 1324-31.

27.     Tam C, Burton E, McKeith I, Burn D, O'Brien J. Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies. Neurology. 2005; 64 (5): 861-5.

28.     Meyer J, Huang J, Chowdhury M. MRI confirms mild cognitive impairments prodromal for Alzheimer's, vascular and Parkinson-Lewy body dementias. J Neurol Sci. 2007; 257 (1-2): 97-104.

29.     Nagano-Saito A, Washimi Y, Arahata Y, Kachi T, Lerch J, Evans AC, et al. Cerebral atrophy and its relation to cognitive impairment in Parkinson disease. Neurology. 2005; 64 (2): 224-9.

30.     Stebbins G, Poldrack R, Klingberg T, Carillo M, Desmond J, Moseley M, et al. Aging effects on white matter integrity and processing speed: A diffusion tensor imaging study. Neurology. 2001; 56 (3): A374.